AU733890B2 - Crystal structures of a protein tyrosine kinase - Google Patents

Description

Description Crystal Structures of a Protein Tyrosine Kinase Introduction The present invention relates to the three dimensional structures of protein kinases.

Background of the Invention The following description of the background of the invention is provided simply as an aid in understanding the invention and is not admitted to describe or constitute prior art to the invention.

Protein tyrosine kinases (PTKs) comprise a large and diverse class of S 15 enzymes (for review, see Schlessinger and Ullrich, 1992, Neuron 9: 383-391). The PTK family contains multiple subfamilies, one of which *0 0000 0 0o o S *00 o^ N:\LIBC\04347.doc WO 98/07835 PCT/US97/14885 2 is the fibroblast growth factor receptor (FGF-R) subfamily (for a review, see Givol and Yayon, 1992, FASEB J. 6 3362-3369).

All PTKs enzymatically transfer a high energy phosphate from adenosine triphosphate to a tyrosine residue in a target protein. These phosphorylation events regulate cellular phenomena in signal transduction processes. Cellular signal transduction processes contain multiple steps that convert an extracellular signal into an intracellular signal. The intracellular signal is then converted into a cellular response. PTKs are components in many signal transduction processes. A PTK regulates the flow of a signal in a particular step in the process by phosphorylating a downstream molecule. The addition of a phosphate can either modulate the activity of the downstream molecule by turning it "on" or "off". Thus, aberrations in a particular PTK's activity can either cause overflow or underflow of the signal. Overflow of a signal can lead to such abnormalities as uncontrolled cell proliferation, which is representative of such disorders as cancer and angiogenesis.

Scientists in the biomedical community are searching for PTK inhibitors that down-regulate overflow signal transduction pathways. In particular, small molecule PTK inhibitors are sought that can traverse the cell membrane and not become hydrolyzed in acidic environments. These small molecule PTK inhibitors can be highly bioavailable and can be administered orally to patients.

Some small molecule PTK inhibitors have already WO 98/07835 PCT/US97/14885 3 been discovered. For example, bis(monocyclic), bicyclic or heterocyclic aryl compounds (PCT WO 92/20642), vinylene-azaindole derivatives (PCT WO 94/14808), 1cyclopropyl-4-pyridyl-quinolones Patent No.

5,330,992), styryl compounds Patent No.

5,217,999), styryl-substituted pyridyl compounds (U.S.

Patent No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 Al), seleoindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660), and benzylphosphonic acid compounds (PCT WO 91/15495) are described as PTK inhibitors.

Although many PTK inhibitors are known, many of these are not specific for PTK subfamilies and will therefore cause multiple side-effects as therapeutics.

Compounds of the indolinone family, however, are specific for the FGFR subfamily and are nonhydrolyzable. WO 96/40116, "Indolinone Compounds for the Treatment of Disease," published December 19, 1996, inventors Tang et al. Although the use of X-ray crystallography has provided three dimensional structures of other PTKs, they are not complexed with PTK subfamily specific, hydrolysis resistant, small molecules.

Despiterecent advances, the need remains in the art for crystallographic analysis of protein kinases, so that improved therapeutic molecules can be designed and synthesized.

SUMMARY OF THE INVENTION The present invention relates to the three 4 dimensional structures of protein tyrosine kinases. The use of X-ray crystallography can define the three dimensional structure of protein tyrosine kinase at atomic resolution.

The three dimensional structures described herein elucidate specific interactions between protein tyrosine kinases and compounds bound to them. The coordinates that define the three dimensional structures of protein tyrosine kinases are useful for determining three dimensional structures of PTKs with unknown structure. In addition.

the coordinates are also useful for designing and identifying modulators of protein tvrosine kinase function. These modulators are potentially useful as therapeutics for diseases. including (but limited to) cell proliferative diseases, such as cancer, angiogenesis, atherosclerosis, and arthritis.

There is herein disclosed a crystalline form of a polypeptide corresponding to the catalytic domain of a protein tyrosine kinase.

According to a first embodiment of the invention, there is provided a crystalline form comprising a polypeptide wherein said polypeptide consists of a catalytic domain of a protein tyrosine kinase wherein said protein tyrosine kinase is a non-insulin receptor protein tyrosine kinase.

According to a second embodiment of the invention, there is provided a polypeptide consisting of a catalytic domain of a protein tyrosine kinase having boundaries consisting of _0 about 20 amino acid residues upstream of the first glycine in the conserved glycinerich region of the catalytic domain, and about 17 amino acid residues downstream of the conserved arginine located at the C-terminal boundary of the catalytic domain; wherein said protein tyrosine kinase is a non-insulin receptor protein tyrosine S 5 kinase.

According to a third embodiment of the invention, there is provided a method of using the polypeptide in accordance with the second embodiment of the invention to form a crystal, comprising the steps of: mixing a volume of polypeptide solution with a reservoir solution; and s incubating the mixture obtained in step over the reservoir solution in a closed container, under conditions suitable for crystallization.

According to a fourth embodiment of the invention, there is provided a method of obtaining an FGF receptor tyrosine kinase domain polypeptide in crystalline form, comprising the steps of: [R:\LIBFF]0375doc:mrr 4a mixing a volume of polypeptide solution with an equal volume of reservoir solution. wherein said polypeptide solution comprises 1 mg/mL to 60 mg/mL FGF-type tyrosine kinase domain protein, 10 mM to 200 mM buffering agent. 0 mM to 20 mM dithiothreitol and has a pH of about 5.5 to about 7.5. and wherein said reservoir solution comprises 10% to 30% polyethylene glycol, 0.1 M to 0.5 M ammonium sulfate. 0% to 20% ethylene glycol or glycerol, 10 miM to 200 mM buffering agent and has a pl-I of about 5.5 to about 7.5; and incubating the mixture obtained in step over said reservoir solution in a closed container at a temperature between 0° and 25° °C until crystals form.

According to a fifth embodiment of the invention, there is provided a cDNA .:ncoding an FGF receptor tyrosine kinase domain protein, wherein a coding strand of the cDNA has the nucleotide sequence of SEQ ID According to a sixth embodiment of the invention, there is provided a method of .ietermining three dimensional structures of protein tyrosine kinases with unknown structure comprising the step of applying structural atomic coordinates set forth in Table SI. Table 2. Table 3. or Table 4.

According to a seventh embodiment of the invention, there is provided a method of identifying a potential modulator of protein tyrosine kinase function by docking a computer representation of a structure of a compound with a computer representation of a structure of a cavity formed by the active-site of a protein tyrosine kinase, wherein said structure of said protein tyrosine kinase is defined by atomic structural coordinates set forth in Table 1, Table 2. Table 3, or Table 4.

According to an eighth embodiment of the invention, there is provided a potential modulator of protein tyrosine kinase function identified by the method in accordance with the seventh embodiment of the invention.

According to a ninth embodiment of the invention, there is provided a method of identifying a potential modulator of protein tyrosine kinase function as a modulator of protein tyrosine kinase function, comprising the following steps: administering said potential modulator to cells; comparing the level of protein tyrosine kinase phosphorylation between cells not administered the potential modulator and cells administered said potential modulator; and identifying said potential modulator as a modulator of protein tyrosine kinase function based on the difference in the level of protein tyrosine kinase phosphorylation.

[R:\LIBFF]03757.doc:mrr 4b According to a tenth embodiment of the invention, there is provided a method of identifying a potential modulator of protein tyrosine kinase function as a modulator of protein tyrosine kinase function, wherein said method comprises the following steps: administering a preparation of said potential modulator to cells: comparing the rate of cell growth between cells not administered the modulator and cells administered the modulator; and identifying said potential modulator as a modulator of protein tyrosine kinase function based on the difference in the rate of cell growth.

According to an eleventh embodiment of the invention, there is provided a method oF treating a disease associated with a protein tyrosine kinase with inappropriate activity in a cellular organism, wherein said method comprises the steps of: administering a modulator of protein tyrosine kinase function to the organism, wherein said modulator is in an acceptable pharmaceutical preparation; and activating or inhibiting the protein tyrosine kinase function to treat the Sdisease.

According to a twelfth embodiment of the invention, there is provided a crystalline orm comprising a polypeptide, wherein said polypeptide consists of a catalytic domain of a protein tyrosine kinase, wherein said protein tyrosine kinase is non-insulin receptor protein tyrosine wherein said crystalline form is prepared by a process comprising the steps of: mixing a volume of polypeptide solution with a reservoir solution; and incubating the mixture obtained in step over the reservoir solution in a closed container, under conditions suitable for crystallisation.

The term "crystalline form," in the context of the invention, is a crystal formed from an aqueous solution comprising a purified polypeptide corresponding to the catalytic domain of a PTK. A crystalline form of a protein tyrosine kinase is characterized as being capable of diffracting x-rays in a pattern defined by one of the crystal forms see depicted in Blundel et al., 1976, Protein Crystallography, Academic Press. A crystalline form of a protein kinase is not characterized as being capable of diffracting x-rays in a pattern analogous to a crystalline form consisting of primarily salt or primarily a compound, for example.

[R:\LIBFF]03757.docmrr WO 98/07835 PCTIUS97/14885 The term "protein tyrosine kinase," or PTK, refers to an enzyme that transfers the high energy phosphate of adenosine triphosphate to a tyrosine residue located on a protein target.

A protein tyrosine kinase catalytic domain of, the invention can originate from receptor protein tyrosine kinases that bind fibroblast growth factor (FGF). These protein tyrosine kinases are known as "FGFR" herein, and can relate to one member of the FGFR family, such as FGFR1.

The term "catalytic domain" refers to the region of a protein that can exist as a separate entity from the protein. The catalytic domain of a protein tyrosine kinase is characterized as having considerable amino acid identity to the catalytic domain of other protein tyrosine kinases. Considerable amino acid identity preferably refers to at least 30% identity, more preferably at least 35% identity, and most preferably at least 40% identity. These degrees of amino acid identity refer to the identity between different protein tyrosine kinase families. Amino acid identity for members of a given protein tyrosine kinase family range from 55% to 90%. The catalytic domain may be functional as a separate entity. The catalytic domain of a protein tyrosine kinase is also characterized as a polypeptide that is soluble in solution.

The term "identity" identity as used herein refers to a property of sequences that measures their similarity or relationship. Identity is measured by dividing the number of identical residues in the two sequences by the total number of residues and WO 98/07835 PCTS97/14885 6 multiplying the product by 100. Thus, two copies of exactly the same sequence have 100% identity, but sequences that are less highly conserved and have deletions, additions, or replacements have a lower degree of identity. Those skilled in the art will recognize that several computer programs are available for determining sequence identity.

The term "functional" refers to the ability of a catalytic domain to convert a substrate into a product by phosphorylating the substrate. The term "functional" also relates to the ability of a catalytic domain to bind natural binding partners. The catalytic region may comprise an N-terminal tail, a catalytic core, and a C-terminal tail. The catalytic core is a polypeptide that can be functional in terms of catalysis. N- and Cterminal tails are polypeptide regions that may not confer appreciable functiqnality in terms of catalysis, but may confer functionality in terms of modulator specificity.

A polypeptide can exist as a catalytic domain eventhough it is not functional. For example, a polypeptide corresponding to a catalytic domain may not be functional if it does not harbor phosphate moieties in key areas. Multiple examples of phosphorylationstate dependent function are well documented in the art.

Therefore, a catalytic domain can also exist without being functional. A measure of a protein kinase catalytic domain is a polypeptide that is homologous to other protein kinase catalytic domains.

The term "polypeptide" refers to an amino acid chain representing a portion of, or the entire sequence WO 98/07835 PCTIUS97/14885 7 of, amino acids comprising a protein.

A preferred embodiment of the invention includes a crystalline form.of a PTK that is a receptor PTK.

Receptors are proteins that straddle the inside and outside of the cell membrane. Receptor PTKs comprise an extracellular region, a transmembrane region, and an intracellular region comprising a catalytic domain.

Another preferred embodiment of the invention is the crystalline form of a receptor PTK selected from the group consisting of FGF-R, PDGF-R, FLK, CCK4, MET, TRKA, AXL, TIE, EPH, RYK, DDR, ROS, RET, LTK, ROR1, and MUSK.

Yet another preferred embodiment of the invention is the crystalline form of a PTK that is a non-receptor PTK. Non-receptor PTKs are located inside the cell and do not harbor extracellular or membrane-spanning polypeptides attached to the polypeptide corresponding to the catalytic domain. Non-receptor PTKs may harbor fatty acids or lipids, which can impart a membrane associated character to a PTK. In preferred embodiments of the invention, crystalline forms of non-receptor PTKs are selected from the group consisting of SRC, BRK, BTK, CSK, ABL, ZAP70, FES, FAK, JAK, and ACK.

In still another preferred embodiment, the invention features a crystalline form of a PTK that comprises a heavy metal atom. These types of crystals can be referred to as derivative crystals.

The term "derivative crystal" refers to a crystal where the polypeptide is in association with one or more heavy-metal atoms.

The term "association" refers to a condition of proximity between a chemical entity or compound, or WO 98/07835 PCT/US97/14885 8 portions or fragments thereof, and tyrosine kinase domain protein, or portions or fragments thereof. The association may be non-covalent, where the juxtaposition is energetically favored by, e.g., hydrogen-bonding, van der Waals, electrostatic or hydrophobic interactions, or it may be covalent.

The term "heavy metal atom" refers to an atom that is a transition element, a lanthanide metal, or an actinide metal. Lanthanide metals include elements with atomic numbers between 57 and 71, inclusive. Actinide metals include elements with atomic numbers between 89 and 103, inclusive.

In a preferred embodiment, the invention features a crystal of an FGF receptor tyrosine kinase domain protein. The FGF receptor tyrosine kinase domain protein can relate to FGFR1.

The term "FGFR1" refers to one member of multiple receptor PTKs that are homologous to one another and bind FGF. In this context, the term "homologous" refers to at least 70% amino acid identity between two members of the FGFR family.

The term "FGFR1" can also refer to a mutant of human FGFR1 which is characterized by the amino acid sequence of SEQ ID NO:2. As compared to human FGFR1, FGFR1 contains the following amino acid substitutions: Cys-488 Ala, Cys-584 Ser, Leu-457 Val, and has an additional five amino acid residues at the N-terminus (Ser-Ala-Ala-Gly-Thr).

The term "human FGFR1" refers to the tyrosine kinase domain of human fibroblast growth factor receptor 1 ("FGFR1") having the amino acid sequence of SEQ ID WO 98/07835 PCT/US97/14885 9 NO:1. Generally, human FGFR1 comprises a 310 amino acid residue fragment (residues 456 to 765) of human FGFR1.

The term "mutant" refers to a polypeptide which is obtained by replacing at least one amino acid residue in a native tyrosine kinase domain with a different amino acid residue. Mutation can be accomplished by adding and/or deleting amino acid residues within the native polypeptide or at the N- and/or C-terminus of a polypeptide corresponding to a native tyrosine kinase domain having substantially the same three-dimensional structure as the native tyrosine kinase domain from which it is derived. By having substantially the same three-dimensional structure is meant having a set of atomic structure coordinates that have a root mean square deviation of less than or equal to about 2 A when superimposed with the atomic structure coordinates of the native tyrosine kinase domain from which the mutant is derived when at least about 50% to 100% of the Ca atoms of the native tyrosine kinase are included in the superposition. A mutant may have, but need not have, PTK activity.

In another preferred embodiment, the invention relates to a crystalline form defined by the structural coordinates set forth in Table 1.

The term "atomic structural coordinates" as used herein refers to a data set that defines the three dimensional structure of a molecule or molecules.

Structural coordinates can be slightly modified and still render nearly identical three dimensional structures. A measure of a unique set of structural coordinates is the root-mean-square deviation of the WO 98/07835 PCTIUS97/14885 resulting structure. Structural coordinates that render three dimensional structures that deviate from one another by a root-mean-square deviation of less than A may be viewed by a person of ordinary skill in the art as identical. Hence, the structural coordinates set forth in Table i, Table 2, Table 3, and Table 4 are not limited to the values defined therein.

In other preferred embodiments, the invention features a crystalline form of the polypeptide in association with a compound. These types of crystalline forms can be referred to as co-crystals. The compound may be a cofactor, substrate, substrate analog, inhibitor, or allosteric effector.

The term "compound" refers to an organic molecule.

The term "organic molecule" refers to a molecule which has at least one carbon atom in its structure. The compound can have a molecular weight of less than 6kDa.

Both the geometry of the compound and the interactions formed between the compound and the polypeptide preferably govern high affinity binding between the two molecules. High affinity binding is preferably governed by a dissociation equilibrium constant on the order of 10-6 M or less. The compound is preferably a modulator that alters the function of a PTK.

The term "function," in reference to the effect of a modulator on PTK function, refers to the ability of a modulator to enhance or inhibit the catalytic activity of a PTK.

The term "catalytic activity", in the context of the invention, defines the ability of a PTK to phosphorylate a substrate polypeptide. Catalytic WO 98/07835 PCT/US97/14885 11 activity can be measured, for example, by determining the amount of a substrate converted to a product as'a function of time. The conversion of the substrate to a product occurs at the active-site of the PTK.

The term "active-site" refers to a cavity located in the PTK in which one or more substrate molecules may bind. Addition of a modulator to cells expressing a PTK may enhance (activate) or lower (inhibit) the catalytic activity of the PTK.

A small number of inhibitors of PTK catalytic activity are known in the art. Small molecule inhibitors may modulate PTK function by blocking the binding of substrates. Indolinone compounds, for example, may bind to the active-site of PTK catalytic domains and inhibit them effectively, as measured by inhibition constants on the order of 10-6 M or less.

Activators of PTK intracellular regions can enhance PTK function by interacting with both the PTK catalytic domain and the substrate. Activators may also promote dimerization of PTKs and thus activate them by bringing them into close proximity with one another. In addition, activators may operate by promoting a conformational change in the intracellular region of the PTK such that the catalytic region modifies substrates at a fasterrate in the presence of the activator.

The term "function" can also refer to the ability of a modulator to enhance or inhibit the association between a PTK and a natural binding partner.

The term "natural binding partner" refers to a polypeptide that normally binds to a PTK in a cell.

These natural binding partners can play a role in WO 98/07835 PCT/US97/14885 12 propagating a signal in a PTK signal transduction process. The natural binding partner can bind to a PTK with high affinity. High affinity represents an equilibrium binding constant on the order of 10- 6 M or less. However, a natural binding partner can also transiently interact with a PTK and chemically modify it. PTK natural binding partners are chosen from a group consisting of, but not limited to, src homology 2 (SH2) or 3 (SH3) domains, other phosphoryl tyrosine binding (PTB) domains, nucleotide exchange factors, and other protein kinases or protein phosphatases.

The term "interactions" refers to hydrophobic, aromatic, and ionic forces and hydrogen bonds formed between atoms in the modulator and the enzyme activesite.

The term "cofactor" refers to a compound that may, in addition to the substrate, bind to a protein and undergo a chemical reaction. Multiple co-factors are nucleotides or nucleotide derivatives, such as phosphate and nicotinamide derivatives of adenosine.

The term "substrate" refers to a compound that reacts with an enzyme. Enzymes can catalyze a specific reaction on a specific substrate. For example, PTKs can phosphorylate specific protein and peptide substrates on tyrosine moieties. In addition, nucleotides can act as substrates for protein kinases.

The term "substrate analog" refers to a compound that is structurally similar, but not identical, to a substrate. The substrate analog may be a nucleotide analog. Examples of nucleotide analogs are described below.

WO 98/07835 PCT/US97/14885 13 The term "inhibitor" refers to a compound that decreases the cellular function of a protein kinase.

The protein kinase function is preferably the interaction with a natural binding partner and more preferably catalytic activity.

The term "allosteric effector" refers to a compound that causes allosteric interactions in a protein. The term "allosteric interactions" refers to interactions between separate sites on a protein. The sites can be different from the active site. The allosteric effector can enhance or inhibit catalytic activity by binding to a site that may be different than the active site.

The term "co-crystal" refers to a crystal where the polypeptide is in association with one or more compounds.

In preferred embodiments, a co-crystal of the invention can be in association with a heavy metal atom.

Examples of heavy metal atoms are described above.

In other preferred embodiments, the invention features a co-crystal comprising the crystalline form of the polypeptide in association with a compound, where the compound is a non-hydrolyzable analog of ATP. These analogs can be referred to as nucleotide analogs.

The term "ATP" refers to the chemical compound adenosine triphosphate.

The term "non-hydrolyzable" refers to a compound having a covalent bond that does not readily react with water. Examples of non-hydrolyzable analogs of ATP are AMP-PNP and AMP-PCP, whose structures are well known to those skilled in the art.

The term "AMP-PNP" refers to adenylyl WO 98/07835 PCT/US97/14885 14 imidodiphosphate, a non-hydrolyzable analog of ATP.

The term "AMP-PCP" refers to adenylyl diphosphonate, a non-hydrolyzable analogue of ATP.

In another preferred embodiment, the invention relates to a crystalline form defined by the structural coordinates set forth in Table 2.

In preferred embodiments, the invention relates to crystalline forms, where the compound in association with the polypeptide is an indolinone.

Certain indolinones are specific modulators of PTK function. A preferred embodiment of the invention is the crystalline form of a PTK complexed with an indolinone of formula I or II:

R

7 WO 98/07835 PCT/US97/14885

A

R4 I4

CR

3

A

1 I I R2

A

3 A4 R7 R(I) or a pharmaceutically acceptable salt, isomer, metabolite, ester, amide, or prodrug thereof, where:

A

2

A

3 and A 4 are independently carbon or nitrogen; R, is hydrogen or alkyl;

R

2 is oxygen in the case of an oxindolinone or sulfur in the case of a thiolindolinone;

R

3 is hydrogen;

R

4 Rs, R 6 and R 7 are optionally present, and are either independently selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO 2 NRR', SO 3

R,

SR, NO 2 NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH 2 )nCO 2

R,

and CONRR' or (ii) any two adjacent R 4 Rs, R 6 and R, taken together form a fused ring with the aryl portion of the indole-based portion of the indolinone;

R

2

R

3 R4', R 5 1 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SONRR', SO 3

R,

SR, NO 2 NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CHI 2

)CO

2

R,

WO 98/07835 PCT/US97/14885 16 and CONRR'; n is 0, 1, 2, or 3; R is hydrogen, alkyl or aryl; R' is hydrogen, alkyl or aryl; and A is a five membered heteroaryl ring selected from the group consisting of thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, furan, 1,2,3oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4oxadiazole, 1,2,3,4-oxatriazole, 1, 2 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5thiatriazole, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl,

S(O)R,

SO

2 NRR', S03R, SR, NO 2 NRR', OH, CN, C(O)R, OC(O)R, NHC(0)R, (CH 2 )nCO 2 R or CONRR'.

The term "pharmaceutically acceptable salt" refers to those salts which retain the biological activity and properties of the free bases. Pharmaceutically acceptable salts can be obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid and the like.

The term "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs may be easier to administer than the parent drug in some situations. For example, the prodrug may be bioavailable by oral administration but the parent is not, or the prodrug may improve solubility to allow for WO 98/07835 PCT/US97/14885 17 intravenous administration.

"Alkyl" refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like. The alkyl group may be optionally substituted with one or more substituents are selected from the group consisting of hydroxyl, cyano, alkoxy,

NO

2 halogen, N(CH 3 2 amino, and

SH.

"Alkenyl" refers to a straight-chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon-carbon double bond. Preferably, the alkenyl group has 2 to 12 carbons. More preferably it is a lower alkenyl of from 2 to 7 carbons, more preferably 2 to 4 carbons. The alkenyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy,

=S,

NO

2 halogen, N(CH 3 2 amino, and SH.

"Alkynyl" refers to a straight-chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Preferably, the alkynyl group has 2 to 12 carbons. More preferably it is a lower alkynyl of from 2 to 7 carbons, more preferably 2 to 4 carbons. The alkynyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy,

=S,

NO

2 halogen,

N(CH

3 2 amino, and SH.

"Alkoxy" refers to an "O-alkyl" group.

WO 98/07835 PCT/US97/14885 18 "Aryl" refers to an aromatic group which has at least one ring having a conjugated pi-electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups. The aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO,, amine, thioether, cyano, alkoxy, alkyl, and amino.

"Alkaryl" refers to an alkyl that is covalently joined to an aryl group. Preferably, the alkyl is a lower alkyl.

"Carbocyclic aryl" refers to an aryl group wherein the ring atoms are carbon.

"Heterocyclic aryl" refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl,

N-

lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.

"Amide" refers to where R is alkyl, aryl, alkylaryl or hydrogen.

"Thioamide" refers to where R is alkyl, aryl, alkylaryl or hydrogen.

"Amine" refers to a group, where R' and are independently selected from the group consisting of alkyl, aryl, and alkylaryl.

"Thioether" refers to where R is alkyl, aryl, or alkylaryl.

"Sulfonyl" refers to -S(0) 2 where R is aryl, C(CN)=C-aryl,

CH

2 CN, alkyaryl, sulfonamide, NH-alkyl,

NH-

WO 98/07835 PCTIUS97/14885 19 alkylaryl, or NH-aryl.

The term "acyl" denotes groups where R is alkyl as defined above, such as formyl, acetyl, propionyl, or butyryl.

It is understood by those skilled in the art that when A 2

A

3 and A 4 are nitrogen or sulfur that the corresponding

R

4

R

5

R

6 and as well as the corresponding bond, do not exist.

Examples of indoles having such fused rings (as described in (ii) above include the following:

N

N=NX

S-N N-S

N~

N N

N-N

N

_rN

N

N

N

N

-C)

N

N-N

N

N

jN

N

I 7

N

N^SN

NIN

II 1 The six membered rings shown above exemplify possible A rings in compound II.

Other preferred embodiments of the invention are crystalline forms comprising 3-[(3-(2-carboxyethyl)-4methylpyrrol-2-yl)methylene]-2-indolinone as well as 3- [4-(4-formylpiperazine-l-yl-)benzylidenyl]-2-indolinone.

The polypeptide of these crystalline forms can be FGFR, and specifically, FGFR1.

In preferred embodiments, the crystalline forms of the invention can be defined by the structural coordinates set forth in Table 3 or Table 4.

The use of X-ray crystallography can elucidate the three dimensional structure of crystalline forms of the invention. The first characterization of crystalline formsby X-ray crystallography can determine the unit cell shape and its orientation in the crystal.

In other preferred embodiments, the invention features a crystal of an FGF receptor tyrosine kinase domain protein, where the crystal is characterized by having monoclinic unit cells. The crystal may also be characterized by having space group symmetry C2.

The term "unit cell" refers to the smallest and simplest volume element parallelpiped-shaped block) of a crystal that is completely representative of the unit of pattern of the crystal. The dimensions of the unit cell are defined by six numbers: dimensions a, b and c and angles a, 0 and y. A crystal can be viewed as an efficiently packed array of multiple unit cells.

Detailed descriptions of crystallographic terms are described in, which is hereby incorporated herein by reference in its entirety, including any drawings, figures, and tables.

The term "monoclinic unit cell" refers to a unit AMENDED

SHEET

WO 98/07835 PCT/US97/14885 21 cell where a b c; a y 90°; and P 90.0.

The term "space group" refers to the symmetry of a unit cell. In a space group designation C2) the capital letter indicates the lattice type and the other symbols represent symmetry operations that can be carried out on the unit cell without changing its appearance.

The term "lattice" in reference to crystal structures refers to the array of points defined by the vertices of packed unit cells.

The term "symmetry operations" refers to geometrically defined ways of exchanging equivalent parts of a unit cell, or exchanging equivalent molecules between two different unit cells. Examples of symmetry operations are screw axes, centers of inversion, and mirror planes.

In a preferred embodiment, the invention features a crystalline form, where the monoclinic unit cells have dimensions of about a=208.3 A, b=57.8 A, c=65.5 A and P=107.20 In a preferred embodiment, the invention features a FGFR1 crystal, where the monoclinic unit cells have dimensions of about a=211.6 A, b=51.3 A, c=66.1 A and P=107.7.

In another aspect the invention features a polypeptide corresponding to the catalytic domain of a protein tyrosine kinase, containing at least about amino acid residues upstream of the first glycine in the conserved glycine-rich region of the catalytic domain, and at least about 17 amino acid residues downstream of the conserved arginine located at the C-terminal WO 98/07835 PCTIUS97/14885 22 boundary of the catalytic domain.

The polypeptides of the invention can be isolated, enriched or purified. In addition, the crystalline forms of the invention can be formed from polypeptides that are isolated, enriched, or purified.

By "isolated" in reference to a polypeptide is meant a polymer of 6, 12, 18 or more amino acids conjugated to each other, including polypeptides that are isolated from a natural source or that are synthesized. The isolated polypeptides of the present invention are unique in the sense that they are not found in a pure or separated state in nature. Use of the term "isolated" indicates that a naturally occurring sequence has been removed from its normal cellular environment. Thus, the sequence may be in a cell-free solution or placed in a different cellular environment.

The term does not imply that the sequence is the only amino acid chain present, but that it is essentially free (about 90 95% pure at least) of material naturally associated with it.

By the use of the term "enriched" in reference to a polypeptide it is meant that the specific amino acid sequence constitutes a significantly higher fraction (2 5 fold) of the total of amino acids present in the cells or solution of interest than in normal or diseased cells or in the cells from which the sequence was taken.

This could be caused by a person by preferential reduction in the amount of other amino acids present, or by a preferential increase in the amount of the specific amino acid sequence of interest, or by a combination of the two. However, it should be noted that "enriched" WO 98/07835 PCTIUS97/14885 23 does not imply that there are no other amino acid sequences present, just that the relative amount of the sequence of interest has been significantly increased.

The term significant here is used to indicate that the level of increase is useful to the person making such an increase, and generally means an increase relative to other amino acids of about at least 2 fold, more preferably at least 5 to 10 fold or even more. The term also does not imply that there are no amino acids from other sources. The other source amino acids may, for example, comprise amino acids encoded by a yeast or bacterial genome, or a cloning vector such as pUC19.

The term is meant to cover only those situations in which a person has intervened to elevate the proportion of the desired nucleic acid.

It is also advantageous for some purposes that an amino acid sequence be in purified form. The term "purified" in reference to a polypeptide does not require absolute purity (such as a homogeneous preparation); instead, it represents an indication that the sequence is relatively purer than in the natural environment (compared to the natural level this level should be at least 2-5 fold greater, in terms of mg/ml). Purification of at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated. The substance is preferably free of contamination at a functionally significant level, for example 90%, 95%, or 99% pure.

In a preferred embodiment, the invention features a.

polypeptide corresponding to the catalytic domain of a WO 98/07835 PCT/US97/14885 24 receptor PTK. The receptor PTK may have a threedimensional structure substantially similar to that of the insulin receptor, even though the amino acid content may be different.

In a preferred embodiment, the invention features a polypeptide corresponding to the catalytic domain of a non-receptor PTK, where the non-insulin receptor tyrosine kinase is a cytoplasmic tyrosine kinase.

In a preferred embodiment, the invention features a polypeptide corresponding to the catalytic domain of a receptor PTK, selected from the group consisting of FGF- R, PDGF-R, KDR, CCK4, MET, TRKA, AXL, TIE, EPH, RYK, DDR, ROS, RET, LTK, ROR1, or MUSK.

In a preferred embodiment, the invention features a polypeptide corresponding to the catalytic domain of a non-receptor PTK, selected from the group consisting of SRC, BRK, BTK, CSK, ABL, ZAP70, FES, FAK, JAK, or ACK.

In a preferred embodiment, the invention features a polypeptide corresponding to the catalytic domain of a PTK, having the amino acid sequence shown in Table 1 or Table 2.

In another aspect, the invention features a method for creating crystalline forms described herein. The method may utilize the polypeptides described herein to form a crystal. The method comprises the steps of: mixing a volume of polypeptide solution with a reservoir solution; and incubating the mixture obtained in step over the reservoir solution in a closed container, under conditions suitable for crystallization.

These processes are described in detail in the WO 98/07835 PCTIUS97/14885 section entitled "Detailed Description of the Invention." In another aspect, the invention features a method of obtaining FGF receptor tyrosine kinase domain polypeptide in crystalline form, comprising the steps of: mixing a volume of polypeptide solution with an equal volume of reservoir solution, where the polypeptide solution comprises 1 mg/mL to 60 mg/mL FGFtype tyrosine kinase domain protein, 10,mM to 200 mM buffering agent, 0 mM to 20 mM dithiothreitol and has a pH of about 5.5 to about 7.5, and where the reservoir solution comprises 10% to 30% polyethylene glycol, 0.1 M to 0.5 M ammonium sulfate, 0% to 20% (w/v) ethylene glycol or glycerol, 10 mM to 200 mM buffering agent and has a pH of about 5.5 to about 7.5; and (b) incubating the mixture obtained in step over said reservoir solution in a closed container at a temperature between 0° and 25°C until crystals form.

In a preferred embodiment, the invention features a method of obtaining FGF receptor tyrosine kinase domain polypeptide in crystalline form, where the polypeptide solution comprises about 10 mg/mL FGF receptor tyrosine kinase domain, about 10 mM sodium chloride, about 2 mM dithiothreitol, about 10 mM Tris-HCl and has a pH of about 8; the reservoir buffer comprises about 16% (w/v) polyethylene glycol (MW 10000), about 0.3 M ammonium sulfate, about 5% ethylene glycol or glycerol, about 100 mM bis-Tris and has a pH of about 6.5; and the temperature is about 4 0

C.

In another preferred embodiment, the invention features a method of obtaining FGF receptor tyrosine WO 98/07835 PCTIUS97/14885 26 kinase domain polypeptide in crystalline form, where the polypeptide solution includes a compound such as a cofactor, substrate, substrate analog, inhibitor or allosteric effector.

In still another preferred embodiment, the invention features a method of obtaining FGF receptor tyrosine kinase domain polypeptide in crystalline form, where the compound is a nucleotide analog, such as a non-hydrolyzable analog of ATP, or an indolinone.

Indolinone compounds have the general structural formula as described herein.

In another aspect, the invention features a cDNA encoding an FGF receptor tyrosine kinase domain protein, where a coding strand of the cDNA has the nucleotide sequence of SEQ ID Another aspect of the invention relates to a method of determining three dimensional structures of ,PTKs with unknown structure by utilizing the structural coordinates of Table 1, Table 2, Table 3, and Table 4.

These methods can relate to homology modeling, molecular replacement, and nuclear magnetic resonance methods.

In a preferred embodiment, the invention relates to a method of determining three dimensional structures of PTKs with unknown structures by utilizing the coordinates of Table 1, Table 2, Table 3, or Table 4 in conjunction with the amino acid sequences of PTKs. This method of homology modeling comprises the steps of: (a) aligning the computer representation of an amino acid sequence of a PTK with unknown structure with that of a PTK with known structure, where alignment is achieved by matching homologous regions of the amino acid sequences; WO 98/07835 PCT/US97/14885 27 transferring the computer representation of an amino acid structure in the PTK sequence of known structure to a computer representation of a structure of the corresponding amino acid in the PTK sequence with unknown structure; and determining low energy conformations of the resulting PTK structure.

The term "amino acid sequence" describes the order of amino acids in the amino acid chain comprising a polypeptide corresponding to the catalytic domain of a

PTK.

The term "aligning" describes matching the beginning and the end of two or more amino acid sequences. Homologous amino acid sequences are placed on top of one another during the alignment process.

The term "homologous" describes amino acids in two sequences that are identical or have similar side-chain chemical groups aliphatic, aromatic, polar, negatively charged, or positively charged).

The term "corresponding" refers to an amino acid that is aligned with another in the sequence alignment mentioned above.

The term "determining the low energy conformation" describes a process of changing the conformation of the PTK structure such that the structure is of low free energy. The PTK structure may or may not have molecules, such as modulators bound to it.

The term "low free energy" describes a state where the molecules are in a stable state as measured by the process. A stable state is achieved when favorable interactions are formed within the complex.

The term "favorable interactions" refers to WO 98/07835 PCTIUS97/14885 28 hydrophobic, aromatic, and ionic forces, and hydrogen bonds.

Another preferred embodiment of the invention relates to a method of determining three dimensional structures of PTKs with unknown structure. This method is accomplished by applying the structural coordinates of Table 1, Table 2, Table 3, or Table 4 to an incomplete X-ray crystallographic data set for a PTK.

The method comprises the steps of: aligning the positions of atoms in the unit cell by matching electron diffraction data from two crystals, where one data set is complete and the other is incomplete; and (b) determining a low energy conformation of the resulting PTK structure.

The term "incomplete data set" relates to a X-ray crystallographic data set that does not have enough information to give rise to a three dimensional structure.

In another preferred embodiment, the invention relates to a method of determining three dimensional structures of PTKs with unknown structure by applying the structural coordinates of Table 1, Table 2, Table 3, or Table 4 to nuclear magnetic resonance (NMR) data of a PTK. This method comprises the steps of: (a) determining the secondary structure of a PTK structure using NMR data; and simplifying the assignment of through-space interactions of amino acids. The PTK structure may not be complexed with compounds or modulators.

The term "secondary structure" describes the arrangement of amino acids in a three dimensional WO 98/07835 PCT/US97/14885 29 structure, such as in c-helix or P-sheet elements.

The term "through-space interactions" defines the orientation of the secondary structural elements in the three dimensional structure and the distances between amino acids from different portions of the amino acid sequence.

The term "assignment" defines a method of analyzing NMR data and identifying which amino acids give rise to signals in the NMR spectrum.

In another aspect, the invention features a method of identifying potential modulators of PTK function.

These modulators are identified by docking a computer representation of a structure of a compound with a computer representation of a cavity formed by the active-site of a PTK. The computer representation of the PTK active-site structure can be defined by structural coordinates.

The term "chemical group" refers to moieties that can form hydrogen bonds, hydrophobic, aromatic, or ionic interactions.

The term "docking" refers to a process of placing a compound in close proximity with a PTK. The term can also refer to a process of finding low energy conformations of the compound/PTK complex.

A preferred embodiment of the invention is a method of identifying potential modulators of PTK function.

The method involves utilizing the structural coordinates or a PTK three dimensional structure. The structural coordinates set forth in Table 1, Table 2, Table 3, and Table 4 can be utilized. The method comprises the steps of: removing a computer representation of a PTK WO 98/07835 PCTIUS97/14885 structure and docking a computer representation of a compound from a computer data base with a computer representation of the active-site of the PTK; (b) determining a conformation of the complex with a favorable geometric fit and favorable complementary interactions; and identifying compounds that best fit the PTK active-site as potential modulators of PTK function. The initial PTK structure may or may not have compounds bound to it.

The term "favorable geometric fit" refers to a conformation of the compound-PTK complex where the surface area of the compound is in close proximity with the surface area of the active-site without forming unfavorable interactions. Unfavorable interactions can be steric hindrances between atoms in the compound and atoms in the PTK active-site.

The term "favorable complementary interactions" relates to hydrophobic, aromatic, ionic, and hydrogen bond donating, and hydrogen bond accepting forces formed between the compound and the PTK active-site.

The term "potential" qualifies the term "modulator of PTK function" because the potential modulator or PTK function has not yet been tested for activity in vitro or in vivo.

The term "best fit" describes compounds that complexed the most surface area in the complex and/or form the most favorable complementary interactions with the PTK in the screen in a given experiment.

Another preferred embodiment of the invention is a method of identifying potential modulators of PTK function. The method involves utilizing a three WO 98/07835 PCT/US97/14885 31 dimensional structure of a PTK, with or without compounds bound to it. The method comprises the steps of: modifying a computer representation of a PTK having one or more compounds bound to it, where the computer representations of the compound or compounds and PTK are defined by structural coordinates; (b) determining a conformation of the complex with a favorable geometric fit and favorable complementary interactions; and identifying the compounds that best fit the PTK active-site as potential modulators of PTK function.

The term "modifying" relates to deleting a chemical group or groups or adding a chemical group or groups.

Computer representations of the chemical groups can be selected from a computer data base.

Yet another preferred embodiment of the invention is a method of identifying potential modulators of PTK function by operating modulator construction or modulator searching computer programs on the compounds complexed with the PTK. The method comprises the steps of: removing a computer representation of one or more compounds complexed with a PTK; and searching a data base for compounds similar to the removed compounds using a compound searching computer program, or replacing portions of the compounds complexed with the PTK with similar chemical structures from a data base using a compound construction computer program where the representations of the compounds are defined by structural coordinates.

The term "operating" as used herein refers to utilizing the three-dimensional conformation of WO 98/07835 PCTIUS97/14885 32 molecules defined by the processes described herein in various computer programs.

The term "similar compound" refers to a compound in a computer data base that has a similar geometric structure as compounds that can bind to a PTK. The similar compound can also have similar chemical groups as the compounds that are either bound to the PTK or once bound to the PTK. The similar chemical groups can form complementary interactions with the PTK.

The term "compound searching computer program" describes a computer program that searches computer representations of compounds from a computer data base that have similar three dimensional structures and similar chemical groups as a compound of interest. The compound of interest is preferably an indolinone compound, The term "similar chemical structures" refers to chemical groups that share similar geometry as portions of the compounds in complex with the PTK or compounds removed from the PTK structure. Similar chemical structures can also refer to chemical groups that may form similar complementary interactions as portions of the compounds in complex with the PTK or compounds removed from the PTK structure.

The term "replacing structures" refers to removing a portion of the compounds in complex with the PTK or compounds removed from the PTK structure and connecting the broken bonds to a similar chemical structure.

The term "compound construction computer program" describes a computer program that replaces computer representations of chemical groups in a compound with WO 98/07835 PCTIS97/14885 33 groups from a computer data base. The compound is preferably an indolinone compound.

The term "similar three dimensional structure" describes two molecules with nearly identical shape and volume.

In another preferred embodiment of the invention, the PTK structures used in the modulator design or identification method of the invention are defined by the structural coordinates of Table 1, Table 2, Table 3, or Table 4.

The methods for using the crystalline forms and three dimensional structures of the invention can relate to a broad range of protein kinases. Thus, in preferred embodiments, the invention relates to a receptor PTK.

The receptor PTK can be selected form the group consisting of FGF-R, PDGF-R, FLK, CCK4, MET, TRKA, AXL, TIE, EPH, RYK, DDR, ROS, RET, LTK, ROR1, and MUSK. The PTK may also exist as a non-receptor PTK. The nonreceptor PTK can be selected from the group consisting of SRC, BRK, BTK, CSK, ABL, ZAP70, FES, FAK, JAK, and

ACK.

In another aspect, the invention features a potential modulator of PTK function identified by methods disclosed in the invention.

A preferred embodiment of the invention is that the potential modulator of PTK function is an oxindolinone or a thiolindolinone of formula I or II disclosed above.

Another aspect of the invention is a method for synthesizing a potential modulator of PTK function or its pharmaceutically acceptable salts, isomers, metabolites, esters, amides, or prodrugs by a standard WO 98/07835 PCT1US9714885 34 synthetic method known in the art. Synthetic procedures are discussed below.

In another aspect, the invention features a method of identifying a potential modulator of PTK function as a modulator of PTK function. The method comprises the steps of: administering a potential modulator of PTK function to cells; comparing the level of PTK phosphorylation between cells not administered the potential modulator and cells administered the potential modulator; and identifying the potential modulator as a modulator of PTK function based on the difference in the level of PTK phosphorylation.

The term "cells" refers to any type of cells either primary or cultured. Primary cells can be extracted directly from an organism whilecultured cells rapidly divide and can be cultured in many successive rounds.

Cells can be grown in a variety of containers including, but not limited to flasks, dishes, and well plates.

The term "administer" refers to a method of delivering a compound to cells. The compound can be prepared using a carrier such as dimethyl sulfoxide (DMSO) in an aqueous solution. The aqueous solution comprising the compound, also termed an "aqueous preparation", can be simply mixed into the medium bathing the layer of cells or microinjected into the cells themselves. The compounds may be administered to the cells using a suitable buffered solution.

The term "suitable buffered solution" refers to an aqueous preparation of the compound that comprises a salt that can control the pH of the solution at low concentrations. Because the salt exists at low WO 98/07835 PCTIUS97/14885 concentrations, the salt preferably does not alter the function of the cells.

The term "PTK phosphorylation" refers to the presence of phosphate on the PTK. Phosphates on PTKs can be identified by antibodies that bind them specifically with high affinity.

In another aspect, the invention features a method of identifying a potential modulator of PTK function as a modulator of PTK function. The method comprises the steps of: administering a potential modulator of PTK function to cells; comparing the level of cell growth between cells not administered the potential modulator and cells administered the potential modulator; and identifying the potential modulator as a modulator of PTK function based on the difference in cell growth.

The term "cell growth" refers to the rate at which a group of cells divides. Cell division rates can be readily measured by methods utilized by those skilled in the art.

Another aspect of the invention features a method of diagnosing a disease by identifying cells harboring a PTK with inappropriate activity. The method comprises the steps of: administering a modulator of PTK function to cells; comparing the rate of cell growth between cells not administered the modulator and cells administered the modulator; and diagnosing a disease by characterizing cells harboring a PTK-with inappropriate activity from the effect of the modulator on the difference in the rate of cell growth. The modulator can be identified by the methods of the WO 98/07835 PCT/US97/14885 36 invention.

The term "inappropriate activity" refers to a PTK that regulates a step in a signal transduction process at a higher or lower rate than normal cells.

Aberrations in the rate of signal transduction can be caused by alterations in the stimulation of a receptor PTK by a growth factor, alterations in the activity of PTK-specific phosphatase, over-expression of a PTK in a cell, or mutations in the catalytic region of the PTK itself.

The term "signal transduction process" describes the steps in a cascade of events where an extracellular signal is transmitted into an intracellular signal.

The term "PTK-specific phosphatase" describes an enzyme that dephosphorylates a particular PTK and thereby regulates that PTK's activity.

Another aspect of the invention is a method of treating a disease associated with a PTK with inappropriate activity in a cellular organism, where the method comprises the steps of: administering the modulator of PTK function to the organism, where the modulator is in an acceptable pharmaceutical preparation; and activating or inhibiting the PTK function to treat the disease.

The term "organism" relates to any living being comprised of at least one cell. An organism can be as simple as one eukaryotic cell or -as complex as a mammal.

The term "administering", in reference to an organism, refers to a method of introducing the compound to the organism. The compound can be administered when the cells or tissues of the organism exist within the WO 98/07835 PCT/US97/14885 37 organism or outside of the organism. Cells existing outside the organism can be maintained or grown in cell culture dishes. For cells harbored within the organism, many techniques exist in the art to administer compounds, including (but not limited to) oral, parenteral, dermal, and injection applications. For cells outside of the patient, multiple techniques exist in the art to administer the compounds, including (but not limited to) cell microinjection techniques, transformation techniques, and carrier techniques.

The term "pharmaceutically acceptable composition" refers to a preparation comprising the modulator of PTK activity. The composition is acceptable if it does not appreciably cause irritations to the organism administered the compound.

Preferred embodiments of the of the invention are that the PTK is a receptor PTK selected from the group consisting of FGF-R, PDGF-R, FLK-1, CCK4, MET, TRKA, AXL, TIE, EPH, RYK, DDR, ROS, RET, LTK, ROR1, and MUSK.

Other preferred embodiments of the invention are that the PTK is a non-receptor PTK selected from the group consisting of SRC, BRK, BTK, CSK, ABL, ZAP70, FES, FAK, JAK, and ACK.

The summary of the invention described above is non-limiting and other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 provides a ribbon diagram of the structure of FGFR1 showing the side chains of tyrosines Tyr-653 WO 98/07835 PCT/US97/14885 38 and Tyr-654 and the a helical (aC, cD, aE, cEF, aF-aI), P strand (01-P5, 37, p8), nucleotide-binding loop, catalytic loop, activation loop and kinase insert regions of the molecule. The termini are denoted by N and C. The loop between 32 and P3 is disordered, indicated by a break in the chain in this region.

FIG. 2 provides a stereo view of a C trace of FGFR1 shown in the same orientation as FIG. 1, with every tenth amino acid residue marked with a filled circle and every twentieth amino acid residue labeled with a residue number.

FIG. 3 provides a structure-based sequence alignment of human fibroblast growth factor receptor 1 (FGFR1), human fibroblast growth factor receptor 2 (FGFR2), human fibroblast growth factor receptor 3 (FGFR3), human fibroblast growth factor receptor 4 (FGFR4), a D. malanogaster homolog (DFGFR1), a C.

elegans homolog (EGL-15) and insulin receptor tyrosine kinase

(IRK).

FIGS. 4A and 4B provide ribbon diagrams of the ,N-terminal lobes (4A) and C-terminal lobes (4B) of FGFR1 and IRK in which the C, atoms of the P sheets (4A) or ahelices (4B) of the two proteins have been superimposed.

FIG. 5 illustrates the side-chain positions of the tyrosine autophosphorylation sites of FGFR1 on the backbone representation of FGFR1.

FIGS. 6A and 6B are amino acid sequence alignments of the catalytic domains of PTKs, including receptor and non-receptor type PTKs. FIG. 6A depicts one representative member from each of the eighteen subfamilies of receptor tyrosine kinases. FIG. 6B depicts one representative member from each of the subfamilies of cytoplasmic tyrosine kinases. In FIGS.

6A and 6B highly conserved residues are boxed. The position of the glycine-rich domain, kinase insert, catalytic loop, and activation loop are indicated. The numbering is for human FGF-receptor.

BRIEF DESCRIPTION OF THE CRYSTALLOGRAPHIC ATOMIC STRUCTURAL COORDINATES The crystallographic structural coordinates are located at the end of the section entitled "Examples" and before the claims. Three sets of coordinates can be found in the Protein Data Bank under accession names 1FGK, 1AGW, and 1FGI. The 1FGK coordinates correspond to those listed in Table 1, the 1AGW coordinates correspond to those listed in Table 4, and the 1FGI coordinates correspond to those listed in Table 3. The 1AGW and 1FGI coordinate sets will be publically available in March 1998.

Table 1 provides the atomic structure coordinates of native FGFR1 crystals of the invention as determined by X-ray crystallography; and Table 2 provides the atomic structure coordinates of FGFR1:AMP-PCP co-crystals of the invention as determined by X-ray crystallography.

Table 3 lists crystallographic coordinates defining the three dimensional structure of FGF-R1 complexed with 3-[(3-(2-carboxyethyl)-4-methylpyrrol-2-yl)methylene]-2indolinone. The columns (from left to right) are descriptions of the atoms by number and type, amino acid and number containing the atom, the x coordinate, y ^ENOEO EET WO 98/07835 PCT/US97/14885 coordinate, z coordinate, bond connectivity, and temperature factor. All of these parameters are well defined in the art.

Table 4 is a file of crystallographic coordinates defining the three dimensional structure of FGF-Ri complexed with (4-formylpiperazine-l-yl) benzylidenyl]-2-indolinone. The columns are as described in Table 3.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the design and identification of modulators of protein tyrosine kinase function that are PTK subfamily specific, nonhydrolyzable under acidic conditions, and highly bioavailable. The three dimensional structures of a PTK optionally complexed with compounds can facilitate design and identification of modulators of PTK function.

Protein tyrosine kinases (PTKs) comprise a large and diverse class of enzymes. Schlessinger and Ullrich, 1992, Neuron 9: 383-391. The PTK family is subdivided into members that are receptors and those that are nonreceptors. The PTK receptor family contains multiple subfamilies, one of which is the fibroblast growth factor receptor (FGF-R) PTK which is a molecule implicated in regulating angiogenesis a well as cellular proliferation and differentiation. Givol and Yayon, 1992, FASEB J.-6 3362-3369.

FGF-R1 can mediates cellular functions by its role in one or more cellular signal transduction processes.

Cellular signal transduction processes comprise multiple steps that convert an extracellular signal into an WO 98/07835 PCTIUS97/14885 41 intracellular signal.

Receptor PTK mediated signal transduction is initiated by binding a specific extracellular ligand, followed by receptor dimerization, and subsequent autophosphorylation of the receptor PTK. The phosphate groups are binding sites for intracellular signal transduction molecules which leads to the formation of protein complexes at the cell membrane. These complexes facilitate an appropriate cellular effect cell division, metabolic effects to the extracellular microenvironment) in response to the ligand that began the cascade of events.

Receptor PTKs function as binding sites for several intracellular proteins. Intracellular PTK binding proteins are divided into two principal groups: (1) those which harbor a catalytic domain; and those which lack such a domain but serve as adapters and associate with catalytically active molecules. Songyang et al., 1993, Cell 72:767-778. SH2 (src homology) domains are common adaptors found in proteins which directly bind to the receptor PTK. SH2 domains are harbored by PTK binding proteins of both groups mentioned above. Fantl et al., 1992, Cell 69:413-423; Songyang et al., 1994, Mol. Cell. Biol. 14:2777-2785); Songyang et al., 1993, Cell 72:767-778; and Koch et al., 1991, Science 252:668-678.

The specificity of the interactions between receptor PTKs and the SH2 domains of their binding proteins is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities of SH2 WO 98/07835 PCT/US97/14885 42 domains is correlated with the observed differences in substrate phosphorylation profiles of downstream molecules in the signal transduction process. Songyang et al., 1993, Cell 72:767-778. These observations suggest that the function of each receptor PTK is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, PTKs provide a controlling regulatory role in signal transduction processes as a consequence of autophosphorylation.

PTK-mediated signal transduction regulates cell proliferative, differentiation, and metabolic responses in cells. Therefore, inappropriate PTK activity can result in a wide array of disorders and diseases. These disorders, which are described below, may be treated by the modulators of PTK function designed or identified by the methods disclosed herein.

The present invention also relates to crystalline polypeptides corresponding to the catalytic domain of receptor tyrosine kinases. Such tyrosine kinases include receptors of a class that are not covalently cross-linked but are understood to undergo ligandinduced dimerization, as well as cytoplasmic tyrosine kinases. Preferably, the crystalline catalytic domains are of sufficient quality to allow for the determination of a three-dimensional X-ray diffraction structure to a resolution of about 1.5 A to about 2.5 A. The invention also relates to methods for preparing and crystallizing the polypeptides. The polypeptides themselves, as well as information derived from their crystal structures can WO 98/07835 PCT/US97/14885 43 be used to analyze and modify tyrosine kinase activity as well as to identify compounds that interact with the catalytic domain.

The polypeptides of the invention are designed on the basis of the structure of a region in the cytoplasmic domain of the receptor tyrosine kinase that.

contains the catalytic domain. By way of illustration, FIG. 6A shows the amino acid sequence alignment of the catalytic domains of eighteen human receptor tyrosine kinases; one representative member from each of the eighteen subfamilies is shown. FIG. 6B shows the alignment for cytoplasmic kinases. The applicants have discovered and determined the boundaries of the domain required for crystallization of the resulting polypeptide. Surprisingly, these boundaries differ from that required for catalytic activity. For example, referring to FIG. 6A, the domain required for catalytic activity is generally believed to span about 7 amino acid residues upstream of the first glycine (FIG. 6A residue number 485) of the N-terminal glycine-rich region through about 10 residues beyond the C-terminal conserved arginine (FIG. 6A, residue number 744).

However, the additional sequence upstream of the Nterminal glycine-rich region and downstream of the Cterminal conserved arginine can be required for crystallization. In particular, at least about 20 amino acid residues 5 amino acid residues) upstream of the first glycine FIG. 6A, residue number 485) in the conserved glycine-rich region of the catalytic domain, and at least about 17 amino acid residues amino acid residues) downstream of the conserved WO 98/07835 PCT/US97/14885 44 arginine FIG. 6A, residue number 744) located at the C-terminal boundary of the catalytic domain can be required to engineer a polypeptide suitable for crystallization.

In those situations where the resulting polypeptide contains cysteine residues that interfere with crystallization cysteine residue numbers 488 and 584 in the FGF-R1 sequence shown in FIG. 6A), such cysteine residues can be substituted with an appropriate amino acid that does not readily form covalent bonds with other amino acid residues under crystallization conditions; by substituting the cysteine with Ala, Ser or Gly. Any cysteine located in a non-helical or non-3-stranded segment, based on secondary structure assignments, are good candidates for replacement. For example, cysteines located in regions corresponding to the glycine-rich-loop, the kinase insert, the juxtamembrane region or the activation loop are prime candidates for replacement. However, substitutions of cysteine residues that-are conserved among the kinases FIG. 6A at positions 725 and 736) are preferably avoided.

I. PTK Associated Diseases Blood vessel proliferative disorders refer to angiogenic and vasculogenic disorders generally resulting in abnormal proliferation of blood vessels.

The formation and spreading of blood vessels play important roles in a variety of physiological processes such as embryonic development, corpus luteum formation, wound healing and organ regeneration. They also play a WO 98/07835 PCT/US97/14885 pivotal role in cancer development. Other examples of blood vessel proliferation disorders include arthritis, where new capillary blood vessels invade the joint and destroy cartilage, and ocular diseases, like diabetic retinopathy, where new capillaries in the retina invade the vitreous, bleed and cause blindness. Conversely, disorders related to the shrinkage, contraction or closing of blood vessels are implicated in such diseases as restenosis.

Fibrotic disorders refer to the abnormal formation of extracellular matrix. Examples of fibrotic disorders include hepatic cirrhosis and mesangial cell proliferative disorders. Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar. Hepatic cirrhosis can cause diseases such as cirrhosis of the liver. An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis.

Mesangial cell proliferative disorders refer to disorders brought about by abnormal proliferation of mesangial cells. Mesangial proliferative disorders include various human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies. The PDGF-R has been implicated in the maintenance of mesangial cell proliferation. Floege et al., 1993, Kidney International 43:47S-54S.

PTKs are directly associated with the cell proliferative disorders described above. For example, WO 98/07835 PCT/US97/14885 46 some members of the receptor PTK family have been associated with the development of cancer. Some of these receptors, like EGFR (Tuzi et al., 1991, Br. J.

Cancer 63:227-233; Torp et al., 1992, APMIS 100:713- 719) HER2/neu (Slamon et al., 1989, Science 244:707-712) and PDGF-R (Kumabe et al., 1992, Oncogene 7:627-633) are over-expressed in many tumors and/or persistently activated by autocrine loops. In fact, PTK overexpression (Akbasak and Suner-Akbasak et al., 1992, J.

Neurol. Sci. 111:119-133; Dickson et al., 1992, Cancer Treatment Res. 61:249-273; Korc et al., 1992, J. Clin.

Invest. 90:1352-1360) and autocrine loop stimulation (Lee and Donoghue, 1992, J. Cell. Biol. 118:1057-1070; Korc et al., supra; Akbasak and Suner-Akbasak et al., supra) account for the most common and severe cancers.

For example, EGFR is associated with squamous cell carcinoma, astrocytoma, glioblastoma, head and neck cancer, lung cancer and bladder cancer. HER2 is associated with breast, ovarian, gastric, lung, pancreas and bladder cancer. PDGF-R is associated with glioblastoma, lung, ovarian, melanoma and prostate cancer. The receptor PTK c-met is generally associated with hepatocarcinogenesis and thus hepatocellular carcinoma. Additionally, c-met is linked to malignant tumor formation. More specifically, c-met has been associated with, among other cancers, colorectal, thyroid,- pancreatic and gastric carcinoma, leukemia and lymphoma. Additionally, over-expression of the c-met gene has been detected in patients with Hodgkins disease, Burkitts disease; and the lymphoma cell line.

The IGF-I receptor PTK, in addition to being WO 98/07835 PCT/US97/14885 47 implicated in nutritional support and in type-II diabetes, is also associated with several types of cancers. For example, IGF-I has been implicated as an autocrine growth stimulator for several tumor types, e.g. human breast cancer carcinoma cells (Arteaga et al., 1989, J. Clin. Invest. 84:1418-1423) and small lung tumor cells (Macauley et al., 1990, Cancer Res. 50:2511- 2517). In addition, IGF-I, integrally involved in the normal growth and differentiation of the nervous system, appears to be an autocrine stimulator of human gliomas.

Sandberg-Nordqvist et al., 1993, Cancer Res. 53:2475- 2478. The importance of the IGF-IR and its modulators in cell proliferation is further supported by the fact that many cell types in culture (fibroblasts, epithelial cells, smooth muscle cells, T-lymphocytes, myeloid cells, chondrocytes, osteoblasts, the stem cells of the bone marrow) are stimulated to grow by IGF-I. Goldring and Goldring, 1991, Eukaryotic Gene Expression 1:301- 326. In a series of recent publications suggest that IGF-IR plays a central role in the mechanisms of transformation and, as such, could be a preferred target for therapeutic interventions for a broad spectrum of human malignancies. Baserga, 1995, Cancer Res. 55:249- 252; Baserga, 1994, Cell 79:927-930; Coppola et al., 1994, Mol. Cell. Biol. 14:4588-4595.

The association between abnormalities in receptor PTKs and disease are not restricted to cancer, however.

For example, receptor PTKs are associated with metabolic diseases like psoriasis, diabetes mellitus, wound healing, inflammation, and neurodegenerative diseases.

EGF-R is indicated in corneal and dermal wound healing.

WO 98/07835 PCT/US97/14885 48 Defects in Insulin-R and IGF-IR are indicated in type-II diabetes mellitus. A more complete correlation between specific receptor PTKs and their therapeutic indications is set forth in Plowman et al., 1994, DN&P 7:334-339.

Non-receptor PTKs, including src, abl, fps, yes, fyn, lyn, Ick, blk, hck, fgr, yrk (reviewed by Bolen et al., 1992, FASEB J. 6:3403-3409), are involved in the proliferative and metabolic signal transduction pathways also associated with receptor PTKs. Therefore, the present invention is also directed towards designing modulators against this class of PTKs. For example, mutated src (v-src) is an oncoprotein in chicken. Moreover, its cellular homolog, the protooncogene ppGO60-sr transmits oncogenic signals of many receptors. For example, over-expression of EGF-R or HER2/neu in tumors leads to the constitutive activation of pp60 s rc, which is characteristic of the malignant cell but absent in the normal cell. On the other hand, mice deficient for the expression of c-src exhibit an osteopetrotic phenotype, indicating a key participation of c-src in osteoclast function and a possible involvement in related disorders. Similarly, Zap 70 is implicated in T-cell signaling. Both receptor PTKs and non-receptor PTKs are connected to hyperimmune disorders.

The instant invention is directed in part towards designing modulators of PTK function that could indirectly kill :tumors by cutting off their source of sustenance. Normal vasculogenesis and angiogenesis play important roles in a variety of physiological processes such as embryonic development, wound healing, organ WO 98/07835 PCT/US97/14885 49 regeneration and female reproductive processes such as follicle development in the corpus luteum during ovulation and placental growth after pregnancy. Folkman and Shing, 1992, J. Biological Chem. 267:10931-34.

However, many diseases are driven by persistent unregulated or inappropriate angiogenesis. For example, in arthritis, new capillary blood vessels invade the joint and destroy the cartilage. In diabetes, new capillaries in the retina invade the vitreous, bleed and cause blindness. Folkman, 1987, in: Congress of Thrombosis and Haemostasis (Verstraete, et. al, eds.), Leuven University Press, Leuven, pp.583-596. Ocular neovascularization is the most common cause of blindness and dominates approximately twenty (20) eye diseases.

Moreover, vasculogenesis and/or angiogenesis can be associated with the growth of malignant solid tumors and metastasis. A tumor must continuously stimulate the growth of new capillary blood vessels for the tumor itself to grow. Furthermore, the new blood vessels embedded in a tumor provide a gateway for tumor cells to enter the circulation and to metastasize to distant sites in the body. Folkman, 1990, J. Natl. Cancer Inst.

82:4-6; Klagsbrunn and Soker, 1993, Current Biology 3:699-702; Folkman, 1991, J. Natl., Cancer Inst. 82:4-6; Weidner et al., 1991, New Engl. J. Med. 324:1-5.

Several polypeptides with in vitro endothelial cell growth promoting activity have been identified.

Examples include acidic and basic fibroblastic growth factor (aFGF, PFGF), vascular endothelial growth factor (VEGF) and placental growth factor. Unlike aFGF and PFGF, VEGF has recently been reported to be an WO 98/07835 PCT/US97/14885 endothelial cell specific mitogen. Ferrara and Henzel, 1989, Biochem. Biophys. Res. Comm. 161:851-858; Vaisman et al., 1990, J. Biol. Chem. 265:19461-19566.

Thus, identifying the specific receptors that bind FGF or VEGF is important for understanding endothelial cell proliferation regulation. Two structurally related receptor PTKs that bind VEGF with high affinity are identified: the flt-i receptor (Shibuya et al., 1990, Oncogene 5:519-524; De Vries et al., 1992, Science 255:989-991) and the KDR/FLK-1 receptor, discussed in the U.S. Patent Application No. 08/193,829. In addition, a receptor that binds aFGF and FGF is identified. Jaye et al., 1992, Biochem. Biophys. Acta 1135:185-199). Consequently, these receptor PTKs most likely regulate endothelial cell proliferation.

FGFRs play important roles in angiogenesis, wound healing, embryonic development, and malignant transformation. Basilico and Moscatelli, 1992, Adv.

Cancer Res. 59:115-165. Four mammalian FGFR (FGFR1-4) have been described and additional diversity is generated by alternative RNA splicing within the extracellular domains. Jaye et al., 1992, Biochem.

Biophys. Acta 1135:185-199. Like other receptor PTKs, dimerization of FGF receptors is essential for their activation. Soluble or cell surface-bound heparin sulfate proteoglycans act in concert with FGF to induce dimerization (Schlessinger et al., 1995, Cell 83:357- 360), which leads to autophosphorylation of specific tyrosine residues in the cytoplasmic domain. Mohammadi et al., 1996, Mol. Cell Biol. 16:977-989.

Mutations in three human FGF receptor genes, FGFR1, WO 98/07835 PCT/US97/14885 51 FGFR2, and FGFR3, have been implicated in a variety of human genetic skeletal disorders. Mutations in FGFR1 and FGFR2 result in the premature fusion of the flat.

bones of the skull and cause the craniosynostosis syndromes, such as Apert (FGFR2) (Wilkie et al., 1994, Nat. Genet. 8:269-274), Pfeiffer (FGFR1 and FGFR2) (Muenke et al., 1994, Nat. Genet. 8:269-274), Jackson-Weiss (FGFR2) (Jabs et al., 1994, Nat. Genet.

8:275-279) and Crouzon (FGFR2) (Jabs et al., 1994, Nat.

Genet. 8:275-279) syndromes. In contrast mutations in FGFR3 are implicated in long bone disorders and cause several clinically related forms of dwarfism including achondroplasia (Shiang et al., 1994, Cell 78:335-342), hypochondroplasia (Bellus et al., 1995, Nat. Genet, 10:357-359) and the neonatal lethal thanatophoric dysplasia (Tavormina et al., 1995, Nat. Genet. 9:321- 328). It has been shown that these mutations lead to constitutive activation of the tyrosine kinase activity of FGFR3 (Webster et al., 1996, EMBO J. 15:520-527).

Furthermore gene-targeting experiments in mice have revealed an essential role for FGFR3 in developmental bone formation (Deng et al., 1996, Cell 84:911-921).

Another major role proposed for FGFs in vivo is the induction of angiogenesis (Folkman and Klagsbrun, 1987, Science 236:442). Therefore, inappropriate expression of FGFs or of their receptors or aberrant function of the tyrosine kinase activity could contribute to several human angiogenic pathologies such as diabeticretinopathy, rheumatoid arthritis, atherosclerosis and tumor neovascularization (Klagsbrun and Edelman, 1989, Arteriosclerosis 9:269). Moreover, FGFs are thought to WO 98/07835 PCT/US97/14885 52 be involved in malignant transformation. Indeed, the genes coding for the three FGF homologues int-2, and hst-1/K-fgf were originally isolated as oncogenes.

Furthermore, the cDNA encoding FGFR1 and FGFR2 are amplified in a population of breast cancers (Adnane et al., 1991, Oncogene 6:659-663). Over-expression of FGF receptors has been also detected in human pancreatic cancers, astrocytomas, salivary gland adenosarcomas, Kaposi sarcomas, ovarian cancers and prostate cancers.

Evidence, such as the disclosure set forth in copending U.S. Application Serial No. 08/193,829, strongly suggests that VEGF is not only responsible for endothelial cell proliferation, but also is a prime regulator of normal and pathological angiogenesis. See generally, Klagsburn and Soker, 1993, Current Biology 3:699-702; Houck et al., 1992, J. Biol. Chem.

267:26031-26037. Moreover, it has been shown that KDR/FLK-1 and flt-1 are abundantly expressed in the proliferating endothelial cells of a growing tumor, but not in the surrounding quiescent endothelial cells.

Plate et al., 1992, Nature 359:845-848; Shweiki et al., 1992, Nature 359:843-845.

The invention is directed to designing and identifying modulators of receptor and non-receptor

PTK

functions that could modify the inappropriate activity of a PTK involved with a clinical disorder. The rational design and identification of modulators of PTK functions can be accomplished by utilizing the structural coordinates that define a PTK three dimensional structure.

WO 98/07835 PCT/US97/14885 53 II. Modulators of PTK functions as Therapeutics for Disease As a consequence of the disorders discussed above, scientists in the biomedical community are searching for modulators of PTK functions that down-regulate signal transduction pathways associated with inappropriate

PTK

activity.

In particular, small molecule modulators of PTK functions are sought as some can traverse the cell membrane and do not hydrolyze in acidic environments.

Some compounds have already been discovered. For example, bis monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92/20642), vinylene-azaindole derivatives (PCT WO 94/14808) l-cyclopropyl-4-pyridylquinolones Patent No. 5,330,992), styryl compounds Patent No. 5,217,999), styryl-substituted pyridyl compounds Patent No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 Al), seleoindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660), and benzylphosphonic acid compounds (PCT WO 91/15495) are described as PTK inhibitors.

Although some modulators of PTK function are known, many of these are not specific for PTK subfamilies and will therefore cause multiple side-effects as therapeutics. Compounds of the oxindolinone/ thiolindolinone family, however, are specific for the FGF receptor subfamily Patent Application Serial No. 08/702,232, filed August 23, -1996, invented by Tang et al., entitled "Indolinone Combinatorial Libraries and Related Products and Methods for the Treatment of WO 98/07835 PCT/US97/14885 54 Disease," Attorney Docket No. 221/187). In addition, compounds of the oxindolinone/thiolindolinone family are non-hydrolyzable in acidic conditions and can be highly bioavailable.

The invention provides information regarding the specific interactions between a PTK and compounds of the oxindolinone/thiolindolinone family. Although the use of X-ray crystallography has provided three dimensional structures of other PTKs, the PTKs in these structures are not complexed with PTK subfamily specific, hydrolysis resistant, highly bioavailable small molecules. The X-ray crystallography techniques used in the current invention resolve interactions between a PTK and compounds in complex with it at the atomic level, which provides detailed information regarding the orientation of chemical groups defining an effective modulator of PTK function.

III. Crystalline Tyrosine Kinases Crystalline PTKs of the invention include native crystals, derivative crystals and co-crystals. The native crystals of the invention generally comprise substantially pure polypeptides corresponding to the tyrosine kinase domain in crystalline form.

It is to be understood that the crystalline tyrosine kinase domains of the invention are not limited to naturally occurring or native tyrosine kinase domains. Indeed, the crystals of the invention include mutants of native tyrosine kinase domains. Mutants of native tyrosine kinase domains are obtained by replacing at least one amino acid residue in a native tyrosine WO 98/07835 PCTIUS97/14885 kinase domain with a different amino acid residue, or by adding or deleting amino acid residues within the native polypeptide or at the N- or C-terminus of the native polypeptide, and have substantially the same threedimensional structure as the native tyrosine kinase domain from which the mutant is derived.

By having substantially the same three-dimensional structure is meant having a set of atomic structure coordinates that have a root-mean-square deviation of less than or equal to about 2A when superimposed with the atomic structure coordinates of the native tyrosine kinase domain from which the mutant is derived when at least about 50% to.100% of the Ca atoms of the native tyrosine kinase domain are included in the superposition.

Amino acid substitutions, deletions and additions whichdo not significantly interfere with the threedimensional structure of the tyrosine kinase domain will depend, in part, on the region of the tyrosine kinase domain where the substitution, addition or deletion occurs. In highly variable regions of the molecule, such as those shown in FIG. 6, non-conservative substitutions as well as conservative substitutions may be tolerated without significantly disrupting the threedimensional structure of the molecule. In highly conserved regions, or regions containing significant secondary structure, such as those regions shown in FIG.

6, conservative amino acid substitutions are preferred.

Conservative amino acid substitutions are wellknown in the art, and include substitutions made on the basis of similarity in polarity, charge, solubility, WO 98/07835 PCT/US97/14885 56 hydrophobicity, hydrophilicity and/or the amphipathic nature of the amino acid residues involved. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; amino acids with uncharged polar head groups having similar hydrophilicity values include the following: leucine, isoleucine, valine; glycine, alanine; asparagine, glutamine; serine, threonine; phenylalanine, tyrosine. Other conservative amino acid substitutions are well known in the art.

For tyrosine kinase domains obtained in whole or in part by chemical synthesis, the selection of amino acids available for substitution or addition is not limited to the genetically encoded amino acids. Indeed, the mutants described herein may contain non-genetically encoded amino acids. Conservative amino acid substitutions for many of the commonly known nongenetically encoded amino acids are well known in the art. Conservative substitutions for other amino acids can be determined based on their physical properties as compared to the properties of the genetically encoded amino acids.

In some instances, it may be particularly advantageous or convenient to substitute, delete and/or add amino acid residues to a native tyrosine kinase domain in order to provide convenient cloning sites in cDNA encoding the polypeptide, to aid in purification of the polypeptide, and for crystallization of the polypeptide. Such substitutions, deletions and/or additions which do not substantially alter the three dimensional structure of the native tyrosine kinase WO 98/07835 PCTIUS97/14885 57 domain will be apparent to those of ordinary skill in the art.

It should be noted that the mutants contemplated herein need not exhibit PTK activity. Indeed, amino acid substitutions, additions or deletions that interfere with the kinase activity of the tyrosine kinase domain but which do not significantly alter the three-dimensional structure of the domain are specifically contemplated by the invention. Such crystalline polypeptides, or the atomic structure coordinates obtained therefrom, can be used to identify compounds that bind to the native domain. These compounds may affect the activity or the native domain.

The derivative crystals of the invention generally comprise a crystalline tyrosine kinase domain polypeptide in covalent association with one or more heavy metal atoms. The polypeptide may correspond to a native or a mutated tyrosine kinase domain. Heavy metal atoms useful for providing derivative crystals include, by way of example and not limitation, gold, mercury, etc.

The co-crystals of the invention generally comprise a crystalline tyrosine kinase domain polypeptide in association with one or more compounds. The association may be covalent or non-covalent. Such compounds include, but are not limited to, cofactors, substrates, substrate analogues, inhibitors, allosteric effectors, etc.

WO 98/07835 PCTIUS97/14885 58 IV. Three Dimensional Structure Determination Using Xray Crystallography X-ray crystallography is a method of solving the three dimensional structures of molecules. The structure of a molecule is calculated from X-ray diffraction patterns using a crystal as a diffraction grating. Three dimensional structures of protein molecules arise from crystals grown from a concentrated aqueous solution of that protein. The process of X-ray crystallography can include the following steps: synthesizing and isolating a polypeptide; growing a crystal from an aqueous solution comprising the polypeptide with or without a modulator; and collecting X-ray diffraction patterns from the crystals, determining unit cell dimensions and symmetry, determining electron density, fitting the amino acid sequence of the polypeptide to the electron density, and refining .the structure.

Production of Polypeptides The native and mutated tyrosine kinase domain polypeptides described herein may be chemically synthesized in whole or part using techniques that are well-known in the art (see, Creighton, 1983).

Alternatively, methods which are well known to those skilled in the art can be used to construct expression vectors containing the native or mutated tyrosine kinase domain polypeptide coding sequence and appropriate

N

WO 98/07835 PCT/US97/14885 59 transcriptional/translational control signals. These methods include in vitro recombinant DNA techniques, synthetic techniques and in vivo recombination/genetic recombination. See, for example, the techniques described in Maniatis et al., 1989 and Ausubel et al., 1989.

A variety of host-expression vector systems may be utilized to express the tyrosine kinase domain coding sequence. These include but are not limited to microorganisms such as bacteria transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing the tyrosine kinase domain coding sequence; yeast transformed with recombinant yeast expression vectors containing the tyrosine kinase domain coding sequence; insect cell systems infected with recombinant virus expression vectors baculovirus) containing the tyrosine kinase domain coding sequence; plant cell systems infected with recombinant virus expression vectors cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors Ti plasmid) containing the tyrosine kinase domain coding sequence; or animal cell systems. The expression elements of these systems vary in their strength and specificities.

Depending on the host/vector system utilized, any of a number of suitable transcription and translation elements, including constitutive and inducible promoters, may be used in the expression vector. For example, when cloning in bacterial systems, inducible promoters such as pL of bacteriophage X, plac, ptrp, WO 98/07835 PCT/US97/14885 ptac (ptrp-lac hybrid promoter) and the like may be used; when cloning in insect cell systems, promoters such as the baculovirus polyhedrin promoter may be used; when cloning in plant cell systems, promoters derived from the genome of plant cells heat shock promoters; the promoter for the small subunit of RUBISCO; the promoter for the chlorophyll a/b binding protein) or from plant viruses the 35S RNA promoter of CaMV; the coat protein promoter of TMV) may be used; when cloning in mammalian cell systems, promoters derived from the genome of mammalian cells metallothionein promoter) or from mammalian viruses the adenovirus late promoter; the vaccinia virus 7.5K promoter) may be used; when generating cell lines that contain multiple copies of the tyrosine kinase domain DNA, SV40-, BPV- and EBVbased vectors may be used with an appropriate selectable marker.

Methods describing methods of DNA manipulation, vectors, various types of cells used, methods of incorporating the vectors into the cells, expression techniques, protein purification and isolation methods, and protein concentration methods are disclosed in detail with respect to the protein PYK-2 in PCT publication WO 96/18738. This publication is incorporated herein by reference in its entirety, including any drawings. Those skilled in the art will appreciate that such descriptions are applicable to the present invention and can be easily adapted to it.

WO 98/07835 PCT/US97/14885 61 Crystal Growth Crystals are grown from an aqueous solution containing the purified and concentrated polypeptide by a variety of techniques. These techniques include batch, liquid, bridge, dialysis, vapor diffusion, and hanging drop methods. McPherson, 1982, John Wiley, New York; McPherson, 1990, Eur. J. Biochem. 189:1-23; Webber, 1991, Adv. Protein Chem. 41:1-36, incorporated by reference herein in its entirety, including all figures, tables, and drawings.

Generally, the native crystals of the invention are grown by adding precipitants to the concentrated solution of the polypeptide corresponding to the PTK catalytic domain. The precipitants are added at a concentration just below that necessary to precipitate the protein. Water is removed by controlled evaporation to produce precipitating conditions, which are maintained until crystal growth ceases.

For crystals of the invention, it has been found that hanging drops containing about 2.0 AL of tyrosine kinase domain polypeptide (10 mg/mL in 10mM Tris-HCl, pH 10 mM NaCI and 2 mM dithiothreitol) and 2.0 AL reservoir solution (16% w/v polyethylene glycol MW 10000, 0.3 M (NH) 2 ,S0 4 5% v/v ethylene glycol or glycerol and 100 mM bis-Tris, pH 6.5) suspended over mL reservoir buffer for about 3-4 weeks at 4 0 C provide crystals suitable for high resolution X-ray structure determination.

Those of ordinary skill in the art will recognize that the above-described crystallization conditions can be varied. Such variations may be used alone or in WO 98/07835 PCTIUS97/14885 62 combination, and include polypeptide solutions containing polypeptide concentrations between about 1 mg/mL and about 60 mg/mL, Tris-HCl concentrations between about 10 mM and about 200 mM, dithiothreitol concentrations between about 0 mM and about 20 mM, pH ranges between about 5.5 and about 7.5; and reservoir solutions containing polyethylene glycol concentrations between about 10% and about 30% polyethylene glycol molecular weights between about 1000 and about 20,000, (NH 4 2

SO

4 concentrations between about 0.1 M and about 0.5 M, ethylene glycol or glycerol concentrations between about 0% and about 20% bis-Tris concentrations between about 10 mM and about 200 mM, pH ranges between about 5.5 and about 7.5 and temperature ranges between' about 0° C and about 25 0 C. Other buffer solutions may be used such as HEPES buffer, so long as the desired pH range is maintained.

Derivative crystals of the invention can be obtained by soaking native crystals in mother liquor containing salts of heavy metal atoms. It has been found that soaking a native crystal in a solution containing about 0.1 mM to about 5 mM thimerosal, 4chloromeruribenzoic acid or KAu(CN) 2 for about 2 hr to about 72 hr provides derivative crystals suitable for use as isomorphous replacements in determining the X-ray crystal structure of the tyrosine kinase domain polypeptide.

Co-crystals of the invention can be obtained by soaking a native crystal in mother liquor containing compound that bind the kinase domain, or described above, or can be obtained by co-crystallizing the kinase WO 98/07835 PCT/US97/14885 63 domain polypeptide in the presence of one or more binding compounds.

For co-crystals of tyrosine kinase domain polypeptide in co-complex with AMP-PCP, it has been found that co-crystallizing the kinase domain polypeptide in the presence of AMP-PCP using the abovedescribed crystallization conditions for obtaining native crystals with a polypeptide solution additionally containing 10 mM AMP-PCP and 20 mM MgC12 yields cocrystals suitable for the high resolution structure determination by X-ray crystallography. Of course, those having skill in the art will recognize that the concentrations of AMP-PCP and MgC1, in the polypeptide solution can be varied, alone or in combination with the variations described above for native crystals. Such variations include polypeptide solutions containing AMP- PCP concentrations between 0.1 mM and 50 mM and MgCl 2 concentrations between 0 mM and 50 mM.

Crystals comprising a polypeptide corresponding to a PTK catalytic domain complexed with a compound can be grown by one of two methods. In the first method, the modulator is added to the aqueous solution containing the polypeptide corresponding to the PTK catalytic domain before the crystal is grown. In the second method, the modulator is soaked into an already existing crystal of a polypeptide corresponding to a PTK catalytic domain.

WO 98/07835 PCT/US97/14885 64 Crystalline FGFR In one illustrative embodiment, the invention provides crystals of FGFR1. The crystals were obtained by the methods provided in the Examples. The FGFR1 crystals, which may be native crystals, derivative crystals or co-crystals, have monoclinic unit cells unit cells wherein a/bfc; a=y=90 0 and 3>90°) and space group symmetry C2. There are two FGFR1 molecules in the asymmetric unit, related by an approximate twofold axis.

Two forms of crystalline FGFR1 were obtained. In one form (designated "C2-A form"), the unit cell has dimensions of a=208.3 A, b=57.2 A, c=65.5 A and (=107.2o. In another form (designated "C2-B form"), the unit cell has dimensions of a=211.6 A, b=51.3 A, c=66.1 A and 0=107.7°.

Three distinct two-fold related FGFR1 dimers are observed in both the C2-A and C2-B forms of the FGFR1 crystal, one non-crystallographically related dimer and two crystallographically related dimers. The noncrystallographically related dimer comprises the two molecules in the asymmetric unit. The residues making up the dimer interface are located in C-terminal lobe.

In this dimer, the C-terminal lobes abut with the Nterminal lobes distal to one another. The total amount of surface area buried in the surface is about 950 A 2 Very few of the interactions in the interface are of a specific nature, hydrogen-bonding or close packing of hydrophobic residues.

There are two crystallographically-related dimers in the C2 lattice. In the first dimer, the residues WO 98/07835 PCT/US97/14885 that constitute the dimer interface are limited to those in the p-sheet of the N-terminal lobe (amino acid residues 477, 479, 498, 506, 508 and 496). The total surface area buried in this interface is about 670 A2.

The interactions are rather specific. Three hydrophobic residues which are partially solvent-exposed in the monomer, Val-479, Ile-498 and Val-508, come together with their two-fold-related residues to form a compact hydrophobic plug. This plug is capped on either side by a salt bridge between Arg-477 and Glu-496. In addition, two main-chain hydrogen-bonds connect the (-sheets of the two monomers at the start of P3 (amino acid residues 506 and 508). The residues in this dimer interface, or their residue character, are generally conserved in the mammalian FGF receptors, but not in the invertebrate homologues.

The other crystallographically-related dimer buries about 1650 A 2 in its interface. In this dimer, the aC helices of the two monomers are nearly parallel and contact each other at their C-terminal ends. Met-534 and Met-537 are in van der Waals contact with their twofold-related residues. Other hydrophobic contacts involve Pro-466 with Ile-648 and Pro-469 with Ile-676 and Thr-678. In addition, hydrogen bonds (side-chain to main-chain) are made between Arg-470 and Lys-618 and between His-649 and Glu-464, and there are several water molecules that bridge the two monomers through hydrogen bonding.

In the C2-B form of the crystal, the monomers of this second crystallographically-related dimer are shifted slightly with respect to one another (6° WO 98/07835 PCT/US97/14885 66 rotation), indicating that this interface is somewhat fluid.

In both of the crystallographically-related dimers, the N-termini of the two molecules comprising the dimer point in the same direction and are reasonably close to one another.

Determining Unit Cell Dimensions and the Three Dimensional Structure of a Polypeptide or Polypeptide Complex Once the crystal is grown, it can be placed in a glass capillary tube and mounted onto a holding device connected to an X-ray generator and an X-ray detection device. Collection of X-raydiffraction patterns are well documented by those in the art. Ducruix and Geige, 1992, IRL Press, Oxford, England, and references cited therein. A beam of X-rays enter the crystal and then diffract from the crystal. An X-ray detection device can be utilized to record the diffraction patterns emanating from the crystal. Although the X-ray detection device on older models of these instruments is a piece of film, modern instruments digitally record Xray diffraction scattering.

Methods for obtaining the three dimensional structure of the crystalline form of a peptide molecule or molecule complex are well known in the art. Ducruix and Geige, 1992, IRL Press, Oxford, England, and references cited therein. The following are steps in the process of determining the three dimensional structure of a molecule or complex from X-ray diffraction data.

WO 98/07835 PCT/US97/14885 67 After the X-ray diffraction patterns are collected from the crystal, the unit cell dimensions and orientation in the crystal can be determined. They can be determined from the spacing between the diffraction emissions as well as the patterns made from these emissions. The unit cell dimensions are characterized in three dimensions in units of Angstroms (one A 10 meters) and by angles at each vertices. The symmetry of the unit cell in the crystals is also characterized at this stage. The symmetry of the unit cell in the crystal simplifies the complexity of the collected data by identifying repeating patterns. Application of the symmetry and dimensions of the unit cell is described below.

Each diffraction pattern emission is characterized as a vector and the data collected at this stage of the method determines the amplitude of each vector. The phases of the vectors can be determined using multiple techniques. In one method, heavy atoms can be soaked into a crystal, a method called isomorphous replacement, and the phases of the vectors can be determined by using these heavy atoms as reference points in the X-ray analysis. Otwinowski, 1991, Daresbury, United Kingdom, 80-86. The isomorphous replacement method usually requires more than one heavy atom derivative. In another method, the amplitudes and phases of vectors from a crystalline polypeptide with an already determined structure can be applied to- the amplitudes of the vectors from a crystalline polypeptide of unknown structure and consequently determine the phases of these vectors. This second method is known as molecular WO 98/07835 PCTIS97/14885 68 replacement and the protein structure which is used as a reference must have a closely related structure to the protein of interest. Naraza, 1994, Proteins 11:281-296.

Thus, the vector information from a PTK of known structure, such as those reported herein, are useful for the molecular replacement analysis of another PTK with unknown structure.

Once the phases of the vectors describing the unit cell of a crystal are determined, the vector amplitudes and phases, unit cell dimensions, and unit cell symmetry can be used as terms in a Fourier transform function.

The Fourier transform function calculates the electron density in the unit cell from these measurements. The electron density that describes one of the molecules or one of the molecule complexes in the unit cell can be referred to as an electron density map. The amino acid structures of the sequence or the molecular structures of compounds complexed with the crystalline polypeptide may then fit to the electron density using a variety of computer programs. This step of the process is sometimes referred to as model building and can be accomplished by using computer programs such as TOM/FRODO. Jones, 1985, Methods in Enzymology 115:157- 171.

A theoretical electron density map can then be calculated from the amino acid structures fit to the experimentally determined electron density. The theoretical and experimental electron density maps can be compared to one another and the agreement between these two maps can be described by a parameter called an R-factor. A low value for an R-factor describes a high WO 98/07835 PCT/US97/14885 69 degree of overlapping electron density between a theoretical and experimental electron density map.

The R-factor is then minimized by using computer programs that refine the theoretical electron density map. A computer program such as X-PLOR can be used for model refinement by those skilled in the art. Branger, 1992, Nature 355:472-475. Refinement may be achieved in an iterative process. A first step can entail altering the conformation of atoms defined in an electron density map. The conformations of the atoms can be altered by simulating a rise in temperature which will increase the vibrational frequency of the bonds and modify positions of atoms in the structure. At a particular point in the atomic perturbation process, a force field, which typically defines interactions between atoms in terms of allowed bond angles and bond lengths, Van der Waals interactions, hydrogen bonds, ionic interactions, and hydrophobic interactions, can be applied to the system of atoms. Favorable interactions may be described in terms of free energy and the atoms can be moved over many iterations until a free energy minimum is achieved.

The refinement process can be iterated until the Rfactor reaches a minimum value.

The three dimensional structure of the molecule or molecule complex is described by atoms that fit the theoretical electron density characterized by a minimum R-value. A file can then be created for the three dimensional structure that defines each atom by coordinates in three dimensions. Examples of such structural coordinate files are defined in Table 1, Table 2, Table 3, and Table 4.

WO 98/07835 PCT/US97/14885 V. Structures of FGFR1 The present invention provides high-resolution three-dimensional structures and atomic structure coordinates of crystalline FGFR1 and crystalline FGFR1:AMP-PCP co-complex as determined by X-ray crystallography. The specific methods used to obtain the structure coordinates are provided in the examples.

The atomic structure coordinates of crystalline FGFR1, obtained from the C2-A form of the crystal to 2.0 A resolution, are listed in Table 3; the coordinates of crystalline FGFR1:AMP-PCP co-complex, obtained from the C2-A form of the crystal to 2.3 A resolution are listed in Table 4.

Those having skill in the art will recognize that atomic structure coordinates as determined by X-ray crystallography are not without error. Thus, it is to be understood that any set of structure coordinates obtained for crystals of FGFR1, whether native crystals, derivative crystals or co-crystals, that have a root mean square deviation of less than or equal to about 1.5 A when superimposed, using backbone atoms C and on the structure coordinates listed in Table 3 or Table 4 are considered to be identical with the structure coordinates listed in the Tables when at least about 50% to 100% of the backbone atoms of FGFR1 are included in the superposition.

Referring now to FIG. 1, the overall structure of FGFR1 is bi-lobate. The N-terminal lobe of FGFR1 spans amino acid residues 456-567 (FIG. 3) and comprises a curled B-sheet of five anti-parallel strands (Pi-P5) and WO 98/07835 PCTI/US97/14885 71 one a-helix The C-terminal lobe spans amino acid residues 568-765 (FIG. 3) and comprises two P-strands (f7, 38) and seven a-helices (xD, aE, aEF, uF-aI). The secondary structure nomenclature follows that used for IRK (Hubbard et al., 1994) which in turn is based on the assignments for cAPK (Knighton et al., 1991). FIG. 2 shows a stereo view of a C, trace of FGFR1 in the same orientation as FIG. 1.

A structure-based sequence alignment of the tyrosine kinase domains of human fibroblast growth factor receptor 1 (human FGFR1; labelled FGFR1), human fibroblast growth factor receptors 2, 3 and 4 (labelled FGFR2, FGFR3 and FGFR4, respectively), a D. melanogaster homologue (labelled DFDFR1), a C elegans homologue (labelled EGL-15) and insulin receptor kinase (labelled IRK), is shown in FIG. 3. The sequence of FGFR1, which is not shown in FIG. 3 is identical to the sequence of FGFR1 except that FGFR1 has the following amino acid substitutions and additions: Cys-488 Ala, Cys-584 Ser, Leu-457 Val and an additional five N-terminal amino acids (Ser-Ala-Ala-Gly-Thr). The secondary structure assignments for FGFR1 and IRK were obtained using the Kabsch and Sander algorithm (Kabsch and Sander, 1983) as implemented in PROCHECK (Laskowski et al., 1993). In the FGF receptor sequences, a period represents sequence identity to FGFR1. In the IRK sequence, residues that are identical to FGFR1 are highlighted. A hyphen denotes an insertion.

The numbers under the EGL-15 sequence represent the fractional solvent accessibility (FSA2) of the residue in the FGFR1 structure. The FSA ratio is the ratio of WO 98/07835 PCT/US97/14885 72 the solvent-accessible surface area of a residue in a Gly-X-Gly tripeptide compared to that in the FGFR1 structure. A value of 0 represents an FSA between 0.00 and 0.09; 1 represents an FSA between 0.10 and 0.19, etc. The higher the value, the more solvent-exposed the residue. An asterisk or pound sign in the FSA line indicates that the residue (asterisk) or side chain (pound sign) is not included in the atom model due to disorder. The numbers below the FSA line are the FSAs for those residues that form part of a dimer interface.

The amino acid residue numbers for FGFR1, and hence FGFR1, and IRK provided in FIG. 3 are used in the discussion that follows. Significant differences in the N-terminal lobe of FGFR1 as compared to IRK are found in the loops between 3 strands.and in aC. Residues from the end of 31 through the beginning of 32 (amino acid residues 485-490) form the nucleotide-binding loop, named because of its role in ATP coordination. This residue stretch contains the protein kinase-conserved GXGXXG sequence motif, where X is any 'amino acid. This loop is poorly ordered in one FGFR1 molecule in the asymmetric unit and disordered not included in the atomic model) in the other FGFR1 molecule in the asymmetric unit. The loop between 31 and 33 is disordered in both FGFR1 molecules comprising the asymmetric unit.

Referring now to FIG. 4A, which provides a ribbon diagram of the N-terminal lobes of FGFR1 and IRK in which the C, atoms of the 3-sheets have been superimposed, it can be seen that in FGFR1 aC is longer by one helical turn than in IRK and is oriented such WO 98/07835 PCT/US97/14885 73 that residues Lys-514 and Glu-531, which are conserved in protein kinases, form a salt bridge (represented by a -black line). While not intending to be bound by theory, this salt bridge is believed to be important for proper positioning of the conserved lysine side chain, which coordinates two phosphate oxygens of ATP. The salt bridge is observed in the structures of cAPK (Knighton et al., 1991) and mitogen-activated protein kinase (MAPK) (Zhang et al., 1994).

Referring now to FIG. 4B, which provides a ribbon diagram of the C-terminal lobes of FGFR1 and IRK in which the Ca atoms of the a-helices have been superimposed, a significant difference is found in the C-terminal helix of FGFR1 when compared to IRK; helix aI of FGFR1 is longer by seven residues (two helical turns) than its counterpart in IRK. The extended length of al is presumably important in the biological functioning of FGF receptors, since the tyrosine autophosphorylation site to which an SH2 domain of PLCy binds is six residues C-terminal to this helix.

The structure of FGFR1 displays an open disposition of the N- and C-terminal lobes. Despite having different sets of lattice contacts, the two FGFR1 molecules in the asymmetric unit have only a difference in relative lobe orientation. It appears as though the stearic interaction between residues in aC (Glu-531 and Met-534) with Phe-642 and Gly-643 of the protein kinase-conserved DFG sequence at the beginning of the activation loop accounts for the open conformation of FGFR1.

The active site of FGFR1 is characterized by at WO 98/07835 PCT/US97/14885 74 least amino acid residues spanning the catalytic loop, activation loop and nucleotide binding loop. Unlike the structure of IRK, in which -Tyr-1162 occupies the active site of the molecule, the active sites of both FGFR1 molecules in the asymmetric unit are unoccupied.

The activation loop, which regulates phosphorylation, is characterized by at least resides 640 to 663. Quite surprisingly, while the activation loops of FGFR1 and IRK contain the same number of amino acid residues and share greater than 50% sequence homology, the paths of the polypeptide chains are strikingly dissimilar, diverging at Ala-640 (Gly-1149 in IRK) and reconverging at Val-664 (Val-1173 in IRK).

Tyr-653 and Tyr 564 are not bound in the active site.

Instead, these residues point away from it. Tyr-653 is in van der Waals contact with several hydrophobic residues (Val-664, Leu-672 and Phe-710) and is hydrogenbonded via its hydroxyl group to a backbone carbonyl oxygen (Leu-672). Tyr-654 is more solvent exposed than Tyr-653, and its only van der Waals contact is with Val- 706. Temperature factor data suggest that the activation loop is relatively mobile and adopts multiple conformations.

The catalytic loop of protein kinases lies between secondary structure elements aE and (7 and contains an invariant aspartic acid residue (Asp-623 in FGFR1) which serves as the catalytic base in the phosphotransfer reaction, abstracting the proton from the hydroxyl group of the substrate tyrosine, serine or threonine. The catalytic loop sequence of FGFR1 comprises at least residues His-621 to Asn-628 (amino acid sequence WO 98/07835 PCT/US97/14885 HRDLAARN), and is identical to that for IRK and most receptor and non-receptor PTKs.

In addition to the two tyrosine autophosphorylation sites in the activation loop (Tyr-653 and Tyr-654), there are four other autophosphorylation sites present in the FGFR1 crystals of the invention: one in the juxtamembrane region (Tyr-463), two in the kinase insert (Tyr-583 and Tyr-585) and one in the C-terminal lobe (Tyr-730) (Mohammadi et al., 1996). They exhibit varying degrees of conservation in mammalian FGF receptors: Tyr-463 and Tyr-585 in FGFR1 and 2; Tyr-583 in FGFR1, 2 and 3; and Tyr-730 in FGFR 1, 2, 3 and 4 (FIG. 3).

Referring now to FIG. 5, the positions of the autophosphorylation sites are mapped onto the FGFR1 structure. The juxtamembrane site (Tyr-463) and the residues N-terminal to it are disordered in one of the FGFR1 molecules in the asymmetric unit. In the other molecule in the asymmetric unit Tyr-463 is involved in a lattice contact.

The kinase insert region (the region between helices aD and aE) contains autophosphorylation sites Tyr-583 and Tyr-585 and is disordered in both FGFR1 molecules in the asymmetric unit of the C2-A form of the crystal. In the C2-B form, several lattice contacts partially pin down this region in one of the two FGFR1 molecules in the asymmetric unit, allowing a trace of the polypeptide chain to be made. There is no welldefined secondary structure for these residues. Tyr- 730, situated in aH in the C-terminal lobe, is nearly buried and the side-chain hydroxyl group makes two WO 98/07835 PCTIUS97/14888 76 hydrogen-bonds. The side chains of neighboring Met-732 and Met-733 are both buried. Therefore, phosphorylation of Tyr-730 would presumably require prior unfolding of cH.

Aside from Tyr-730, the five other autophosphorylation sites (including Tyr-653 and Tyr- 654) are found in relatively mobile segments of the FGFR1 molecule. While not intending to be bound by theory, the spatial positions of the autophosphorylation sites relative to the active site suggest that autophosphorylation occurs by a trans mechanism between two kinase domains, supporting the hypothesis that ligand-induced receptor dimerization is critical for the initiation of autophosphorylation events.

The structure of crystalline FGFR1:AMP-PCP cocomplex is essentially similar to that observed for crystalline FGFR1. There are no significant changes in the structure of FGFR1 induced by AMP-PCP binding. In particular, binding of AMP-PCP, and by extension ATP, does not by itself promote lobe closure under the crystallization conditions used. Furthermore, complexation did not result in any noticeable changes in the conformations of the activation and nucleotidebinding loops.

The crystalline FGFR1:AMP-PCP co-complex contains hydrogen bonds that are present between N1 of adenine and the amide nitrogen of Ala-564 and between N6 of adenine and the carbonyl oxygen of Glu-562. The adenine ring is flanked on one side by Leu-484 and Val-492 (Nterminal lobe) and on the other side by Leu-630 (C-terminal lobe). The ribose hydroxyl groups make no WO 98/07835 PCT/US97/14885 77 direct hydrogen bonds with protein atoms. Lys-514 is hydrogen-bonded to oxygens of the 3- and y-phosphates.

There is no unambiguous electron density that would indicate the positions of Mg 2 ions. Generally, AMP-PCP appears to be coordinated rather loosely to unphosphorylated FGFR1, being bound to the "roof" of the cleft rather than being tightly sandwiched between the two kinase lobes.

Structural Differences Between FGF-R and IRK Several features distinguish the FGF-receptor structure from that of the insulin-receptor tyrosine kinase. These distinctions are likely to be important in signaling by FGF-receptors, and other monomeric receptors that are believed to undergo ligand-induced dimerization.

The most significant difference between the structures of FGFR1 and IRK is the conformation of the activation loop. In FGFR1, the activation loop is disposed such that the binding site for substrate peptides is blocked not by an activation loop tyrosine, as in IRK, but by Arg-661 and PTK-invariant Pro-663, while the ATP binding site is accessible. This represents another molecular mechanism by which a receptor PTK may be autoinhibited. The observed autoinhibition in FGFR1 would appear to be weaker than that in IRK because of fewer specific interactions made by residues in the FGFR1 activation loop (manifested in the relatively higher B-values) and the accessibility of the ATP site. One obvious distinction between the insulin and FGF receptor families is that in the former, WO 98/07835 PCT/US97/14885 78 receptors are covalently linked heterotetramers (a 2

P

2 whereas in the latter, receptor dimerization is ligand dependent. Receptors whose kinase domains are always in close proximity may require a stronger autoinhibition mechanism than those receptors that associate only upon ligand binding (Taylor et al., 1995). Since most growth factor receptors undergo ligand-dependent dimerization and activation, the FGF receptor autoinhibition mechanism appears to be a more general one.

VI. Uses of the Crystals and Atomic Structure Coordinates The crystals of the invention, and particularly the atomic structure coordinates obtained therefrom, have a wide variety of uses. For example, the crystals described herein can be used as a starting material in any of the art-known methods of use for receptor and non-receptor tyrosine kinases. Such methods of use include, for example, identifying molecules that bind to the native or mutated catalytic domain of tyrosine kinases. The crystals and structure coordinates are particularly useful for identifying compounds that inhibit receptor and non-receptor tyrosine kinases as an approach towards developing new therapeutic agents (see, Levitzki and Gazit, 1995).

The structure coordinates described herein can be used as phasing models for determining the crystal structures of additional native or mutated tyrosine kinase domains, as well as the structures of co-crystals of such domains with ligands such as inhibitors, agonists, antagonists, and other molecules. The WO 98/07835 PCT/US97/14885 79 structure coordinates, as well as models of the threedimensional structures obtained therefrom, can also be used to aid the elucidation of solution-based structures of native or mutated tyrosine kinase domains, such as those obtained via NMR. Thus, the crystals and atomic structure coordinates of the invention provide a convenient means for elucidating the structures and functions of receptor and non-receptor tyrosine kinases.

For purposes of clarity and discussion, the crystals of the invention will be described by reference to specific FGFR1 exemplary crystals. Those skilled in the art will appreciate that the principles described herein are generally applicable to crystals of the tyrosine kinase domain of any cytoplasmic tyrosine kinase that undergoes ligand-induced dimerization or receptor tyrosine kinase, including but not limited to the tyrosine kinases of FIG. 6.

VII. Structure Determination for PTKs with Unknown Structure Using Structural Coordinates Structural coordinates, such as those set forth in Table 1, Table 2, Table 3, and. Table 4, can be used to determine the three dimensional structures of PTKs with unknown structure. The methods described below can apply structural coordinates of a polypeptide with known structure to another data set, such as an amino acid sequence, X-ray crystallographic diffraction data, or nuclear magnetic resonance (NMR) data. Preferred embodiments of the invention relate to-determining the three dimensional structures of PTKs and related polypeptides. These include receptor PTKs such as FGF- WO 98/07835 PCT/US97/14885 R, PDGF-R, KDR, CCK4, MET, TRKA, AXL, TIE, EPH, RYK, DDR, ROS, RET, LTK, ROR1, and MUSK. Non-receptor PTKs such as SRC, BRK, BTK, CSK, ABL, ZAP70, FES, FAK, JAK, and ACK can also be used in the methods described -herein.

Structures Using Amino Acid Homology Homology modeling is a method of applying structural coordinates of a polypeptide of known structure to the amino acid sequence of a polypeptide of unknown structure. This method is accomplished using a computer representation of the three dimensional structure of a polypeptide or polypeptide complex, the computer representation of amino acid sequences of the polypeptides with known and unknown structures, and standard computer representations of the structures of amino acids. Homology modeling comprises the steps of aligning the amino acid sequences of the polypeptides with and without known structure; (b) transferring the coordinates of the conserved amino acids in the known structure to the corresponding amino acids of the polypeptide of unknown structure; refining the subsequent three dimensional structure; and (d) constructing structures of the rest of the polypeptide.

One skilled in the art recognizes that conserved amino acids between two proteins can be determined from the sequence alignment step in step The above method is well known to those skilled in the art. Greer, 1985, Science 228, 1055. Blundell et al., 1988, Eur. J. Biochem. 172, 513. A computer program currently utilized for homology modeling by WO 98/07835 PCT/US97/14885 81 those skilled in the art is the Homology module in the Insight II modeling package distributed by Molecular Simulations Inc.

Alignment of the amino acid sequence is accomplished by first placing the computer representation of the amino acid sequence of a polypeptide with known structure above the amino acid sequence of the polypeptide of unknown structure. Amino acids in the sequences are then compared and groups of amino acids that are homologous amino acid side chains that are similar in chemical nature aliphatic, aromatic, polar, or charged) are grouped together. This method will detect conserved regions of the polypeptides and account for amino acid insertions or deletions.

Once the amino acid sequences of the polypeptides with known and unknown structures are aligned, the structures of the conserved amino acids in the computer representation of the polypeptide with known structure are transferred to the corresponding amino acids of the polypeptide whose structure is unknown. For example, a tyrosine in the amino acid sequence of known structure may be replaced by a phenylalanine, the corresponding homologous amino acid in the amino acid sequence of unknown structure.

The structures of amino acids located in nonconserved regions are to be assigned manually by either using standard peptide geometries or molecular simulation techniques, such as molecular dynamics. The final step in the process is accomplished by refining the entire structure using molecular dynamics and/or energy minimization.

WO 98/07835 PCT/US97/14885 82 The homology modeling method is well known to those skilled in the art and has been practiced using different protein molecules. The three dimensional structure of the polypeptide corresponding to the catalytic domain of a serine/threonine protein kinase, myosin light chain protein kinase, was homology modeled from the cAMP-dependent protein kinase catalytic subunit. Knighton et al., 1992, Science 258:130-135.

Structures Using Molecular Replacement Molecular replacement is a method of applying the X-ray diffraction data of a polypeptide of known structure to the X-ray diffraction data of a polypeptide of unknown sequence. This method can be utilized to define the phases describing the X-ray diffraction data of a polypeptide of unknown structure when only the amplitudes are known. X-P;OR is a commonly utilized computer software package used for molecular replacement. BrUnger, 1992, Nature 355:472-475.

AMORE

is another program used for molecular replacement.

Navaza, 1994, Acta Crystallogr. A50:157-163.

Preferably, the resulting structure does not exhibit a root-mean-square deviation of more than 3 A.

A goal of molecular replacement is to align the positions of atoms in the unit cell by matching electron diffraction data from two crystals. A program such as X-PLOR can involve four steps. A first step can be to determine the number of molecules in the unit cell and define the angles between them. A second step can involve rotating the diffraction data to define the orientation of the molecules in the unit cell. A third WO 98/07835 PCTIUS97/14885 83 step can be to translate the electron density in three dimensions to correctly position the molecules in the unit cell. Once the amplitudes and phases of the X-ray diffraction data is determined, an R-factor can be calculated by comparing electron diffraction maps calculated experimentally from the reference data set and calculated from the new data set. An R-factor between 30-50% indicates that the orientations of the atoms in the unit cell are reasonably determined by this method. A fourth step in the process can be to decrease the R-factor to roughly 20% by refining the new electron density map using iterative refinement techniques described herein and known to those or ordinary skill in the art.

Structures Using NMR Data Structural coordinates of a polypeptide or polypeptide complex derived from X-ray crystallographic techniques can be applied towards the elucidation of three dimensional structures of polypeptides from nuclear magnetic resonance (NMR) data. This method is used by those skilled in the art. Wuthrich, 1986, John Wiley and Sons, New York:176-199; Pflugrath et al., 1986, J. Molecular Biology 189:383-386; Kline et al., 1986, J. Molecular Biology 189:377-382. While the secondary structure of a polypeptide is often readily determined by utilizing two-dimensional NMR data, the spatial connections between individual pieces of secondary structure are not as readily determinable.

The coordinates defining a three-dimensional structure of a polypeptide derived from X-ray crystallographic WO 98107835 PCTIUS97/14885 84 techniques can guide the NMR spectroscopist to an understanding of these spatial interactions between secondary structural elements.in a polypeptide of related structure.

The knowledge of spatial interactions between secondary structural elements can greatly simplify Nuclear Overhauser Effect (NOE) data from twodimensional NMR experiments. Additionally, applying the crystallographic coordinates after the determination of secondary structure by NMR techniques only simplifies the assignment of NOEs relating to particular amino acids in the polypeptide sequence and does not greatly bias the NMR analysis of polypeptide structure.

Conversely, using the crystallographic coordinates to simplify NOE data while determining secondary structure of the polypeptide would bias the NMR analysis of protein structure.

As the analysis of polypeptide structure by NMR methods is a relatively new technique, the use of structural coordinates defining a PTK structure will most likely be utilized more frequently in the near future. As the method progresses, the three dimensional structure analysis of polypeptides of the same size as a PTK catalytic domain will become more frequent.

VIII. Structure-Based Design of Modulators of PTK Function Utilizing Structural Coordinates Structure-based modulator design and identification methods are powerful techniques that can involve searches of computer data bases containing a wide variety of potential modulators and chemical functional WO 98/07835 PCT/US97/14885 groups. The computerized design and identification of modulators is useful as the computer data bases contain more compounds than the chemical libraries, often by an order of magnitude. For reviews of structure-based drug design and identification see Kuntz et al., 1994, Acc.

Chem. Res. 27:117; Guida, 1994, Current Opinion in Struc. Biol. 4: 777; Colman, 1994, Current Opinion in Struc. Biol. 4: 868.

The three dimensional structure of a polypeptide defined by structural coordinates can be utilized by these design methods. The structural coordinates of Table 1, Table 2, Table 3, and Table 4 can be utilized by this method. In addition, the three dimensional structures of receptor and non-receptor PTKs determined by the homology, molecular replacement, and NMR techniques described herein can also be applied to modulator design and identification methods. Thus, the structures of receptor PTKs, FGF-R, PDGF-R, FLK, CCK4, MET, TRKA, AXL, TIE, EPH, RYK, DDR, ROS, RET, LTK, ROR1, and MUSK, can be utilized by the methods described herein. The structures of non-receptor PTKs, SRC, BRK, BTK, CSK, ABL, ZAP70, FES, FAK, JAK, and ACK, can also be utilized by the rational modulator design method.

Design by Searching Molecular Data Bases Onemethod of rational modulator design searches for modulators by docking the computer representation of compounds from a data base of molecules. Publicly available data bases include: a) ACD from Molecular Designs Limited WO 98/07835 PCTUS97/14885 86 b) NCI from National Cancer Institute c) CCDC from Cambridge Crystallographic Data Center d) CAST from Chemical Abstract Service e) Derwent from Derwent Information Limited f) Maybridge from Maybridge Chemical Company LTD g) Aldrich from Aldrich Chemical Company h) Directory of Natural Products from Chapman Hall One such data base (ACD distributed by Molecular Designs Limited Information Systems) contains, for example, 200,000 compounds that are synthetically derived or are natural products. Methods available to those skilled in the art can convert a data set represented in two dimensions to one represented in three dimensions.

These methods are enabled by such computer programs as CONCORD from Tripos Associates or DB-Converter from Molecular Simulations Limited.

Multiple methods of structure-based modulator design are known to those in the art. Kuntz et al., 1982, J. Mol. Biol. 162: 269; Kuntz et al., 1994, Acc. Chem. Res. 27: 117; Meng et al., 1992, J. Compt.

Chem. 13: 505; Bohm, 1994, J. Comp. Aided Molec. Design 8: 623.

A computer program widely utilized by those skilled in the art of rational modulator design is DOCK from the University of California in San Francisco. The general methods utilized by this computer program and programs like it are described in three applications below. More detailed information regarding some of these techniques can be found in the Molecular Simulations User Guide, 1995.

WO 98/07835 PCT/US97/14885 87 A typical computer program used for this purpose can comprise the following steps: remove the existing compound from the protein; dock the structure of another compound into the active-site using the computer program (such as DOCK) or by interactively moving the compound into the active-site; characterize the space between the compound and the active-site atoms; search libraries for molecular fragments which (i)can fit into the empty space between the compound and the active-site, and (ii) can be linked to the compound; and link the fragments found above to the compound and evaluate the new modified compound.

Part refers to characterizing the geometry and the complementary interactions formed between the atoms of the active-site and the compounds. A favorable geometric fit is attained when a significant surface area is shared between the compound and active-site atoms without forming unfavorable steric interactions.

One skilled in the art would note that the method can be performed by skipping parts and and screening a data base of many compounds.

Structure-based design and identification of modulators of PTK function can be used in conjunction with assay screening. As large computer data base of compounds (around 10,000 compounds) can be searched in a matter of hours, the computer based method can narrow the compounds tested as potential modulators of PTK function in cellular assays.

WO 98/07835 PCTIUS97/14885 88 The above descriptions of structure-based modulator design are not all encompassing and other methods are reported in the literature: CAVEAT: Bartlett et al.,1989, in "Chemical and Biological Problems in Molecular Recognition", Roberts, Ley, Campbell, M.M. eds.; Royal Society of Chemistry: Cambridge, pp182-196.

FLOG: Miller et al., 1994, J. Comp. Aided Molec. Design 8:153.

PRO Modulator: Clark et al., 1995, J. Comp.

Aided Molec. Design 9:13.

MCSS: Miranker and Karplus, 1991, Proteins: Structure, Function, and Genetics 11:29.

AUTODOCK: Goodsell and Olson, 1990, Proteins: Structure, Function, and Genetics 8:195.

GRID: Goodford, 1985, J. Med. Chem. 28:849.

Design by Modifying Compounds in Complex with PTKs Another way of identifying compounds as potential modulators is to modify an existing modulator in the polypeptide active-site. For example, the computer representation of modulators can be modified within the computer representation of a PTK active-site. Detailed instructions for this technique can be found in the Molecular Simulations User Manual, 1995 in LUDI. The computer representation of the modulator is modified by the deletion of a chemical group or groups or by the addition of a chemical group or groups.

Upon each modification to the compound, the atoms of the modified compound and active-site can be shifted in conformation and the distance between the modulator WO 98/07835 PCT/US97/14885 89 and the active-site atoms may be scored along with any complimentary interactions formed between the two molecules. Scoring-can be complete when a favorable geometric fit and favorable complementary interactions are attained. Compounds that have favorable scores are potential modulators of PTK function.

Design by Modifying the Structure of Compounds that Bind PTKs A third method of structure-based modulator design is to screen compounds designed by a modulator building or modulator searching computer program. Examples of these types of programs can be found in the Molecular Simulations Package, Catalyst. Descriptions for using this program are documented in the Molecular Simulations User Guide (1995). Other computer programs used in this application are ISIS/HOST, ISIS/BASE, ISIS/DRAW) from Molecular Designs Limited and UNITY from Tripos Associates.

These programs can be operated on the structure of a compound that has been removed from the active-site of the three dimensional structure of a compound-PTK complex. Operating the program on such a compound is preferable since it is in a biologically active conformation.

A modulator construction computer program is a computer program that may be used to replace computer representations of chemical groups in a compoundcomplexed with a PTK with groups from a computer data base. A modulator searching computer program is a computer program that may be used to search computer WO 98/07835 PCTIUS97/14885 representations of-compounds from a computer data base that have similar three dimensional structures and similar chemical groups as compound bound to a PTK.

A typical program can operate by using the following general steps: map the compounds by chemical features such as by hydrogen bond donors or acceptors, hydrophobic/lipophilic sites, positively ionizable sites, or negatively ionizable sites; add geometric constraints to the mapped features; and search data bases with the model generated in Those skilled in the art recognize that for indolinones, the important chemical features include, but are not limited to, a hydrogen bond donor, a hydrogen bond acceptor, and two hydrophobic points of contact. Those skilled in the art also recognize that not all of the possible chemical features of the compound need be present in the model of One can use any subset of the model to generate different models for data base searches.

IX. Organic Synthetic Techniques The versatility of computer-based modulator design and identification lies in the diversity of structures screened by the computer programs. The computer programs can search data bases that contain 200,000 molecules and can modify modulators already complexed with the enzyme with a wide variety of chemical WO 98/07835 PCT/US97/14885 91 functional groups. A consequence of this chemical diversity is that a potential modulator of PTK function may take a chemical form that is not predictable.

A

wide array of organic synthetic techniques exist in the art to meet the challenge of constructing these potential modulators of PTK function. Many of these organic synthetic methods are described in detail in standard reference sources utilized by those skilled in the art. One exanple of such a reference is March, 1994, Advanced Organic Chemistry; Reactions. Mechanisms.

and Structure, New York, McGraw Hill. Thus, the techniques required to synthesize a potential modulator of PTK function identified by computer-based methods are readily available to those skilled in the art of organic chemical synthesis.

X. Cellular Assays Measuring the Effect of a PTK Modulator in Signal Transduction Pathways Cellular assays can be used to test the activity of a potential modulator of PTK function as well as diagnose a disease associated with inappropriate

PTK

activity. A potential modulator of PTK function can be tested for activity in vitro by assays that measure the effect of a potential modulator on the autophosphorylation of a particular PTK over-expressed in a cell line. Thus, a modulator that acts as a potent inhibitor of the catalytic domain corresponding to a PTK would decrease the amount of autophosphorylation catalyzed by that PTK. Potential modulators could also be tested for activity in cell growth assays in vitro as well as in animal model assays in vivo.

WO 98/07835 PCT/US97/14885 92 In vivo assays are also useful for testing the bioactivity of a potential modulator designed by the methods of the invention.

Materials, methods, and experimental data for these assays are fully described in WO 96/40116 published on December 19, 1996, entitled "Indolinone Compounds for the Treatment of Disease". This application is incorporated herein by reference in its entirety, including all drawings, figures, and tables.

XI. Administration of Modulators of PTK Function as Therapeutics for Disease Methods of administering compounds to organisms as therapeutics for disease are fully described in WO 96/40116 published on December 19, 1996, entitled "Indolinone Compounds for the Treatment of Disease".

This application is incorporated herein by reference in its entirety, including all drawings, figures, and tables.

EXAMPLES

The examples below are non-limiting and are merely representative of various aspects and features of the present invention. The examples provide illustrative methods for obtaining crystalline forms of protein kinase polypeptides, methods for determining three dimensional structures of these protein kinase polypeptides, and methods for identifying modulators of protein kinases using the three dimensional structures of the protein kinases.

WO 98/07835 PCT/US97/14885 93 EXAMPLE 1: X-ray Crystallographic Structure Determination of FGFR1 Polypeptide Synthesis and Isolation A recombinant baculovirus was engineered to encode residues 456-765 of human FGFR1. A cleavable N-terminal histidine tag was incorporated to aid in protein purification. Three amino acid substitutions were introduced: Cys-488 to Ala, Cys-584 to Ser and Leu-457 to Val. The two cysteine substitutions were made to prevent the formation of disulfide-linked oligomers, which occurs for the native protein. The substitution Leu-457 to Val introduced a Ncol cloning site near Met- 456. The codon for Tyr-766 (TAC) was changed to a stop codon (TAG) and a HindIII-cloning site was generated following this stop codon. These substitutions were introduced into the full length human cDNA of FGFR1 in ml3MPI9 by site-directed mutagenesis according to the manufacturer's protocol (Amersham).

The resulting construct was digested with Ncol and HindIII and was ligated into appropriately digested pBlueBac HistagB (Invitrogen). Transfection of insect cells (Sf9) was performed with the BaculoGold transfection system according to the manufacturer's protocol (Pharmingen). Following identification of positive plaques, the recombinant baculovirus was amplified to high titer (5x10 7 virus particles/ml). Sf9 cells were grown in 175-cm 2 flasks to a density of 2- 3x10 7 per flask and infected with recombinant baculovirus with a multiplicity of infection (MOI) of After 48 hr, cells were harvested by centrifugation WO 98/07835 PCT/US97/14885 94 at 3,000g for 35 min at 4 0 C and then lysed in 25 mM HEPES (pH 150 mM NaC1, 10% glycerol, 1.5 mM MgC1 2 1 Triton.X-100, 10 gg/ml aprotonin, 10 Ag/ml leupeptin, and 1 mM phenylmethylsulfonyl fluoride (PMSF). Lysates were centrifuged in a Sorval RC (Dupont) for 1 hr at 4 0 C at 40,000g followed by ultracentrifugation in an XL-80 (Beckman) at 100,000g for 1 hr. After centrifugation, the clarified lysate was passed over a Ni 2 -chelating column (Pharmacia), and the bound histidine-tagged fusion protein was eluted with 100 mM imidazole (pH Pooled fractions were loaded onto a Mono Q anion exchange column (Pharmacia) and eluted with a NaCl gradient from 0 to 500 mM.

The fractions containing the fusion protein were concentrated in a Centricon-30 (Amicon), and the histidine tag was removed by overnight digestion with enterokinase (Biozyme) at 20 0 C. The digestion was terminated by the addition of aprotonin, leupeptin, PMSF, TPCK, and bovine pancreatic trypsin inhibitor (BPTI). The cleaved kinase domain was then separated from the histidine tag on a Superose 12 size-exclusion column (Pharmacia). The eluted kinase domain was further purified on a Mono Q column. The purified kinase domain was analyzed by N-terminal sequencing and mass spectrometry. Five amino acids (SAAGT) remained from the histidine tag. The predicted molecular mass was confirmed by mass spectrometry.

Crystal Growth Purified FGFR1 was concentrated to 20-50 mg/ml and exchanged into 10 mM Tris-HC1 (pH 10 mM NaCI, and 2 mM DTT using a Centricon-30. Crystals were grown at 4°C by vapor diffusion in hanging drops containing gl of 10 mg/ml protein solution and 2.0 Al of reservoir solution: 16% polyethylene glycol (PEG) 10000, 0.3 M

(NH

4 2

SO

4 5% ethylene glycol, and 100 mM bis-Tris (pH Crystals of native FGFR1 were soaked in 500 ml stabilizing solution [25% PEG 10000, 0.3 M (NH 4 2

SO

4 0.1 M Bis-Tris (pH 5% ethylene glycol] containing 3- [(3-(2-carboxyethyl)-4-methylpyrrol-2-yl)methylene]-2indolinone (1-5 mM) or 3-[4-(4-formylpiperazine-l-yl)benzylidenyl]-2-indolinone (1 mM) at 4 0 C for 24 to 48 hours. The final soaking concentration of DMSO was between 1 to The crystals cracked at higher concentrations of DMSO.

Co-crystals of FGFR1 with the inhibitors could also be obtained by vapor diffusion in hanging drops containing 2.0 .l of 10 mg/ml protein solution and .l of reservoir solution containing 1 mM carboxyethyl)-4-methylpyrrol-2-yl)methylene]-2indolinone and 3-[4-(4-formylpiperazine-l-yl- )benzylidenyl]-2-indolinone.

Co-crystals of FGFR1 complexed with AMP-PCP were obtained as described for the creation of native crystals, except that the protein solution additionally contained 10 mM AMP-PCP and 20 MM MgCl 2 Preparation Of Heavy Atom Derivative Crystals Heavy atom derivative crystals were obtained by soaking FGFR1 native crystals (C2-A form) in a solution containing ethylmercurithiosalicylic acid (thimerosal), h..l WO 98/07835 PCT/US97/14885 96 KAu(CN) 2 or 4-chloromercuribenzoic acid, as provided in Table 1, infra,, and containing 25% PEG 10000, 0.3M

(NH

4 2

SO

4 5% ethylene glycol or glycerol, and 100 mM bis-Tris (pH and were flash-cooled either in liquid nitrogen directly (Synchrotron) or in a dry nitrogen stream at -175 0 C (rotating anode).

Data Collection and Structure Determination For native crystals and crystals comprising the nucleotide analog AMP-PCP, data were collected either on a Rigaku RU-200 rotating anode operated at 50 kV and 100 mA (Cu Ka) and equipped with double-focusing mirrors and an R-AXIS IIC image plate detector, or at beamline X-4A at the National Synchrotron Light Source, Brookhaven National Laboratory. Synchrotron data (X=1.07A) were collected on Fuji image plates and read with a Fuji scanner. One cryo-cooled crystal was used for each of the data sets. To obtain cryo-cooled crystals, crystals were soaked in a cryo-protectant solution containing PEG 10000, 0.3 M (NH 4 2

SO

4 5% ethylene glycol or glycerol and 100 mM bis-Tris (pH and were flashcooled either in liquid nitrogen directly (synchrotron data) or in a dry nitrogen stream at -175 0 C (rotating anode data). All data were processed using DENZO and SCALEPACK. Otwinowski, 1993, "Oscillation data reduction program," Proceedings of the CCP4 Study Weekend, Sawyer et al., eds. (Daresbury, United Kingdom: SERC Daresbury Laboratory), 56-62.

For native crystals and crystals comprising the nucleotide analog AMP-PCP, a molecular replacement solution was found initially for the C2-B crystal form WO 98/07835 PCT/US97/14885 97 using an IRK search model that consisted of polyalanine with the common side chains for residues 993-1263 (FGFR1 residues 475-754), excluding residues 1094-1105 (kinase insert) and 1153-1170 (activation loop). With AMORE (Navaza, 1994, AmoRe: an automated package for molecular replacement," Acta Crystallogr. A50: 157-163), using of the structure factor amplitudes between 15.0 and A, one of the two molecules in the asymmetric unit was located. The correlation coefficient for the correct 1-molecule solution was 0.23 (versus 0.20 for the highest incorrect solution). This molecule was rigid body-refined in X-PLOR (BrUnger, 1992, X-PLOR (Version 3.1) Manual (New Haven, Conneticut: The Howeard Hughes Medical Institute and Department of Molecular Biophysics and Biochemistry, Yale Uiversity)), first as one rigid body unit, then as two units each comprising a lobe of the kinase. Rigid body refinement (12.0-3.5 A, F>3a) resulted in a relative rotation of the two lobes of -10° and an increase of the c.c. from 0.20 to 0.25.

The rigid body-refined molecule was then used as a new search model in AMORE, and this time both molecules in the asymmetric unit were located. The c.c. for the correct 2-molecule solution was 0.35 (versus 0.27 for the highest incorrect solution).

Multiple cycles of model building and refinement against 6.0-2.4 A data resulted in the addition to the model of many of the side chains and some of the missing polypeptide chain. Model building was performed using TOM/FRODO (Jones, 1985, "Diffraction methods for biological macromolecules. Interactive computer graphics: FRODO," Methods in Enzymology 115: 157-171) WO 98/07835 PCT/US97/14885 98 and conjugate-gradient minimization and simulated annealing were performed using X-PLOR. Bringer, supra.

At this stage, the R-value was 30% (free R-value of To help expedite model building and refinement, experimental phases were obtained. Because crystals grown in the presence of ethylene glycol were easier to manipulate than those grown in glycerol, several heavyatom derivative data sets were collected from C2-A crystals that had been soaked in various heavy atom solutions. The C2-B structure was subsequently refined against 6.0-2.4 A data to an R-value of 23.8% (free Rvalue of 30.4%) with r.m.s.d. values of 0.008 A for bond distances and 1.40 for bond angles.

Molecular replacement was used to locate the two FGFR1 molecules (designated FLGK-A and FLGK-B) in the asymmetric unit of the C2-A crystal form. Using AMORE with 80% of structure factor amplitudes between 15.0 and A and the C2-B model, the c.c. for the correct 2molecule solution was 0.62 (versus 0.35 for the highest incorrect solution). Heavy atom positions were determined from difference Fourier maps using the calculated phases from the partial model. Refinement of heavy atom parameters and phase determination were performed with MLPHARE (Otwinowski, 1991, "Maximum likelihood refinement of heavy atom parameters," Isomorphous replacement and anomolous Ssattering, Evans and Leslie eds. (Darsbury, United Kingdom: SERC Daresbury Laboratory), 56-62)). An initial molecular isomorphous replacement (MIR)-phased electron density map was calculated with data between 2.0. and 2.8 A resolution. This map was improved by solvent WO 98/07835 PCT/US97/14885 99 flattening, histogram matching, and non-crystallographic symmetry (NCS) averaging using DM (Cowtan, 1994, "Protein Crystallography," CCP4 and ESF-EACBM Newsletter (joint) 31: 34-38).

Refinement of the C2-A FGFR1 structure against A data proceeded by conjugate-gradient minimization and simulated annealing using X-PLOR. Tight NCS restraints were imposed until data to 2.0 A resolution were included in the refinement, at which point the restraints were lifted. An overall anisotropic B-value was calculated using X-PLOR and applied to the observed structure factors, reducing the R-value by Water molecules whose B-values refined to 70 A 2 were omitted from the subsequent refinement round. The average Bvalue is 37.5 A2 for all protein atoms, 35.4 A2 for protein atoms in FLGK-A, 39.7 A 2 for protein atoms in FLGK-B, and 40.2 A 2 for water molecules. The side chains for Cys-603 in FLGK-A and FLGK-B and for Met-534 in FLGK-B have been modeled in two different conformations.

Residues that are not included in the atomic model due to poor supporting electron density are for FLGK-A: 456- 463, 486-490, 501-504, 580-591, 763-765; and for FLG-B: 456-460, 501-504, 578-593, 646-651, 657-659, 762-765.

The positions of the two AMP-PCP molecules (one per FGFR1 molecule) were easily identified in 2Fobs(co,-c=1e Fcalc(GRI) difference Fourier maps. The AMP-PCP molecule bound to FLGK-B is less tightly bound and has been modeled with an occupancy of Table A summarizes the X-ray crystallography data sets of FGFR1 derivative crystals that were used to determine the structures of crystalline FGFR1 and WO 98/07835 WO 9807835PCT/IUS97/14885 100 crystalline FGFR1:AMP-PCP co-complex of the invention.

TABLE Data Collection and MIR Phasingy Summary X-ray source Resolution limit (A) Number of sites Conc. (mM)ftime (h) Total observations Unique reflections Completeness Signal (%1>3a) Native X-4A 2.0 4.8(19.7)r 122569 50771 97.3(96.3)c 80.7(50.3)c

AMP-PCP

RU-200 2.3 Thi-1h1 RU-200 2.6 4 0.1/24 4.5(23.3)c 5.5 91324 55456 31997 42820d 95.5(93.7)C 95.0 79.6(51.7)' 69.8 Thi-2a RU-200 2.8 7 0.1/48 9.8 59488 35538 8d 96.7 66.8 PCMB a RU-200 2.8 2 0.2/2 6.8 67988 18619 98.0 84.7 KAu(CN).

RU-200 2.8 2 5.0/72 6.8 45303 18202 97.7 77.6 Phasing power' RcuIi,B(%/) Overall FOMh 31.2 0.50 0 'Thi- 1, Thi-2; ethylmercurithiosalicylic acid (thimerosal); PCMB: 4-chloromercuribenzoic acid.

bp~m 100 x Eh~ I I/ZEjII(h) 'Value in parentheses is for the highest resolution shell.

dI(+h) and processed as independent reflections. Anomalous scattering contributions were included.

e 100 x I IFP(h)±FP(h)jIF~pH(h)j I/EhIF,(h)I, where Fp and FPH are the native and derivative structure factors, respectively. fPhasing power: r.m.s. heavy atom structure factor r.m.s. lack of closure (for acentric reflections from 20.0 to 2.84) 9R~,=100 x EII FpH(h)IFH(C&,jh)I/EhIjFpH(h)±FP(h)I (for centric reflections from 20.0 to 2.8A).

'Figure of merit: f P(4O)exp(i4O)d4)/ f P(4)d(4O), where P is the probability distribution of.the phase angle WO 98/07835 PCT/US97/14885 101 For crystals comprising FGFR1 and compounds 1 and 2, data were collected on a Rigaku RU-200 rotating anode (Cu Ka) operating at 50 kV and 100 mA and equipped with double-focusing mirrors and an R-AXIS IIC image plate detector. One cryo-cooled crystal was used for each of the data sets. Crystals were soaked in a cryo-protectant [25% PEG 10000, 0.3 M ethylene glycol, 100 mM bis-Tris (pH and 1 mM: 3- [(3-(2-carboxyethyl)-4-methylpyrrol-5-yl)methylene]-2indolinone (hereafter referred to as compound 1) or 3- [4-(4-formylpiperazine-l-yl-)benzylidenyl]-2-indolinone (hereafter referred to as compound 2) and flash-cooled in a dry nitrogen stream at -175 0 C. Data were processed using DENZO and SCALEPACK. Otwinowski, 1993, Proceedings of the CCP4 Study Weekend (Daresbury, United Kingdom: SERC Daresbury Laboratory) pp 56-62.

A summary of the data collection parameters are included in the following Table 6: TABLE6 Resolution Observa- Complete- Redundan- Rym 8 Signal limit tions ness cy ol) compound 2.5 93535 97.6(96.1) 2.7 6.8 11.8 1 (23.0) compound 2.4 94093 99.1(97.9) 3.3 6.3 11.4 2 (32.2) compound 1 structure: 550 residues, 252 water molecules, 2 compound I molecules (4589 atoms) compound 2 structure: 550 residues, 248 water molecules, 2 compound 2 molecules (4646 atoms) Structure Analyses Atomic superpositions were performed with TOSS WO 98/07835 PCT/US97/14885 102 (Hendrickson, 1979). Per residue solvent accessible surface calculations were done with X-PLOR. The surface area buried in a dimer interface was calculated with GRASP (Nicholls et al., 1991) using a probe radius of 1.4 A. The stereochemical quality of the atomic model was monitored using PROCHECK (Laskowski et al., 1993, PROCHECK: a computer program to check the stereochemical quality of protein structures," J. Appl. Cryst. 26: 283- 291). As defined in PROCHECK, 93% of the residues in the model have main-chain torsion angles in the most favored Ramachandran regions. There are no residues in disallowed regions, and three residues in generously allowed regions: Arg-622 in FLGK-A and FLGK-B and Arg- 554 in FLGK-A. The overall G-factor score is 0.42.

Table 7 summarizes the X-ray crystallography refinement parameters of the structures of crystalline FGFR1 and crystalline FGFR1:AMP-PCP co-complex of the invention. Table 8 summarizes the X-ray crystallography refinement parameters for the FGFRl/compound complexes.

TABLE 7 Refinement Parameters FGFRI: 550 residues, 252 water molecules (4589 atoms) FGFR1:AMP-PCP: 550 residues, 238 water molecules, 2 AMP-PCP molecules (4638 atoms) Model d-spacings Reflection R-value' R.m.s.d.

s bonds angles B-valuesb (A2) FGFRI: 6.0-2.0 42548 21.3 (26.2) c 0.008 1.3 1.6 FGFRI:AMP-PCP: 6.0-2.3 26729 20.1 (27.5)c 0.009 1.4 1.7 "R-value 100 x IFob,(h)l IF,(h) I IhIFb,(h) for reflections with Fobs> 2 o.

WO 98/07835 PCT/US97/14885 103 bFor bonded protein atoms.

cValue in parentheses is the free R-value (BrUinger, 1993) determined from 5% of the data.

TABLE 8 Model d-spacings Reflec- R- bonds angles Btions value' values'

(A

2 compound 6.0-2.4 42548 19.7 0.008 1.3 1.6 1 2 7 0 )k compound 6.0-2.5 26729 20.0 0.008 1.4 1.7 2 (28.0)k Rym 100 x S,S, j1 1 I(h)°l ShS, I,(h) cValue in parentheses is for the highest resolution shell.

'R-value 100 x S, jI|F(h)| IF,(h)ll S, IF,(h)l, where Fo and F, are the observed and calculated structure factors, respectively (Fo 2s).

jFor bonded protein atoms.

kValue in parentheses is the free R-value determined from 5% of the data.

Atomic Structural Coordinates Tables 1 and 2 provide the atomic structural coordinates of unphosphorylated FGFR1 and unphosphorylated FGFR1:AMP-PCP co-complex, respectively.

In the Tables, coordinates for both of the FGFR1 molecules of the dimer comprising the asymmetric unit are provided. The amino acid residue numbers coincide with those used in FIG. 3. In the first FGFR1 molecule of the dimer the residue number is preceded by a 1, residue number 464 of the first FGFR1 molecule of the dimer is denoted by "1464". Tables 3 and 4 provide the atomic structural coordinates of FGFR1 in complex with indolinone compounds found to inhibit FGFR1 function.

WO 98/07835 PCT/US97/14885 104 The following abbreviations are used in the Tables: "Atom Type" refers to the element whose coordinates are provided. The first letter in the column defines the element.

refers to amino acid.

"1XY d" provide the Cartesian coordinates of the element.

is a thermal factor that measures movement of the atom around its atomic center.

"OCC" refers to occupancy, and represents the percentage of time the atom type occupies the particular coordinate. OCC values range from 0 to i, with 1 being 100%.

"P or "PRT2" relate to occupancy, with PRTI designating the coordinates of the atom when in the first conformation and PRT2 designating the coordinates of the atom when in the second or alternate conformation.

Structural coordinates for FGFR1 may be modified by mathematical manipulation. Such manipulations include, but are not limited to, crystallographic permutations of the raw structure coordinates, fractionalization of the raw structure coordinates, integer additions or subtractions to sets of the raw structure coordinates, inversion of the raw structure coordinates and any combination of the above.

In addition, the structural coordinates can be slightly modified and still render nearly identical three dimensional structures. Therefore, a measure of a unique set of structural coordinates is the root-meansquare deviation of the resulting structure. Structural 105 coordinates that render three dimensional structures that deviate from one another by a root-mean-square deviation of less than 1.5 A may be viewed as identical.

EXAMPLE 2: Computer-Based Design of modulators of PTK Function Potential modulators of PTK function were designed and identified by operating the program Catalyst on the structure of 3-[(3-(2-carboxyethyl)-4-methylpyrrol-2yl)methylene]-2-indolinone. The chemical features constraining the search model include a hydrogen bond donor, a hydrogen bond acceptor, and two hydrophobic points of contact. Approximately 40 compounds were identified as potential modulators of PTK function using this method.

The compounds identified by the method as potential modulators of PTK function were commercially available.

These compounds were then tested for their ability to inhibit the FLK PTK in an enzyme linked immunosorbant assay (ELISA). The method of performing this assay is taught in WO .96/40116, entitled "Indolinone Compounds for the Treatment of Disease," published on December 19, 1996, invented by Tang et al., incorporated by reference herein in its entirety, including all figures, drawings, and tables. Flk-1 specific antibodies can be prepared from the following protocol: 1. Prepare a Tresyl-Activated Agarose/Flk-l-D column by incubating 10 ml of Tresyl-Activated Agarose with 20 mg of purified GST-Flk-1-D fusion protein WO 98/07835 PCIUS97/14885 in 100mM sodium bicarbonate (pH 9.6) buffer overnight at 4 0

C.

2. Wash the column once with PBS.

3. Block the excess sites on the column with 2 M glycine for 2 hours at 4 0

C.

4. Wash the column with PBS.

Incubate the column with Rabbit anti-Flk-1D production bleed for 2 hours at 4C.

6. Wash the column with PBS.

7. Elute antiserum with 100 mM Citric Acid, pH3.0 and neutralize the eluate immediately with 2 M Tris, pH 8. Dialyize the eluate against PBS overnight at 4oC with 3 changes of buffer (sample to buffer ratio is 1:100).

9. Adjust the dialyized antiserum to 5% glycerol and store at -80 0 C in small aliquotes.

The Flk-1 ELISA can include a 2,2-azino-bis(3ethylbenz-thiazoline-6-sulfonic acid (ABTS) solution, which can comprise 100mM citric acid (anhydrous), 250 mM Na 2 HPO, (pH 0.5 mg/ml ABTS (Sigma catalog no. A- 1888). The solution is most appropriately stored in dark at 4"C until ready for use.

The FLK-1 specific antibodies can also be purchased from Santa Cruz Biotechnology (Catalog No. SC-504).

Four of the forty compounds identified as potential modulators of PTK function were potent modulators of FLK function. These molecules have the following structures: WO 98/07835 PCT/US97/14885 107 S--N S-

CI

F

F

'F

F

F

F

3

N-N

The modulators inhibit the FLK protein kinase with the following ICs 5 values: TABLE 9 Compound FLK kinase FLK kinase EGFR IGF- R ICso ICo ICo ICso (AM) compounds compounds tested at 100 pM tested at 1 14.8 14 >100 >100 2 15.7 10.6 >100 >100 3 21.4 16.6 68 30.9 4 22.9 16.4 >100 >100 The invention illustratively described herein may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have WO 98/07835 PCTIUS9714885 108 been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Those references not previously incorporated.herein by reference, including both patent and non-patent references, are expressly incorporated herein by reference for all purposes. Other embodiments are within the following claims.

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TELEPHONE: (213) 489-1600 TELEFAX: (213) 955-0440 TELEX: 67-3510 INFORMATION FOR SEQ ID NO:1: SEQUENCE CHARACTERISTICS: LENGTH: 310 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL:

NO

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: Met Leu Ala Gly Val Ser Glu Tyr Glu Leu Pro Glu Asp Pro Arg Trp 1 5 10 Glu Leu Pro Arg Asp Arg Leu Val Leu Gly Lys Pro Leu Gly Glu Gly 25 Cys Phe Gly Gin Val Val Leu Ala Glu Ala Ile Gly Leu Asp Lys Asp 40 Lys Pro Asn Arg Val Thr Lys Val Ala Val Lys Met Leu Lys Ser Asp 55 Ala Thr Glu Lys Asp Leu Ser Asp Leu Ile Ser Glu Met Glu Met Met 70 75 80 Lys Met Ile Gly Lys His Lys Asn Ile Ile Asn Leu Leu Gly Ala Cys 90 Thr Gin Asp Gly Pro Leu Tyr Val Ile Val Glu Tyr Ala Ser Lys Gly 100 105 110 Asn Leu Arg Glu Tyr Leu Gin Ala Arg Arg Pro Pro Gly Leu Glu Tyr 115 120 125 Cys Tyr Asn Pro Ser His Asn Pro Glu Glu Gin Leu Ser Ser Lys Asp 130 135 140 WO 98/07835 PCTIUS97/14885 111 Leu Val Ser Cys Ala Tyr Gin Val Ala Arg Gly Met Glu Tyr Leu Ala 145 150 155 160 Ser Lys Lys Cys Ile His Arg Asp Leu Ala Ala Arg Asn Val Leu Val 165 170 175 Thr Glu Asp Asn Val Met Lys Ile Ala Asp Phe Gly Leu Ala Arg Asp 180 185 190 Ile His His Ile Asp Tyr Tyr Lys Lys Thr Thr Asn Gly Arg Leu Pro 195 200 205 Val Lys Trp Met Ala Pro Glu Ala Leu Phe Asp Arg Ile Tyr Thr His 210 215 220 Gin Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu Ile Phe Thr 225 230 235 240 Leu Gly Gly Ser Pro Tyr Pro Gly Val Pro Val Glu Glu Leu Phe Lys 245 250 255 Leu Leu Lys Glu Gly His Arg Met Asp Lys Pro Ser Asn Cys Thr Asn 260 265 270 Glu Leu Tyr Met Met Met Arg Asp Cys Trp His Ala Val Pro Ser Gin 275- 280 285 Arg Pro Thr Phe Lys Gin Leu Val Glu Asp Leu Asp Arg Ile Val Ala 290 295 300 Leu Thr Ser Asn Gin Glu 305 310 INFORMATION FOR SEQ ID NO:2: SEQUENCE CHARACTERISTICS: LENGTH: 315 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Ser Ala Ala Gly Thr Met Val Ala Gly Val Ser Glu Tyr Glu Leu Pro 1 5 10 Glu Asp Pro Arg Trp Glu Leu Pro Arg Asp Arg Leu Val Leu Gly Lys 25 WA on Qg,7QIK PCT1US97/14885 112 Pro Leu Gly Glu Giy Ala Phe Gly Gin Val Val Leu Ala Glu Ala Ile Gly Leu 50 Met Leu Glu Met Leu Leu Tyr Ala Pro Gly 130 Leu Ser 145 Met Giu Arg Asn Gly Leu Asn Gly 210 Arg Ile 225 Trp Giu Glu Glu Ser Asn Ala Val 290 Asp Lys Glu Gly Ser 115 Leu Ser Tyr Val Al a 195 Arg Tyr Ile Leu Cys 275 Pro Lys Ser Met Ala 100 Lys Glu Lys Leu Leu 180 Arg Leu Thr Phe Phe 260 Thr Ser Asp Asp Met Cys Gly Tyr Asp Ala 165 Val Asp Pro His Thr 245 Lys Asn Gin Lys Al a 70 Lys Thr Asn Ser Leu 150 Ser Thr Ile Val Gin 230 Leu Leu Glu Arg Pro 55 Thr Met Gin Leu Tyr 135 Val Lys Glu His Lys 215 Ser Gly Leu Leu Pro 295 Asn Giu Ile Asp Arg 120 Asn Ser Lys Asp His 200 Trp, Asp Gly Lys Tyr 280 Thr Arg Lys Gly Gly 105 Giu Pro Cys Cys Asn 185 Ile Met Val Ser Glu 265 Met Phe Val Asp Lys 90 Pro Tyr Ser Ala Ile 170 Val Asp Ala Trp Pro 250 Gly Met Lys Thr Leu 75 His Leu Leu His Tyr 155 His Met Tyr Pro Ser 235 Tyr His Met Gin Lys Ser Lys Tyr Gin Asn 140 Gin Arg Lys Tyr Giu 220 Phe Pro Arg Arg Leu 300 Val Ala Asp Leu Asn Ile Val Ile 110 Ala Arg 125 Pro Glu Val Ala Asp Leu Ile Ala 190 Lys Lys 205 Ala Leu Gly Val Giy Val Met Asp 270 Asp Cys 285 Val Glu Val Lys Ile Ser Ile Asn Val Glu Arg Pro Glu Gin Arg Gly 160 Ala Ala 175 Asp Phe Thr Thr Phe Asp Leu Leu 240 Pro Val 255 Lys Pro Trp His Asp Leu Asp Arg Ile Val Ala Leu Thr Ser Asn Gin Glu 305 310 315 WO 98/07835 PCT/US97/14885 113 INFORMATION FOR SEQ ID NO:3: SEQUENCE CHARACTERISTICS: LENGTH: 351 amino acids (i TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein .ii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: Met Arg Gly Ser His His His His His Hi 1 5 10 Gly Gly Gin Gin Met Gly Arg Asp Leu Ty 25 Pro Ser Ser Arg Ser Ala Ala Gly Thr Me 40 Tyr Glu Leu Pro Glu Asp Pro Arg Trp Gl Val Leu Gly Lys Pro Leu Gly Glu Gly Al 70 Ala Glu Ala Ile Gly Leu Asp Lys Asp Ly 90 Val Ala Val Lys Met Leu Lys Ser Asp Al 100 105 Asp Leu Ile Ser Glu Met Glu Met Met Ly 115 120 Asn Ile Ile Asn Leu Leu Gly Ala Cys Th 130 135 Val Ile Val Glu Tyr Ala Ser Lys Gly As 145 150 Ala Arg Arg Pro Pro Gly Leu Glu Tyr Se 165 17 Pro Glu Glu Gin Leu Ser Ser Lys Asp Le 180 185 s Gly Met Ala r t u a s a s .r n r 0 u Asp Val Leu Phe 75 Pro Thr Met Gin -Leu 155 Tyr Val Asp Gly Arg Gln Arg Lys Gly 125 Gly Glu Pro Cys Ser Asp Val Asp Val Val Asp 110 Lys Pro Tyr Ser Ala 190 Met Lys Ser Arg Val Thr Leu His Leu Leu His 175 Tyr Thr Asp Glu Leu Leu Lys Ser Lys Tyr Gin 160 Asn Gin Val Ala Arg Gly Met Glu Tyr Leu Ala Ser Lys Lys Cys Ile His Arg 195 200 2nr WO 98/07835 PCTIUS97/14885 114 Asp Leu Ala Ala Arg Asn Val Leu Val Thr Glu Asp Asn Val Met Lys Ile 225 Lys Ala Asp Phe Gly Leu 230 Gly Arg Asp Ile His 235 Lys Ile Asp Tyr Lys Thr Thr Asn 245 Arg Arg Leu Pro Trp Met Ala Pro Glu 255 Ala Leu Phe Gly Val Leu 275 Gly Val Pro Asp 260 Leu Ile Tyr Thr His 265 Thr Ser Asp Val Trp Giu Ile Phe 280 Phe Leu Gly Gly Ser 285 Glu Trp Ser Phe 270 Pro Tyr Pro Gly His Arg Val Giu Glu 290 Met Asp Leu 295 Cys Lys Leu Leu Lys Pro Ser 305 Asp Val Asn 310 Thr Asn Glu Leu 315 Pro Met Met Met Arg 320 Leu Cys Trp His Ala Val 325 Glu Asp Leu Asp Arg 340 Pro Ser Gin Thr Phe Lys Gin 335 Ile Val Ala Leu Thr Ser Asn Gin Glu INFORMATION FOR SEQ ID NO:4: SEQUENCE CHARACTERISTICS: LENGTH: 933 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA to rRNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: ATGCTAGCAG GGGTCTCTGA GTATGAGCTT CCCGAAGACC

CTCGCTGGGA

GACAGACTGG TCTTAGGCAA ACCCCTGGGA GAGGGCTGCT

TTGGGCAGGT

GAGGCTATCG GGCTGGACAA GGACAAACCC AACCGTGTGA

CCAAAGTGGC

TTGAAGTCGG ACGCAACAGA GAAAGACTTG TCAGACCTGA

TCTCAGAAAT

AAGATGATCG GGAAGCATAA GAATATCATC AACCTGCTGG

GGGCCTGCAC

CCCTTGTATG TCATCGTGGA GTATGCCTCC AAGGGCAACC

TGCGGGAGTA

CGGAGGCCCC CAGGGCTGGA ATACTGCTAC AACCCCAGCC

ACAACCCAGA

GCTGCCTCGG

GGTGTTGGCA

TGTGAAGATG

GGAGATGATG

GCAGGATGGT

CCTGCAGGCC

GGAGCAGCTC

120 180 240 300 360 420 WO 98/07835 WO 9807835PCTIUS97/1488

TCCTCCAAGG

TCCAAGAAGT

GTGATGAAGA

AAGACAACCA

ATCTACACCC

CTGGGCGGCT

GGTCACCGCA

TGCTGGCATG

CGCATCGTGG

ACCTGGTGTC

GCATACACCG

TAGCAGACTT

ACGGCCGACT

ACCAGAGTGA

CCCCATACCC

TGGACAAGCC

CAGTGCCCTC

CCTTGACCTC

CTGCGCCTAC

AGACCTGGCA

TGGCCTCGCA

GCCTGTGAAG

TGTGTGGTCT

CGGTGTGCCT

CAGTAACTGC

ACAGAGACC C

CAACCAGGAG

115

CAGGTGGCCC

GCCAGGAATG

CGGGACATTC

TGGATGGCAC

TTCGGGGTGC

GTGGAGGAAC

ACCAACGAGC

ACCTTCAAGC

TAG

GAGGCATGGA

TCCTGGTGAC

ACCACATCGA

CCGAGGCATT

TCCTGTGGGA

TTTTCAAGCT

TGTACATGAT

AGCTGGTGGA

GTATCtGGCC

AGAGGACAAT

CTACTATAAA

ATTTGACCGG

GATCTTCACT

GCTGAAGGAG

GATGCGGGAC

AGACCTGGAC

480 540 600 660 720 780 840 900 933 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 1056 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID ATGCGGGGTT CTCATCATCA TCATCATCAT GGTATGGCTA

ATGGGTCGGG

ACCATGGTAG

CGGGACAGAC

GCAGAGGCTA

ATGTTGAAGT

ATGAAGATGA

GGTCCCTTGT

GCCCGGAGGC

CTCTCCTCCA

ATCTGTACGA

CAGGGGTCTC

TGGTCTTAGG

TCGGGCTGGA.

CGGACGCAAC

TCGGGAAGCA

ATGTCATCGT

CCCCAGGGCT

AGGACCTGGT

CGATGACGAT

TGAGTATGAG

CAAACCCCTG

CAAGGACAAA

AGAGAAAGAC

TAAGAATATC

GGAGTATGCC

GGAATACTCC

GTCCTGCGCC

AAGGATCCGA

CTTCCCGAAG

GGAGAGGGCG

CCCAACCGTG

TTGTCAGACC

ATCAACCTGC

TCCAAGGGCA

TACAACCCCA

TACCAGGTGG

GCATGACTGG

GCTCGAGATC

ACCCTCGCTG

CCTTTGGGCA.

TGACCAAAGT

TGATCTCAGA

TGGGGGCCTG

ACCTGCGGGA

GCCACAACCC

CCCGAGGCAT

TGGACAGCAA

TGCAGCTGGT

GGAGCTGCCT

GGTGGTGTTG

GGCTGTGAAG

AATGGAGATG

CACGCAGGAT

GTACCTGCAG

AGAGGAGCAG

GGAGTATCTG

120 180 240 300 360 420 480 540 600 GCCTCCAAGA AGTGCATACA CCGAGACCTG GCAGCCAGGA ATGTCCTGGT GACAGAGGAC WO 98/07835 PCTIUS97/14885

AATGTGATGA

AAAAAGACAA

CGGATCTACA

ACTCTGGGCG

GAGGGTCACC

GACTGCTGGC

GACCGCATCG

AGATAGGAGA

CCAACGGCCG

CCCACCAGAG

GCTCCCCATA

GCATGGACAA

ATGCAGTGCC

TGGCCTTGAC

CTTTGGCCTC

ACTGCCTGTG

TGATGTGTGG

CCCCGGTGTG

GCCCAGTAAC

CTCACAGAGA

CTCCAACCAG

116 GCACGGGACA TTCACCACAT AAGTGGATGG CACCCGAGGC TCTTTCGGGG TGCTCCTGTG CCTGTGGAGG AACTTTTCAA TGCACCAACG AGCTGTACAT CCCACCTTCA AGCAGCTGGT

GAGTAG

CGACTACTAT

ATTATTTGAC

GGAGATCTTC

GCTGCTGAAG

GATGATGCGG

GGAAGACCTG

720 780 840 900 960 1020 1056 WO 98/07835 PCT/US97/1488 117 TABLE 1 Atom Atom A.A A.A No. Type No.

Z OCC B

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

I

N

CA

CB

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

CD

OE1 OE2

C

0

N

CA

CB

CG

ODI

OD2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PRO

PRO

PRO

PRO

PRO

PRO

PRO

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ARG

ARG

ARG

1464 1464 1464 1464 1464 1465 1465 1465 1465 1465 1465 1465 1465 1466 1466 1466 1466 1466 1466 1466 1467 1467 1467 1467 1467 1467 1467 1467 1467 1468 1468 1468 1468 1468 1468 1468 1468 1469 1469 1469 1469 1469 1469 1469 1470.

1470 1470 -13.639 -12.479 -11.400 -11.914 -11.845 -11.562 -11.018 -10.236 -8.719 -8.346 -8.061 -12.092 -13 .187 -11. 802 -10.597 -12.741 -12.110 -10.629 -12.846 -11.847 -14.060 -14.268 -15.744 -16.375 -17.819 -18.446 -18.314 -13.838 -13.899 -13.299 -12.883 -11.384 -10.985 -11.833 -9.817 -13.252 -12.481 -14.435 -15.354 -14.971 -16.244 -16.665 -14.012 -14.085 -13.106 -12.139 -11.301 16. 975 17.105 17.974 15.738 15.407 14.925 13.599 13.066 13.196 14.654 12.671 12.594 12.590 11.748 11.793 10.727 10.262 10.459 9.595 9.174 9.121 8.053 7.965 9.280 9.145 8.071 10.109 6.714 6.511 5.854 4.516 4.424 3.072 2.159 2.916 3.564 3.364 2.939 3.091 1.987 1.473 2.630 0.848 0.251 0.556 -0.520 -0.707 8. 571 7.695 8.349 7.319 6.136 8.310 8. 037 9.235 9.130 8. 891 10.395 7 .656 8 .219 6.657 5.810 6.189 4. 878 5.135 7.201 7.788 7.429 8.377 8.746 9.098 9.596 9.378 10.230 7.801 6.591 8.659 8.262 7.975 7.408 7.359 7.003 9.384 10.336 9.268 8.120 10.244 9.553 8.690 10.563 11.636 9.631 9.810 8.533 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1 .00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 54 .29 52.62 54 .64 49.74 52 04 44 41.04 40.18 43.70 46.74 40.72 39.18 38.05 37.20 36.41 36.13 37.50 36.20 35.61 35.18 35.38 35.43 41.10 48.25 50.24 52.82 51.26 32.65 35.'06 30.46 28.85 29.34 27.57 27.78 30.64 29.29 27.76 28.99 28.09 30.01 33 .33 30.53 28.96 28.52 27.59 27.37 28.84 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 118

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

53 54 55 57 58 61 64 65 66 68 69 70 71 72 73 74 75 77 78 79 80 81 82 84 85 86 87 88 89 90 91 92 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 110 ill 112 113 114 116 117

CG

CD

NE

Cz NH1 NH2

C

0

N

CA

CB

CG

CD2 CE2 CE3 CD1

NEI

CZ2 CZ3 CH2

C

0

N

CA

CB

CG

CD

OE1 OE2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

CD

NE

Cz NH1

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

1470 1470 1470 1470 1470 1470 1470 1470 1471 1471 1471 1471 1471 1471 1471 1471 1471 1471 1471 1471 1471 1471 1472 1472 1472 1472 1472 1472 1472 1472 1472 1473 1473 1473 1473 1473 1473 1473 1473 1474 1474 1474 1474 1474 1474 1474 1475 1475 1475 1475 1475 1475 1475 1475 -12.049 -11.137 -10.489 -9.603 -9.241 -9.067 -11.180 -10.757 -10.909 -9.940 -8.729 -8.044 -7.156 -6 .782 -6.642 -8.166 -7.413 -5.912 -5.778 -5.424 -10.371 -9.664 -11.521 -11.981 -13.245 -13.552 -12.692 -12.134 -12.596 -12.217 -12.763 -11.750- -11.962 -10.645 -10.750 -11.323 -9.390 -12.546 -12.122 -13.610 -14.435 -14.215 -15.368 -15.768 -13 .173 -12 .427 -13.107 -12.149 -12.362 -12.178 -12.048 -11.733 -10.503 -9.470 279 352 -0.068 0. 151 -0.828 1. 359 -0.285 -1.230 0. 977 1.314 1. 944 0. 976 060 -0.776 -0.460 0.860 192 -1.866 -1.545 -2.237 2.223 2.321 2. 874 3.823 4. 534 5.869 7. 042 7. 009 8. 024 3.269 2.196 3.991 3.608 3.266 3. 025 1.636 3.183 4.856 5.973 4.703 3.500 5.870 5.251 4.097 6.528 5.841 7.849 8.588 10.083 10.536 12.027 12.317 12.501 12.447 7.317 6.068 5.793 4.823 3. 999 4. 686 10.981 11.641 11.280 12.306 11. 609 10. 728 11. 144 9. 989 12 .389 9. 374 8. 922 10. 036 12.435 11.266 13.440 14.442 13.293 14.297 13.799 14.520 14. 054 12. 938 14. 801 15. 701 15.861 16. 711 18. 104 18. 817 20.337 20. 642 21. 000 18. 740 18.411 19.554 19.770 20.207 21. 003 20. 154 21.124 21.828 21. 097 21. 900 21. 743 20. 342 20.206 1.00 1.00 1.00 1.00 1.00 1.oo 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00.

30.57 26.71 31.26 32.60 33.19 28.65 29.21 28.47 27.80 28.62 24.97 24.86 28.00 29.23 26.59 27.23 30.10 28.70 27.18 27.23 28.42 26.48 28.62 27.16 28.89 29.09 26.43 28.59 27.28 25.10 26.48 24.65 26.27 28.24 27.23 25.23 26.33 26.52 25.16 28.52 29.65 29.18 28.58 28.17 29.75 31.78 30.76 32.26 31.58 37.54 36.96 40.07 37.59 34.89 18.813 1.00 18.352 1.oo 19.186 1.00 SSSD/55145. v01 WO 98/07835 PCTIUS97/14885 119

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

-ATOM

ATOM

ATOM

120 123 124 125 127 128 129 130 131 132 133 134 136 137 138 139 140 142 143 146 149 150 151 153 154 155 156 157 158 159 160 162 163 164 165 166 167 168 170 171 172 173 174 175 176 177 179 180 181 182 184 185 186 187 NI{2

C-

0

N

CA

CB

CG

ODI

0D2

C

0

N

CA

CB

CG

CD

NE

cz NH1 N'H2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

C

0

N

CA

CB

CG

CD

ARG

ARG

ARG

AS P

ASP

ASP

ASP

AS P

ASP

AS P

ASP

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

VAL

VAL

VAL

VAL

VAL

VAL

VAL

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

GLY

GLY

GLY

GLY

LYS

LYS

LYS

LYS

LYS

1475 1475 1475 1476 1476 1476 1476 1476 1476 1476 1476 1477 1477 1477 1477 1477 1477 1477 1477 1477 1477 1477 1478 1478 1478 1478 1478 1478 1478 1478 1479 1479 1479 1479 1479 1479 1479 1480 1480 1480 1480 1480 1480 1480 1480 1481 1481 1481 1481 1482 1482 1482 1482 1482 -10 .308 -12.173 -11.135 -13.356 -13.498 -14 .967 -15.851 -15.412 -17.003 -12.922 -12.923 -12.478 -11.889 -12 .214 -13.693 -14.366 -14.596 -14.845 -14.906 -15.024 -10 .373 -9.679 -9.856 -8.426 -7.964 -6.498 -6 .059 -6.335 -8.054 -8.366 -7.442 -7 .008 -7.041 712 -8.404 -5.577 -4 .622 -5.439 -4 .132 -4.298 -4 .991 -5.135 -4.200 -3.211 -3 .621 958 -1.016 0.296 0 .360 1.349 2 .697 3 .636 5 .115 5. 938 12 .669 8.261 8 .318 7 .958 7.647 7. 759 6. 704 6.015 6. 558 6.292 5. 928 5. 527 4.221 3.262 2.965 2.365 3.372 3.102 1.846 4.102 4.338 3.362 5. 544 5.739 6.360 6.291 4.833 7. 048 6.625 7.815 6. 023 6.745 5.829 6.627 5.163 7.224 6.443 8.506 9.086 10. 421 10. 369 11.774 9.508 9.233 9.739 8. 816 8.889 9.617 10.638 9. 070 9.627 8.776 9.023 7.831 17. 049 23 .371 24. 036 23 .889 25.307 25. 740 25.115 24. 179 25.563 25. 701 26. 878 24. 711 24. 961 23. 809 23. 580 24. 809 25. 838 27 .113 27. 542 27. 961 25. 105 25. 365 24. 978 25. 054 23. 737 23 .331 23 .192 22. 020 26.243 26 .263 27 .257 28 .449 29.688 30.926 29. 825 28.197 28.269 27.878 27. 572 26.842 25.471 24. 924 24. 502 28. 778 29. 822 28.612 29. 708 29.472 28. 781 30. 068 30. 000 30.859 30.628 31.089 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00.

1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 34 .54 35.58 37.03 36 .68 37.07 37.87 38.93 43 45.77 35.86 37.98 33.37 31.84 31.84 29.70 33 .88 33 .86 34 .14 30.58 33 .14 31.30 32.32 32.85 35.64 34. 96 36.36 30.71 33 .97 37.60 41.20 36.52 35.59 35 .92 39.40 34.46 35.36 32.50 37 .77 42.77 41.84 42.45 42.58 43 .09 45.25 45.47 46 .82 50.47 52 .24 53 .41 53 .64 56 .19 57.19 61.02 63 .12 SSSD/55145. vOl WO 98/07835 PCTUS97/14885 120 ATOM 188 CE LYS 1482 5.494 6.547 30.395 1.00 61.98 ATOM 189 NZ LYS 1482 6.252 5.368 30.899 1.00 63.38 ATOM 193 C LYS 1482 3.297 9.795 28.604 1.00 56.56 ATOM 194 0 LYS 1482 3.291 8.868 27.791 1.00 55.03 ATOM 195 N PRO 1483 3.852 10.983 28.323 1.00 58.31 ATOM 196 CD PRO 1483 3.859 12.191 29.167 1.00 56.98 ATOM 197 CA PRO 1483 4.465 11.254 27.020 1.00 59.52 ATOM 198 CB PRO 1483 4.910 12.711 27.155 1.00 58.75 ATOM 199 CG PRO 1483 3.927 13.278 28.141 1.00 58.79 ATOM 200 C -PRO 1483 5.673 10.335 26.834 1.00 61.17 ATOM 201 0 PRO 1483 6.509 10.216 27.731 1.00 61.31 ATOM 202 N LEU 1484 5.728 9.643 25.702 1.00 64.31 ATOM 204 CA LEU 1484 6.838 8.738 25.408 1.00 67.77 ATOM 205 CB LEU 1484 6.349 7.512 24.640 1.00 67.66 ATOM 206 CG LEU 1484 5.415 6.558 25.386 1.00 69.00 ATOM 207 CD1 LEU 1484 4.943 5.457 24.445 1.00 66.76 ATOM 208 CD2 LEU 1484 6.126 5.972 26.604 1.00 67.77 ATOM 209 C LEU 1484 7.934 9.431 24.608 1.00 70.82 ATOM 210 0 LEU 1484 9.117 9.115 24.759 1.00 71.82 ATOM 211 N GLY 1485 7.534 10.357 23.742 1.00 73.28 ATOM 213 CA GLY 1485 8.492 11.077 22.922 1.00 74.53 ATOM 214 C GLY 1485 7.819 11.754 21.747 1.00 75.19 ATOM 215 0 GLY 1485 6.635 12.090 21.822 1.00 75.61 ATOM 216 N GLN 1491 4.406 14.274 18.638 1.00 50.72 ATOM 218 CA GLN 1491 4.042 13.876 19.994 1.00 47.33 ATOM 219 CB GLN 1491 3.033 14.869 20.587 1.00 46.67 ATOM 220 C GLN 1491 3.486 12.449 20.073 1.00 46.66 ATOM 221 0 GLN 1491 2.581 12.074 19.323 1.00 45.20 ATOM 222 N VAL 1492 4.072 11.650 20.960 1.00 45.41 ATOM 224 CA VAL 1492 3.646 10.274 21.184 1.00 43.83 ATOM 225 CE VAL 1492 4.680 9.244 20.709 1.00 41.60 ATOM 226 CG1 VAL 1492 4.138 7.849 .20.937 1.00 41.35 ATOM 227 CG2 VAL 1492 5.007 9.445 19.237 1.00 42.72 ATOM 228 C VAL 1492 3.458 10.084 22.683 1.00 44.45 ATOM 229 0 VAL 1492 4.335 10.437 23.482 1.00 43.86 ATOM 230 N VAL 1493 2.309 9.548 23.070 1.00 42.67 ATOM 232 CA VAL 1493 2.029 9.321 24.477 1.00 41.05 ATOM 233 CE VAL 1493 0.884 10.242 25.013 1.00 40.64 ATOM 234 CG1 VAL 1493 1.177 11.693 24.722 1.00 42.40 ATOM 235 CG2 VAL 1493 -0.459 9.844 24.427 1.00 43.36 ATOM 236 C VAL 1493 1.626 7.880 24.704 1.00 40.09 ATOM 237 0 VA. 1493 1.129 7.212 23.796 1.00 39.99 ATOM 238 N LEU 1494 1.927 7.374 25.890 1.00 37.10 ATOM 240 CA LEU 1494 1.535 6.036 26.250 1.00 35.08 ATOM -241 CB3 LEU 1494 2.359 5.542 27.440 1.00 35.57 ATOM 242 CG LEU 1494 2.036 4.161 28.007 1.00 36.87 ATOM 243 CD1 LEU 1494 2.123 3.085 26.931 1.00 36.90 ATOM 244 CD2 LEU 1494 2.998 3.860 29.143 1.00 41.99 ATOM 245 C LEU 1494 0.077 6.236 26.648 1.00 33.31 ATOM 246 0 LEU 1494 -0 311 7.318 27.097 1.00 32.93 ATOM 247 N ALA 1495 -0.740 -5.219 26.435 1.00 33.3.5 ATOM 249 CA ALA .1495 2.147 5.292 26.773 1.00 30.67 ATOM 250 CE ALA 1495 -2.923 5.937 25.637 1.00 30.35 ATOM 251 C ALA 1495 -2.661 3.893 27.025 1.00 29.97 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 121

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

252 253 255 256 257 258 259 260 261 262 263 265 266 267 268 269 271 272 273 274 275 276 277 278 280 281 282 283 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 301 302 303 304 305 308 309 310 3i2 313 314 0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

C

0

-N

CA

CB

CG2 CG1 CD1

C

0

N

CA

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

OD1 ND2

C

0

N

CA

CB

CG

ALA

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ALA

ALA

ALA

ALA

ALA

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

GLY

GLY

GLY

GLY

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ARG

ARG

ARG

ARG

1495 1496 1496 1496 1496 1496 1496 1496 1496 1496 1497 1497 1497 1497 1497 1498 1498 1498 1498 1498 1498 1498 1498 1499 1499 1499 1499 1500 1500 1500 1500 1500 1500 1500 1500 1505 1505 1505 1505 1505 1505 1505 1506 1506 1506 1506 1506 1506 1506 1506 1507 1507 1507 1507 -1.944 -3.898 -4.537 -4,~862 -3.627 -3.938 -4.328 -3.797 -5.806 -6.586 -5.953 -7.117 -6.691 -8.056 -7.648 -9.286 -10.276 11. 329 -12.341 -10.647 11. 543 -10.994 11. 618 -10.890 11. 553 -10.670 -9.934 -10.713 -9.9.57 -8.444 -7.562 -6.110 -7.768 -10.453 -10.376 -13.315 -13.945 -14.306 -15.635 -15.241 -14.03 9 -14.065 -13.711 -13.433 -14.283 -15.752 -16.132 -16.589 11. 954 11. 597 11. 100 -9.660 -9.131 -9.407 2 .909 3 .813 2 .536 2 .392 2 .239 2 .426 3 .548 1.453 2 .524 3 .478 1 .494 1 .353 0 .879 0. 343 -0.773 0. 759 -0.126 0.668 -0.288 1 .496 2 .572 -0.830 -0.181 -2 .147 -2 .884 -3.233 -4 .226 -2 .394 -2 .603 -2 .726 -1.472 -1.891 711 -3 .830 -4 .963 -5 .836 -7 .3148 -4 .848 -5.607 031 -4 .348 -3.143 -5.261 -4.892 -5.728 -5.395 -4.232 -6.418 -5.008 -5.084 -5.010 122 -6 .354 -7 .685 26. 840 27. 488 27. 745 29. 223 30. 093 31. 565 31. 944 32 .341 26. 916 26. 954 26. 094 25. 239 23 .859 25 .885 26 .197 26 .160 26. 766 27. 592 28 .240 28. 686 29. 258 25. 624 24. 786 25. 573 24. 516 23 .330 23 .380 22 .294 21. 055 21. 305 21. 241 21. 367 19. 935 20.288 20. 774 25. 394 25.167 25. 846 25. 715 25. 950 27.273 27. 524 28 .181 29. 566 30. 529 30 .441 30 .390 30.406 29.939 31.121 28. 924 29. 117 28 .375 29 .043 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 28.15 30.37 31.47 32.48 37.81 41.09 41.53 44 .12 32. 72 33.91 31. 06 32 .33 29. 56 32.26 33 32 .99 34 .00 34 .69 34 .24 33. 56 31.25 35 .71 34 .88 40.43 47.63 53 .08 54. 97 54 .18 55.26 55.39 54 .27 52 .89 50.91 55.39 56 .23 53. 03 55.12 50.62 50.09 52 .18 46.35 45.82 42.76 45.29 45:-92 46 .17 48.57 48.63 45.33 44.53 45.63 45.57 53.33 61.39 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 122 ATOM 315 CD ARC 1507 -8.336 -8.028 30.063 1.00 67.74 ATOM 316 NE ARC 1507 -8.525 -9.376 30.585 1.00 74.64 ATOM 318 CZ ARt- 1507 -7.970 -9.842 31.701 1.00 80.01 ATOM 319 NH1 ARG' 1507 -7.166 -9.075 32.433 1.00 80.04 ATOM 322 NH2 ARG 1507 -8.268 -11.068 32.115 1.00 83.41 ATOM 325 C ARG 1507 -8.964 -3.897 28.555 1.00 40.94 ATOM- 326 0 ARG 1507 -9.370 -3.375 27.517 1.00 37.60 ATOM 327 N VAL 1508 -7.956 -3.409 29.267 1.00 39.33 ATOM 329 CA VAL 1508 -7.190 -2.269 28.789 1.00 37.26 ATOM 330 CB VAL 1508 -6.854 -1.224 29.905 1.00 36.25 ATOM 331 CG1 VAL 1508 -8.124 -0.739 30.571 1.00 39.63 ATOM 332 CG2 VAL 1508 -5.903 -1.796 30.928 1.00 36.92 ATOM 333 C VAL 1508 -5.898 -2.818 28.188 1.00 34.38 ATOM '334 0 VAL 1508 -5.387 -3.851 28.630 1.00 32.85 ATOM 335 N THR 1509 -5.406 -2.140 27.159 1.00 30.47 ATOM 337 CA THR 1509 -4.174 -2.523 26.491 1.00 31.65 ATOM 338 CE THR 1509 -4.455 -2.959 25.027 1.00 34.13 ATOM 339 OGi THR 1509 -5.426 -4.013 25.018 1.00 40.74 ATOM 341 CG2 THR 1509 -3.184 -3.458 24.345 1.00 31.06 ATOM 342 C THR 1509 -3.270 -1.299 26.461 1.00 28.38 ATOM 343 0 THR 1509 -3.716 -0.219 26.104 1.00 27.78 ATOM 344 N LYS 1510 -2.023 -1.442 26.896 1.00 29.48 ATOM 346 CA LYS 1510 -1.101 -0.312 26.835 1.00 30.54 ATOM 347 CB LYS 1510 0.172 -0.558 27.635 1.00 27.88 ATOM 348 CC LYS 1510 -0.037 -0.600 29.118 1.00 33.91 ATOM 349 CD LYS 1510 1.284 -0.759 29.840 1.00 40.30 ATOM 350 CE LYS 1510 1 *145 -1.674 31.062 1.00 46.24 ATOM 351 NZ LYS 1510 0.338 -1.096* 32.187 1.00 49 09 ATOM 355. C LYS 1510 -0.757 -0.166 25.365 1.00 28.64 ATOM 356 0 LYS 1510 -0.402 -1.142 24.704 1.00 28.76 ATOM 357 N VAL 1511 -0.902 1.048 24.856 1.00 29.34 ATOM 359 CA VAL 1511 -0.627 1.347 23.463 1.00 29.79 ATOM 360 CB VAL 1511 -1.951 1.457 22.658 1.00 27.14 ATOM 361 CG1 VAL 1511 -2.681 0.111 22.657 1.00 24.56 ATOM 362 CG2 VAL 1511 -2.837 2.561 23.243 1.00 22.15 ATOM *363 C VAL 1511 0.123 2.672 23.361 1.00 29.83 ATOM 364 0 VAL 1511 0.213 3.413 24.338 1.00 33.14 ATOM 365 N ALA 1512 0.705 2.939* 22.196 1.00 27.86 ATOM 367 CA ALA 1512 1.405 4.192 21.962 1.00 25.55 ATOM 368 CB ALA 1512 2.743 3.935 21.297 1.00 24.69 ATOM 369 C ALA 1512 0.500 5.009 21.057 1.00 25.25 ATOM 370 0 ALA 1512 -0.061 4.483 20.107 1.00 27.18 ATOM 371 N VAL 1513 0.340 6.289 21.360 1.00 29.63 ATOM 373 CA VAL 1513 -0.520 7.165 20.573 1.00 32.66 ATOM 374 CB VAL 1513 -1.704 7.713 21.422 1.00 32.47 ATOM 375 CG1 VAL 1513 -2.609 8.585 20.574 1.00 32.29 ATOM 376 CG2 VAL 1513 -2.508 6.559 22.031 1.00 32.15 ATOM 377 C VAL 1513 0.238 8.334 19.938 1.00 34.67 ATOM 378 0 VAL 1513 0.792 9.185 20.635 1.00 34.65 ATOM 379 N LYS 1514 0.207 8.367 18.605 1.00 36.88 ATOM 381 CA LYS 1514 0.859 9.390 17.789 1.00 36.43 ATOM- 382 CB LYS 1514 1.349 6. 764 16.489 1.00 36.37 ATOM 383 CC LYS 1514 2.250 7.563 16.697 1.00 39.49 ATOM 384 CD LYS 1514 2.559 6.854 15.390 1.00 45.29 SSSD/55145. vOl WO 98/07835 PCTIUS97/14889 123 ATOM 385 CE LYS 1514 3.080 7.815 14.331 1.00 50.70 ATOM 386 NZ LYS 1514 4.212 8.685 14.798 1.00 51.41 ATOM 390 C LYS 1514 -0.121 10.496 17.459 1.00 36.75 ATOM 391 0 LYS 1514 -1.228 10.234 16.978 1.00 35.42 ATOM 392 N MET 1515 0.294 11.731 17.700 1.00 38.12 ATOM 394 CA MET 1515 0.545 12.882 17.432 1.00 41.90 ATOM 395 CB MET 1515 -1.371 13.238 18.668 1.00 43.08 ATOM 396 CG MET 1515 -0.536 13.601 19.880 1.00 45.01 ATOM 397 SD MET 1515 -1.561 13.784 21.324 1.00 46.03 ATOM 398 CE MET 1515 -1.675 12.072 21.885 1.00 44.02 ATOM 399 C MET 1515 0.314 14.065 17.021 1.00 44.65 ATOM 400 0 MET 1515 1.543 14.013 17.094 1.00 45.64 ATOM 401 N LEU 1516 -0.347 15.123 16.568 1.00 47.08 ATOM 403 CA LEU 1516 0.329 16.337 16.134 1.00 48.08 ATOM 404 CB LEU 1516 -0.500 17.033 15.054 1.00 45.50 ATOM 405 CG LEU 1516 -0.764 16.265 13.764 1.00 43.22 ATOM 406 CD1 LEU 1516 -1.783 17.014 12.946 1.00 40.32 ATOM 407 CD2 LEU 1516 0.540 16.072 12.991 1.00 43.78 ATOM 408 C LEU 1516 0.516 17.302 17.297 1.00 51.27 ATOM 409 0 LEU 1516 -0.214 17.249 18.291 1.00 50.37 ATOM 410 N LYS 1517 1.491 18.191 17.157 1.00 55.47 ATOM 412 CA LYS 1517 1.757 19.2'07 18.168 1.00 59.10 ATOM 413 CB LYS 1517 3.203 19.702 18.068 1.00 61.61 ATOM 414 CG LYS 1517 4.251 18.669 18.462 1.00 64.82 ATOM 415 CD LYS 1517 5.635 19.109 18.018 1.00 67.42 ATOM 416 CE LYS 1517 6.696 18.102 18.432 1.00 71.76 ATOM 417 NZ LYS 1517 8.021 18.411 17.812 1.00 73.57 ATOM 421 C LYS 1517 0.794 20.365 17.920 1.00 59.91 ATOM 422 0 LYS 1517 0.187 .20.456 16.852 1.00 59.88 ATOM 423 N SER 1518 0.686 21.267 18.886 1.00 61.85 ATOM 425 CA SER 1518 -0.216 22.409 18.760 1.00 63.70 ATOM 426 CB3 SER 1518 -0.158 23.274 20.024 1.00 64.21 ATOM 427 C SER 1518 0.079 23.263 17.529 1.00 64.37 ATOM 428 0 SER 1518 -0.841 23.757 16.875 1.00 66.16 ATOM 429 N ASP 1519 1.359 23.410 17.202 1.00 64.15 ATOM 431 CA ASP 1519 1.767 24.217 16.054 1.00 64.55 ATOM 432 CB ASP 1519 3.109 24.897 16.343 1.00 65.84 ATOM 433 C ASP 1519 1.858 23.441 14.742 1.00 63.95 ATOM 434 0 ASP 1519 2.432 23.931 13.769 1.00 64.95 ATOM 435 N ALA 1520 1.303 22.232 14.719 .1.00 62.57 ATOM 437 CA ALA 1520 1.329 21.398 13.521 1.00 60.34 ATOM 438 CB ALA 1520 0.704 20.039 13.810 1.00 60.53 ATOM 439 C ALA 1520 0.616 22.062 12.353 1.00 58.21 ATOM 440 0 ALA 1520 -0.464 22.631 12.506 1.00 58.32 ATOM 441 N THR 1521 1..241 22- *001 11.186 1.00 55.96 ATOM 443 CA TER 1521 0.673 22.582 9.981 1.00 54.98 ATOM 444 CB THR 1521 1.783 23.013 9.031 1.00 53.84 ATOM 445 OGi THR 1521 2.554 21.862 8.659 1.00 55.84 ATOM 447 CG2 THR 1521 2.693 24.026 9.703 1.00 55.01 ATOM 448 C TER 1521 -0.184 21.545 9.261 1.00 54.25 ATOM 449 0 THR 1521 -0.190 20.371 9.629 1.00 54.74 ATOM 450 N GLU 1522 -0.877 21.974 8.212 1.00 53.32 ATOM 452 CA GLU 1522 -1.702 21.066 7.423 1.00 52.64 ATOM 453 CB GLU 1522 -2.472 21.829 6.339 1.00 53.55 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 124 ATOM 454 ATOM 455 ATOM 456 ATOM 458 ATOM 459 ATOM 460 ATOM 461 ATOM 462 ATOM 463 ATOM 467 ATOM 468 ATOM 469 ATOM 471 ATOM 472 ATOM 473 ATOM 474 ATOM 475 ATOM 476 ATOM 477 ATOM 478 ATOM 480 ATOM 481 ATOM 482 ATOM 483 ATOM 484 ATOM 485 ATOM 486 ATOM 487 ATOM 489 ATOM 490 ATOM 491 ATOM 493 ATOM 494 ATOM 495 ATOM 497 ATOM 498 ATOM 499 ATOM 500 ATOM 501 ATOM 502 ATOM 503 ATOM 504 ATOM 506 ATOM 507 ATOM 508 ATOM 509 ATOM 510 ATOM 511 ATOM 512 ATOM 513 ATOM 515 ATOM 516 ATOM 517 ATOM 518 SSSD/55145. v01 C GLU 1522 O GLU 1522 N LYS 1523 CA LYS 1523 CB LYS 1523 CG LYS 1523 CD LYS 1523 CE LYS 1523 NZ LYS 1523 C LYS 1523 O LYS 1523 N ASP 1524 CA ASP 1524 CB ASP 1524 CG ASP 1524 OD1 ASP 1524 OD2 ASP 1524 C ASP 1524 O ASP 1524 N LEU 1525 CA LEU 1525 CB LEU 1525 CG LEU 1525 CD1 LEU 1525 CD2 LEU 1525 C LEU 1525 0 LEU 1525 N SER 1526 CA SER 1526 CB SER 1526 OG SER 1526 C SER 1526 O SER 1526 N ASP 1527 CA ASP 1527 CB ASP 1527 CG ASP 1527 ODI ASP 1527 OD2 ASP 1527 C ASP 1527 O ASP 1527 N LEU 1528 CA LEU 1528 CB LEU 1528 CG LEU 1528 CD1 LEU 1528 CD2 LEU 1528 C LEU 1528 O LEU 1528 N ILE 1529 CA ILE 1529 CB ILE 1529 CG2 ILE 1529 CG1 ILE 1529 -0.793 -1.226 0.464 1.429 2.730 3.889 3.487 4.688 4.271 1.699 1.747 1.857 2. 114 2.313 3.623 3.692 4.590 0. 956 1.164 -0.261 -1.461 -2.720 -4.081 -4.184 -5.162 -1.406 -1.575 -1.136 -1.039 -0.669 -1.736 -0.021 -0.273 1.142 2.177 3.497 4.100 3.750 4.932 1.749 2.000 1.055 0.581 -0.002 -0.440 0.705 -0.891 -0.468 -0.494 -1.336 -2.376 -3.336 -4.229 -4.200 20.012 18.895 20.377 19.460 20.201 19.308 18.388 17.635 16.629 18.391 17.202 18.828 17.915 18.701 19.490 20.512 19.084 16.931 15.738 17.438 16.610 17.470 16.760 15.668 17.789 15.560 14.377 16.005 15.128 15.931 16.779 14.016 12.873 14.349 13.342 13.998 14.850 14.653 15.726 12.274 11.090 12.684 11.730 12.471 11.623 10.708 12.512 10.792 9.589 11.357 10.591 11.505 10.662 12.344 6.780 1.00 51.95 6.504 1.00 53.28 6.544 1.00 48.66 5.963 1.00 46.30 5.620 1.00 48.30 5.164 1.00 49.58 4.016 1.00 50.87 3.466 1.00 54.08 2.440 1.00 57.87 7.006 1.00 43.89 6.697 1.00 43.92 8.249 1.00 42.71 9.351 1.00 42.11 10.653 1.00 44.94 10.673 1.00 48.90 11.392 1.00 51.88 9.990 1.00 50.06 9.481 1.00 39.85 9.748 1.00 39.01 9.296 1.00 38.32 9.355 1.00 36.16 9.200 1.00 35.13 9.186 1.00 34.70 10.252 1.00 36.15 9.395 1.00 32.96 8.254 1.00 34.31 8.518 1.00 33.34 7.030 1.00 36.40 5.865 1.00 37.16 4.618 1.00 38.84 4.245 1.00 49.61 6.044 1.00 35.90 5.670 1.00 36.68 6.591 1.00 35.89 6.796 1.00 35.25 7.201 1.00 35.58 6.081 1.00 37.19 4.895 1.00 37.38 6.395 1.00 42.93 7.799 1.00 31.77 7.594 1.00 30.58 8.853 1.00 31.80 9.857 1.00 33.53 11.076 1.00 32.20 12.275 1.00 32.63 12.709 1.00 33.09 13.426 1.00 31.52 9.235 1.00 32.89 9.521 1.00 32.39 8.393 1.00 33.72 7.711 1.00 30.48 6.895 1.00 28.85 5.997 1.00 28.54 7.843 1.00 29.52 WO 98/07835 PCTIUS97I14SS5 125 ATOM 519 CD1 ILE 1529 -5.143 13.308 7.133 1.00 32.07 ATOM 520 C ILE 1529 -1.698 9.608 6.768 1. 00 31.50 ATOM 521 0 ILE 1529 -2.009 8.419 6.780 1.00 30.75 ATOM 522 N SER 1530 -0.749 10.100 5.974 1.00 33.28 ATOM 524 CA SER 1530 -0.011 9.250 5.038 1.00 32.48 ATOM 525 CB SER 1530 1.114 10.042 4.368 1.00 37.20 ATOM 526 OG SER 1530 0.604 11:218 3.766 1.00 49.93 ATOM 528 C SER 1530 0.583 8.045 5.756 1.00 29.05 ATOM 529 0 SER 1530 0.397 6.909 5.316 1.00 28.66 ATOM 530 N GLU 1531 1.259 8.290 6.878 1.00 28.21 ATOM 532 CA GLU 1531 1.880 7.207 7.631 1.00 27.30 ATOM 533 CB GLU 1531 2.656 7.733 8.839 1.00 28.90 ATOM 534 CG GLU 1531 3.271 6.609 9.672 1.00 27.17 ATOM 535 CD GLU 1531 4.047 7.081 10.886 1.00 30.07 ATOM 536 OE1 GLU 1531 4.779 6.244 11.448 1.00 34.78 ATOM 537 0E2 GLU 1531 3.931 8.256 11.291 1.00 31.96 ATOM 538 C GLU 1531 0.870 6.162 8.072 1.00 27.73 ATOM 539 0 GLU 1531 1.160 4.961 8.028 1.00 28.72 ATOM 540 N MET 1532 -0.286 6.621 8.555 1.00 29.78 ATOM 542 CA MET 1532 -1.373 5.734 8.990 1.00 28.79 ATOM 543 CB MET 1532 -2.501 6.553 9.646 1.00 28.90 ATOM 544 CG MET 1532 -3.763 5.741 9.993 1.00 29.73 ATOM 545 SD MET 1532 -5.089 6.693 10.765 1.00 30.19 ATOM 546 CE MET 1532 -5.455 7.870 9.494 1.00 26.70 ATOM 547 C MET 1532 -1.935 4.937 7.796 1.00 28.34 ATOM 548 0 MET 1532 -2.166 3.730 7.893 1.00 26.62 ATOM 549 N GLU 1533 -2.165 5.624 .6.678 1.00 28.85 ATOM 551 CA GLU 1533 -2.684 4.984 5.467 1.00 28.24 ATOM 552 CB GLU 1533 -2.936 6.027 4.384 1.00 25.42 ATOM 553 CG GLU 1533 -4.099 6.956 4.719 1.00 30.05 ATOM 554 CD GLU 1533 -5.393 6.201 5.021 1.00 29.47 ATOM 555 OE1 GLU 1533 -5.794 5.336 4.211 .1.00 29.01 ATOM 556 0E2 GLU 1533 -6.011 6.472 6.073 1.00 33.98 ATOM 557 C GLU 1533 -1.694 3.944 4.968 1.00 28.01 ATOM 558 0 GLU 1533 -2.072 2.845 4.573 1.00 27.39 ATOM 559 N MET 1534 -0.416 4.293 5.036 1.00 29.06 ATOM 561 CA MET 1534 0.662 3.413 4.621 1.00 29.74 ATOM 562 CB MET 1534 1.992 4.155 4.755 1.00 33.16 ATOM 563 CG MET 1534 3.198 3.270 4.682 1.00 42.88 ATOM 564 SD MET 1534 3-.805 3.127 3.042 1.00 50.20 ATOM 565 CE MET 1534 5.137 4.169 3.159 1.00 42.64 ATOM 566 C MET 1534 0.641 2.156 5.493 1.00 26.90 ATOM 567 0 MET 1534 0.755 1.038 4.990 1.00 27.05 ATOM 568 N MET 1535 0.512 2.348 6.803 1.00 25.42 ATOM 570 CA MET 1535 0.437 1.233 17.737 1.00 25.88 ATOM 571 CB MET 1535 0.325 1.741 9.181 1.00 27.63 ATOM 572 CG MET 1535 1.607 2.391 9.737 1.00 27.26 ATOM 573 SD MET 1535 1.584 2.56.1 11.564 1.00 29.49 ATOM 574 CE MET 1535 1.294 4.255 11.699 1.00 28.22 ATOM 575 C MET 1535 -0.754 0.324 7.396 1.00 26.28 ATOM 576 0 MET 1535 -0.645 -0.908 7.469 1.00 25.93 ATOM 577 N LYS 1536 -1.890 0-92,8 7.032 1.00 27.19 ATOM 579 CA LYS 1536 -3.087 0.162 6.647 1.00 27.20 ATOM 580 CB LYS 1536 -4.257 1.088 6.310 1.00 25.29 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 126

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

581 582 583 584 588 589 590 592 593 594 595 596 597 598 599 601 602 603 604 605 606 607 608 610 611 612 613 615 616 617 618 619 620 624 625 626 628 629 630 631 632 634 635 637 638 639 641 642 643 644 645 646 650 651

CG

CD

CE

NZ

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG

CD2 ND1 CEl NE2

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

LYS

LYS

LYS

LYS

LYS

LYS

MET

MET

MET

MET

MET

MET

MET

MET

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

GLY

GLY

GLY

GLY

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

1536 1536 1536 1536 1536 1536 1537 1537 1537 1537 1537 1537 1537 1537 1538 1538 1538 1538 1538 1538 1538 1538 1539 1539 1539 1539 1540 1540 1540 1546 1540 1540 1540 1540 1540 1541 1541 1541 1541 1541 1541 1541 1541 1541 1541 1542 1542 1542 1542 1542 1542 1542 1542 1542 -4.897 -5.884 -6.460 -7.484 -2.785 -3.069 -2 .183 -1.843 -1.269 -2.265 -3 .699 -2.912 -0.857 -1.060 0.188 1.234 2 .454 3.424 3 .223 4 .373 0.760 1.242 -0.193 -0.661 0.191 1 .214 -0.204 0.467 -0.552 -1.573 -2.528 -3.559 -2 .956 1.609 1.627 2 .545 3 .666 4 .772 5 .798 5 .823 6.939 7 .619 6 .966 4 .234 4 .364 4 .560 5.127 5 .515 6 .061 6.289 7 .041 7 .511 6 .342 6 .519 1. 770 2.820 3. 588 4. 541 -0.699 889 093 -0.815 0. 147 1. 164 0. 444 -0.057 952 065 -1.678 -2.674 006 051 -1.131 -0.372 922 033 767 940 280 -4.637 327 -6.716 -7.283 -6.303 943 5.927 800 705 -8.600 -7.538 -8.440 -8.228 -9.320 -10. 522 -9.268 -10.389 -11. 167 -8.328 -7.239 -9.476 -9.552 -11.003 -11.252 -12.735 -13.374 -14.763 -8.652 -8.113 7.491 7.017 8 .174 7.713 5 .423 5.403 4.411 3 .194 2 .147 1.591 0.727 -0.793 3.447 2 .963 4 .229 4 .535 5.255 5.811 4 .269 4 .901 5.292 5.035 6.208 6 .934 8 .149 8.414 8 .862 10.092 11 .084 11.550 12.546 13 .057 13.833 10 .014 9.181 10.936 11 .091 10.057 10.068 9.444 10.843 10.697 9.854 12.494 13 .050 13 .063 14.401 14 .692 16 .077 16.294 15.114 15.424 14 .624 15.711 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 23.86 22.16 22.25 23.40 24.52 26.61 27.12 28.06 30.36 36.31 42 .19 36.22 26 .98 25.34 27.69 25.39 24 .42 25.28 23 .88 27.19 25.59 26.11 26.13 25.25 26 .77 25.42 25 .62 26 .38 27.15 34 .23 40.69 44 .08 44 24.37 26.12 24.41 25.41 21.88 22 .68 21.40 22.12 24 .78 27.00 25.47 26.77 26.38 30.07 31.38 42.79 50.84 56.75 61.29 27.65 26.83 SSSD/55145. vOl WO 98/07835 PTU9/48 PCTIUS97/14885 127

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

652 654 655 656 657 658 661 662 663 665 666 667 668 669 670 671 672 674 675 676 677 678 679 680 681 683 684 685 686 687 690 691 692 694 695 696 697 698 699 700 701 703 704 705 706 707 708 709 710 712 713 714 715 717

N

CA

CB

CG

ODi ND2

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

CG

ODI

ND2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD1 CD2

C

.0

N

CA

C

0

N

CA

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

LEU

LEO

LEU

LEU

LEO

LEO

LEU

LEO

LEO

LEO

LEO

LEO

L21O

LEO

LEU

LEO

GLY

GLY

GLY

GLY

ALA

ALA

1543 1543 1543 1543 1543 1543 1543 1543 1544 1544 1544 1544 1544 1544 1544 1544 1545 1545 1545 1545 1545 1545 1545 1545 1546 1546 1546 1546 1546 1546 1546 1546 1547 1547 1547 1547 1547 1547 1547 1547 1548 1548 1548 1548 1548 1548 1548 1548 1549 1549 1549 1549 1550 1550 7 .146 8.354 9.578 9. 712 9. 522 9.970 8 .374 9.417 7.209 7 .065 6 .524 7 .401 5.057 4 .446 6 .075 5 .364 6 .111 5 .169 5 .602 4.452 6 .839 6 .591 3 .877 3 .823 2.849 1.577 0 .922 1 .730 1.856 2 .278 0 .578 0 .630 -0.301.

-1.357 -1.945 -3.173 -2 .790 -3 .757 -2.415 -2.663 -3 .000 -4 .017 -3.623 -2.327 -2.189 -2.337 -5.369 -6.392 -5.378 -6 .643 -6 .417 -5.267 -7.501 -7.408 -8.445 -7.642 -8.431 -9.767 -10.821 -9.727 213 -5.692 -5.575 -4.177 972 720 -4.411 -4.121 -3 .598 345 -2.290 650 199 0. 554 -0.219 797 -1.612 988 -2.293 354 727 839 -4.947 686 276 724 -0.956 0. 019 0.481 1.400 2.763 1.569 -0.771 -1.952 -0.130 -0.770 -0.735 -1.450 -1.428 -2.886 -0.113 -0.752 1.163 1.855 3.336 3. 7-81 4. 104 5.550 13.585 13 .735 13 .260 13 .974 13 .371 15 .273 13 .226 12 .842 13 .244 12 .868 11.409 10.403 11.279 9.901 13 .881 14 .559 14 .076 14 .989 15.364 16.035 16 .285 17.686 14 .179 13 .122 14 .669 13 .956 14 .137 13 .539 12.329 14 .384 14.349 15.453 13.407 13 .622 12 .284 12.337 12 .929 10.923 14 .396 14.103 15.400 16.223 17.708 18 .108 19.613 17.621 16 .042 16 .238 15.684 15.516 15.367 15.287 15.349 15.198 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 27.20 25.50 25.59 22.64 26 .76 25.56 25.48 24 .58 24 22.32 25. 82 24 .24 26 .04 23.20 22 .37 21. 68 23 .72 25 .92 27.24 22 .76 25.57 24 .66 26 .03 25 24 .79 25. 51 25.17 21.67 24.29 22 .24 26.85 28.67 27.70 27.64 24 .87 23.25 23 .76 23 .47 27.27 25.27 27.94 26. 98 24 25.38 25.73 23 .92 26 27.11 25.04 25.47 26.23 28.41 25.49 24 .81 SSSD/55145. vOl WO 98/07835 PCTUS97/14885 128 ATOM 718 CB ALA 1550 -7.176 5.913 13.724 1.00 21. 79 ATOM 719 C ALA 1550 -8 '.645 6.271 15.691 1.00 25.51 ATOM 720 0 ALA 1550 -9.738 5.702 15.726 1.00 24.09 ATOM 721 N CYS 1551 -8.440 7.527 16.080 1.00 24.90 ATOM 723 CA CYS 1551 -9.492 8.438 16.511 1.00 26.80 ATOM 724 CB CYS 1551 -9.243 8.932 17.944 1.00 26.32 ATOM 725 SG CYS 1551 -9.333 7.655 19.223 1.00 32.31 ATOM 726 C CYS 1551 -9.341 9.585 15.502 1.00 28.31 ATOM 727 0 CYS 1551 -8.361 10.338 15.537 1.00 28.42 ATOM 728 N THR 1552 -10.261 9.660 14.547 1.00 28.38 ATOM 730 CA THR 1552 -10.198 10.671 13.498 1.00 31.26 ATOM 731 'CB THR 1552 -10.159 9.977 12.095 1.00 30.07 ATOM 732 OGi THR 1552 -11.406 9.309 11.836 1.00 29.64 ATOM 734 CG2 THR 1552 -9.044 8.945 12.053 1.00 28.65 ATOM 735 C THR 1552 -11.355 11.662 13.509 1.00 33.31 ATOM 736 0 THR 1552 -11.295 12.722 12.874 *0 31.94 ATOM 737 N GLN 1553 -12.420 11.309 14.214 1.00 36.09 ATOM 739 CA GLN 1553 -13.598 12.158 14.245 1.00 39.26 ATOM 740 CB GLN 1553 -14.864 11.299 14.145 1.00 36.61 ATOM 741 CG GLN 1553 -14.932 10.436 12.881 1.00 37.72 ATOM 742 CD GLN 1553 -14.762 11.247 11.601 1.00 38.41 ATOM 743 OE1 GLN 1553 -15.491 12.210 11.363 1.00 37.88 ATOM 744 NE2 GLN 1553 -13.798 10.858 10.770 1.00 37.67 ATOM 747 C GLN 1553 -13.671 13.079 15.451 1.00 41.28 ATOM 748 0 GLN 1553 -13.150 12.758 16.513 1.00 41.37 ATOM 749 N ASP 1554 -14.282 14.246 15.243 1.00 44.93 ATOM 751 CA ASP 1554 -14.487 15.254 16.281 1.00 48.05 ATOM 752 CB ASP 1554 -15.828 15.009 16.975 1.00 50.80 ATOM 753 CG ASP 1554 -17.007 15.281 16.067 1.00 56.88 ATOM 754 ODi ASP 1554 -17.921 16.019 16.491 1.00 63.89 ATOM 755 0D2 ASP 1554 -17.016 14.776 14.925 1.00 58.98 ATOM 756 C ASP 1554 -13.367 15.366 17.316 1.00 48.04 ATOM 757 0 ASP 1554 -13.556 15.056 18.502 1.00 48.73 ATOM 758 N GLY 1555 -12.205 15.819 16.860 1.00 44.30 ATOM 760 CA GLY 1555 -11.080 15.960 17.756 1.00 42.32 ATOM 761 C GLY 1555 -9.761 15.713 17.052 1.00 40.69 ATOM 762 0 GLY 1555 -9.740 15.465 15.848 1.00 40.71 ATOM 763 N PRO 1556 -8.644 15.776 17.782 1.00 39.49 ATOM 764 CD PRO 1556 -8.585 15.983 19.235 1.00 40.36 ATOM 765 CA PRO 1556 -7.298 15.566 17.250 1.00 38.37 ATOM 766 CB PRO 1556 -6.405 15.771 18.470 1.00 38.47 ATOM 767 CG PRO 1556 -7.226 16.573 19.388 1.00 41.77 ATOM 768 C PRO 1556 -7.140 14.154 16.746 1.00 36.92 ATOM 769 0 PRO 1556 -7.606 13.208 17.371 1.00 37.04 ATOM 770 N LEU 1557 -6.447 14.017 15.627 1.00 36.70 ATOM 772 CA LEU 1557 -6.201 12.719 15.037. 1.00 34.81 ATOM 773 CB LEU 1557 -5.528 12.885 13.664 1.00 32.49 ATOM 774 CG LEU 1557 -5.004 11.623 12.954 1.00 30.83 ATOM 775 CD1 LEU 1557 -6.146 10.655 12.664 1.00 26.28 ATOM 776 CD2 LEU 1557 -4.283 12.014 11.672 1.00 25.55 ATOM 777 C LEU .1557 -5.290 11.925 15.961 1.00 33.63 ATOM 778 0 -LEU 1557 -4.229 12.410 16.369 1.00 33.62 ATOM 779 N TYR 1558 -5.718 10.724 16.319 1.00 31.97 ATOM 781 CA TYR 1558 -4.902 9.863 17.147 1.00 31.81 145. vOl WO 98/07835 WO 9807835PCT/tUS97/14885 129 ATOM 782 CB TYR 1558 -5.614 9.500 18.462 1.00 33.55 ATOM 783 CG TYR 1558 -5.710 10.638 19.461 1.00 35.33 ATOM 784 CD1 TYR 1558 -6.644 10.608 20.499 1.00 35.68 ATOM 785 CEl TYR 1558 -6.757 11.670 21.394 1.00 38.60 ATOM 786 CD2 TYR 1558 -4.883 11.759 19.349 1.00 38.62 ATOM 787 CE2 TYR 1558 -4.985 12.824 20.235 1.00 40.33 ATOM 788 CZ TYR 1558 -5.924 12.781 21.254 1.00 41.70 ATOM 789 OH TYR 1558 -6.040 13.867 22.104 1.00 42.66 ATOM 791 C TYR 1558 -4.607 8.604 16.345 1.00 31.08 ATOM 792 0 TYR 1558 -5.527 7.937 15.857 1.00 31.28 ATOM 793 N VAL 1559 -3.328 8.336 16.116 1.00 28.34 ATOM 795 CA VAL 1559 -2.934 7.132 15.403 1.00 26.39 ATOM 796 CB VAL 1559 -1.830 7.401 14.364 1.00 29.17 ATOM 797 CG1 VAL 1559 -1.463 6.103 13.648 1.00 26.25 ATOM 798 CG2 VAL 1559 -2.297 8.461 13.360 1.00 29.56 -ATOM 799 C VAL 1559 -2.411 6.226 16.498 1.00 25.14 ATOM 800 0 VAL 1559 -1.396 6.522 17.120 1.00 28.04 ATOM 801 N ILE 1560 -3.164 5.171 16.783 1.00 25.28 ATOM 803 CA ILE 1560 -2.832 4.208 17.831 1.00 24.81 ATOM 804 CB ILE 1560 -4.133 3.669 18.496 1.00 24.63 ATOM 805 CG2 ILE 1560 -3.790 2.812 19.728 1.00 20.93 ATOM 806 CG1 ILE 1560 -5.044 4.854 18.869 1.00 22.94 ATOM 807 CD1 ILE 1560 -6.499 4.502 19.028 1.00 25.34 ATOM 808 C ILE 1560 -1.994 3.051 17.286 1.00 26.38 ATOM 809 0 ILE 1560 -2.429 2.301 16.398 1.00 26.14 ATOM 810 N VAL 1561 -0.782 2.911 17.809 1.00 27.31 ATOM 812 CA VAL 1561 0.112 1.852 17.359 1.00 27.32 ATOM 813 CB VAL 1561 1.309 2.435 16.527 1.00 25.01 ATOM 814 CG1 VAL 1561 0.785 3.220 15.338 1.00 19.39 ATOM 815 CG2 VAL 1561 2.170 3.340 17.397 1.00 26.08 ATOM 816 C VAL 1561 0.615 1.029 18.548 1.00 25.89 ATOM 817 0 VAL 1561 0.364 1.373 19.713 1.00 25.64 ATOM 818 N GLU 1562 1.288 -0.076 18.250 1.00 24.49 ATOM 820 CA GLU 1562 1.806 -0.949 19.284 1.00 25.00 ATOM 821 CB GLU 1562 2.357 -2.231 18.677 1.00 23.69 ATOM 822 CG GLU 1562 1.272 -3.170 18.219 1.00 24.29 ATOM 823 CD GLU 1562 1.814 -4.393 17.514 1.00 27.65 ATOM 824 OE1 GLU 1562 1.218 -5.480 17.649 1.00 29.50 ATOM 825 0E2 GLU 1562 2.832 -4.270 16.807 1.00 32.34 ATOM 826 C GLU 1562 2.840 -0.279 20.170 1.00 27.*27 ATOM 827 0 GLU 1562 3.596 0.576 19.729 1.00 26.18 ATOM 828 N TYR 1563 2.822 -0.663 21.441 1.00 30.39 ATOM 830 CA TYR 1563 3.715 -0.121 22.454 1.00 32.48 ATOM 831 CB TYR 1563 2.932 0.132 23.750 1.00 33.91 ATOM 832 CG TYR 1563 3.788 0.535 24.-928 1.00 34.93 ATOM 833 CD1 TYR 1563 4.606 1.664 24.871 1.00 34.50 ATOM 834 CEl TYR .1563 5.374 2.051 25.967 1.00 37.77 ATOM 835 CD2 TYR 1563 3.758 -0.201 26.108 1.00 33.54 ATOM 836 CE2 TYR 1563 4.519 0.171 27.205 1.00 34.94 ATOM 837 CZ TYR 1563 5.321 1.296 27.128 1.00 37.22 ATOM 838 OH TYR 1563 6.087 1.648 28.206 1.00 45.36 ATOM 840 C TYR 1563 4.896 -1.039 22.730 1.00 31.53 ATOM 841 0 TYR 1563 4.737 -2.252 22.895 1.00 30.43 ATOM 842 N ALA 1564 6.082 -0.444 22.761 1.00 32.28 SSSD/55145. vOl WO 98/07835 WO 98/07835PCT/2US97/14885 130

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

844 845 846 847 848 850 851 852 854 855 856 858 859 860 861 862 863 867 868 869 871 872 873 874 876 877 878 879 880 883 884 885 887 888 889 890 891 892 893 894 896 897 898 899 900 902 903 906 909 910 911 913 914 915

CA

CB

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

C

0

N

CA

CB

CG

OD1 ND2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

0

N

CA

CB

CG

ALA

ALA

ALA

ALA

SER

SER

SER

SER

SER

SER

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

GLY

GLY

GLY

GLY

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

GLU

GLU

GLU

GLU

1564 1564 1564 1564 1565 1565 1565 1565 1565 1565 1566 1566 1566 1566 1566 1566 1566 1566 1566 1567 1567 1567 1567 1568 1568 1568 1568 1568 1568 1568 1568 1569 1569 1569 1569 1569 1569 1569 1569 1570 1570 1570 1570 1570 1570 1570 1570 1570.

1570 1570 1571 1571 1571 1571 7.326 8 .308 7.897 8 .563 7.619 8.039 7.400 7.689 9.526 9.947 10.321 11.756 12.291 11.674 12 .162 11.763 12 .288 12 .567 13.785 11.892 12 .582 13.245 12.975 14.091 14 .774 15.203 16.420 17.453 16 .317 15 .927 16.490 16.276 17.333 17.437 18.438 18 .285 18.263 18 .706 19.400 19.097 20.386 20.597 21.873 21.966 20 749 20.376 21.118 19.246 20.434 21.324 19.444 19.331 18.055 18 .061 167 957 608 0 .427 -1.296 -0.853 -1-725 -3.084 -0.769 001 -1.557 559 990 865 -5.287 042 -7 .433 -0.613 -0.740 0. 338 1. 322 0. 864 -0 .222 1. 719 1.375 2 .627 3 .321 2 .709 4 .624 0.401 0. 315 317 316 -2 .008 148 -4.219 740 805 -1.501 0. 396 0. 951 2 .349 3. 009 4.481 5. 222 5.600 5 .316 6 .284 1. 022 0. 444 1. 695 1. 835 2 .607 4. 056 23 .026 21 .863 24 .334 24 .345 25.434 26 763 27.829 27 .579 27.041 27. 902 26 .330 26 562 26 508 27 .586 27 .508 28.761 28 748 25 .691 25 .607 25.049 24 .222 22 933 22 439 22 .360 21 .121 20 .332 20.910 21 .156 21 .066 21 .325 22 .414 20.263 20.298 18 .928 18 .741 19. 840 17 .338 20 .762 21 .496 20 .344 20 .758 20.160 20.662 20 .332 20 .664 21 .889 22 .960 22 .033 22 .298 22 .939 22 .880 24 .328 24 .667 24 .208 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 32 .59 30.11 31.81 34 .11 34 .09 35.05 30.13 38.17 35.03 37.12 34 33.48 31 28.63 34 .97 36.82 41.32 34 .98 38.03 36 .00 34 .14 32 .01 31 33.51 34.20 34 .07 35 .09 34 .36 38.38 33.38 34 .93 31 .11 30 '44 29.46 29.01 28 .81 26 .62 30.16 27.32 30 .74 33 .72 32 .82 36 39.32 50.32 51.90 50 53.67 35.75 35.67 35.56 36.50 39.08 46 SSSDI55145. vOl WO 98/07835 WO 9807835PCT/US97/14885 131

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

916 917 918 919 920 921 923 924 925 926 927 928 929 930 931 933 934 935 937 938 939 940 941 942 943 944 946 947 948 949 950 951 954 955 956 958 959 960 961 962 964 965 966 967 968 970 971 974 977 978 979 981 982 983

CD

OE 1 0E2

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2

CZ

OH

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD

OE1 NE2

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

0

N

CA

CB

CG

GLU

GLU

GLU

GLU

GLU

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

GLN

GLN

GLN

GLN

GLN

GIN

GLN

GLN

GLN

ALA

ALA

ALA

ALA

ALA

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

1571 1571 1571 1571 1571 1572 1572 1572 1572 1572 1572 1572 1572 1572 1572 1572 1572 1573 1573 1573 1573 1573 1573 1573 1573 1574 1574 1574 1574 1574 1574 1574 1574 1574 1575 1575 1575 1575 1575 1576 1576 1576 1576 1576 1576 1576 1576 1576 1576 1576 1577 1577 1577 1577 16.694 15.676 16.635 19.314 20.018 18 .520 18 .366 17.365 17.170 16.193 15.977 17.933 17.725 16.742 16 .518 19.692 19.959 20.517 21.803 22.357 21.669 22.161 21.932 22.799 23 .511 22.814 23.729 23.624 24.208 24.030 23 .362 24.613 23 .490 24.440 22.220 21.842 20.349 22.192 22.098 22.602 22.945 22.034 20.594 19.622 18. 267 17.565 18.083 16.310 24 .413 24.801 25.233 26 .671 27.307 26.992 4. 721 3.996 5.972 0.469 0.242 -0.441 -1.796 -2.544 -4.008 -4.420 -5.760 -4.985 -6.329 -6.708 -8.041 -2.556 -3.308 -2.370 -3.053 -3.027 -3.891 -3.503 -5.351 -2.420 -3.123 092 -0.368 1.138 1,549 3.018 3.755 3.448 -0.697 -0.:93 9 -0.783 -1.088 -0.81.9 -2.53.4 -2.843 -3.357 -4.729 -5.689 -5.547 -6.281 -6.255 -5.150 -3.960 -5.237 -5.073 -6.249 -4.036 196 -2.870 -2.408 24 .311 24 .417 24 .267 25. 022 26 .013 24 .469 24 .986 24 .102 24.408 25.313 25.574 23 .772 24 .027 24.935 25.214 25.044 25.992 24 .020 23 .961 22 .531 21.464 20.087 21.710 24 .933 25.659 24. 969 25.838 25.572 24 .217 23.896 24 .615 22 .790 27.310 28.059 27.696 29.069 29.273 29.503 30.690 28.561 28.896 28 .137 28.589 27.711 28.265 28 .484 28 .209 28.909 28.704 28.699 28 .570 28.413 28.000 26 .610 1 .00 1.00 1.00 1.00 1.00 1.00 1 .bo 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1 .00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1 .00 1 .00 1.00 1.00 1.-00 1.00 1.00 51.36 55.22 53 .59 34.82 35.05 33.35 31.83 30.77 28.50 30.48 30. 97 26.14 26 .21 30.30 33.52 34.83 34.93 34.34 35.38 32 .71 29.16 26 .98 28.85 37 .54 36.67 37.90 39.77 40.09 42.28 44.28 47.55 46.09 40.75 41.29 40.10 38 .81 35.69 40.63 43 .39 38.39 37.69 38.16 37.89 37.36 34.99 36 .94 36.18 40.93 38 .93 39.75 39.21 38.97 36.06 36.41 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 132

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

984 985 987 988 991 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1012 1013 1014 1015 1016 1018 1019 1020 1021 1022 1024 1025 1026 1027 1028 1029 1032 1033 1034 1036 1037 1038 1039 1040 1041 1042 1043 1045 1046 1047 1049 1050

CD

NE

cz NH1 NH2

C

0

N

CD

CA

CB

CG

C

0

N

Ca-

CA

CB

CG

C

0

N

CA

CB

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD

OE1 NE2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

OG

C

0

ARG

ARG

ARG

ARG

ARG

ARG

ARG

PRO

PRO

PRO

PRO

PRO

PRO

PRO

PRO

PRO

PRO

PRO

PRO

PRO

PRO

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLN

GLN,

GLN

GLN

GIN

GLN

GLN

GLN

GLN

LEU

LETJ

LEU

LEU

LEU

LEU

LEU

LEU

SER

SER

SER

SER

SER

SER

1577 1577 1577 1577 1577 1577 1577 1578 1578 1578 1578 1578 1578 1578 1579 1579 1579 1579 1579 1579 1579 1592 1592 1592 1592 1592 1593 1593 1593 1593 1593 1594 1594 1594 1594 1594 1594 1594 1594 1594 1595 1595 1595 1595 1595 1595 1595 1595 1596 1596 1596 1596 1596 1596 27 .695 27 .776 28 .284 28 .764 28 .311 27.247 26 .680 28.358 29.077 28.952 30 .065 30.431 29.513 29.809 29.649 29.315 30. 173 30. 138 29.027 31.591 32.483 19.165 20.603 20 .969 21.448 22 .653 20.8.21 21 .534 20.595 22 .141 21.494 23 .388 24 .101 25.501 26 .439 27.682 28.241 28 .117 23 .331 22.637 23 .438 22 .782 22.459 21.463 21 .617 20.060 .23.747 24 .953 23.230 24 .085 23.410 22 .188 24 .322 23.657 094 806 0.309 1. 262 0. 469 571 -4 .217 -5.327 980 -5-692 673 -6 .229 -4 .420 -3 .439 414 492 247 706 711 -2.888 733 -5.411 147 421 -6 .413 -G6.336 575 844 -10. 017 953 631 405 558 -10. 141 252 997 -10. 858 662 -10. 438 -11.389 -10. 091 -10. 836 907 815 583 -9.389 -11. 900 -11. 675 -13. 081 -14. 150 -15. 502 -15. 596 -13. 914 -13. 077 26.337 24.907 24.387 25. 175 23.071 29.772 30.800 29.796 28.692 31.088 30.689 29.308 31.734 31.043 33.067 34. 012 33. 784 35.238 35.259 33.357 33.361 32.444 32.491 33.784 32.335 32.098 32.485 32.342 32.600 30.944 29.945 30.888 29.625 29.865 30.679 31. 180 30.488 32.393 28.640 29.025 27.366 26.308 25.135 25.523 24.644 25.480 25.858 25.841 25.553 25.077 25.298 24.595 23.587 22.966 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1 .00 1.00 1.00 1.00 1. .00 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1.00 1 .00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 36.17 38.45 39.00 38.88 37 .76 40.59 38 .52 43 .19 44 .84 45. 06 44.86 44 .56 44 .93 43 .13 47.61 48.39 48.74 49. 73 49.21 49.67 52 .07 64 .83 64.82 67.61 63 .99 65.67 62 .41 61.23 61.20 59.26 59.84 57 .94 54 .91 55 .13 56 .93 59.60 58.45 58.95 52.30 52 .03 49.60 45 .16 41.36 39.43 36.21 34 .91 43.30 43 .62 42 .92 41.86 40.86 37.88 41.59 41.94 145. vOl WO 98/07835 WO 9807835PCT/US97/14885 133

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1051 1053 1054 1055 1057 1058 1059 1061 1062 1063 1064 1065 1066 1070 1071 1072 1074 1075 1076 1077 1078 1079 1080 1081 1083 1084 1085 1086 1087 1088 1089 1090 1092 1093 1094 1095 1096 1097 1098 1100 1101 1102 1104 1105 1166~ 1108 1109 1110 1111 1112 1113 1115 1116 1117 SER 1597 SER 1597 SER 1597 SER 1597 SER 1597 SER 1597 LYS 1598 LYS 1598 LYS 1598 LYS 1598 LYS 1598 LYS 1598 LYS 1598 LYS 1598 LYS 1598 ASP 1599 ASP 1599 ASP 1599 ASP 1599 ASP 1599 ASP 1599 ASP 1599 ASP 1599 LEU 1600 LEU 1600 LEU 1600 LEU 1600 LEU 1600 LEU 1600 LEU 1600 LEU 1600 VAL 1601 VAL 1601 VAL 1601 VAL 1601 VAL 1601 VAL 1601 VAL 1601 SER 1602 SER 1602 SER 1602 SER 1602 SER 1602 SER 1602 CYS 1603 CYS 1603 CYS 1603 CYS 1603 CYS 1603 CYS 1603 ALA 1604 ALA 1604 ALA 1604 ALA 1604 25.275 25.557 26.729 27.824 24.315 24.0 36 23.560 22.362 21.791 20.989 20 .164 19.792 20.993 21.324 20.567 21.316 20.380 20.556 19.970 20.270 19.204 20.633 19.694 21.912 22.323 23.823 24.275 25.794 23.549 21.949 21.352 22.269 21.954 22.593 22.355 24.093 20.438 19.946 19.702 18.243 17.680 16.266 17.649 16.662 18.274 17.870 18.784 18 .575 17 .988 17.087 19.113 19.376 20.783 18.349 -14 .637 -14 .518 -15 .409 -15 .147 -14.921 -14.353 -15 .891 -16.312 -17.594 -18 .402 -19.499 -20.572 -21.338 -15.194 -14.983 -14 .458 -13 .352 -12.686 -13 .493 -13 .143 -14.450 -12 .306 -11.779 -11.999 -10.998 -10 .722 -10.162 -9.931 -8.863 -11.390 -10.601 -12.623 -13 .115 -14.497 -14.936 -14 .434 -13.181 -12.914 -13.511 -13 .585 -14.189 -14.074 -12.199 -12.039 -11 .202 -9.823 -8.943 -7.212 -9.422 -8.796 -9.778 9.484 -9.941 -10.203 23.018 21,. 603 21.223 22.077 20.818 19.769 21.327 20. 634 21.228 20. 198 20.838 19.829 19.362 20.696 19.738 21.807 21.983 23.346 24.483 25.642 24.235 20.922 20.311 20.724 19.744 19. 875 21. 235 21. 242 21. 514 18.311 17. 574 17. 933 16.602 16.349 14. 914 16.622 16.405 15.310 17.468 17. 400 18.679 18.692 17.156 16.426 17.765 17.599 18.438 18.103 16.112 15. 552 15.491 14. 077 13.690 13.223 1. 00 1. 00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1.00 1. 00 1. 00 1.00 1.00 1. 00 1.00 1. 00 1.00 1. 00 1.00 1. 00 1. 00 1. 00 1.00 1. 00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1. 00 1. 00 0. 50 1.00 1.00 1.00 1.00 1.00 1.00 39.60 39.74 41.38 50.59 38 .16 38.03 36.40 35.97 36.69 40.42 40.37 46 .34 45.29 37.49 38 35.21 34 .02 37.78 40.05 42 .73 42.39 32 .84 30.59 31.11 32 .17 32 31.08 30.59 28.89 30.77 29.87 30.19 29.25 31.27 31.60 31.91 29.06 27 .71 29.10 29.29 30.81 35 .78 28 .98 26 .82 29.06 29.22 29.66 23.69 PRT1 29.23 27.52 27.87 26.37 23.88 25.82 145. vOl WO 98/07835 PCT/US97/14889 134

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1118 0 1119 N 1121 CA 1122 CB 1123 CG 1124 CD1 1125 CEl 1126 CD2 1127 CE2 1128 CZ 1129 OH 1131 C 1132 0 1133 N 1135 CA 1136 CB 1137 CG 1138 CD 1139 OE1 1140 NE2 1143 C 1144 0 1145 N 1147 CA 1148 CB 1149 CG1 1150 CG2 1151 C 1152 .0 1153 N 1155 CA 1156 CB 1157 C 1158 0 1159 N 1161 CA 1162 CB 1163 CG 1164 CD 1165 NE 1167 CZ 1168 NH1 1171 NH2 1174 C 1175 0 1176 N 1178 CA 1179 C 1180 0 1181 N 1183 CA 1184 CB 1185 CG 1186 SD

ALA

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

VAL

VAL

VAL

VAL

VAL

VAL

VAL

ALA

ALA

ALA

ALA

ALA

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

GLY

GLY

GLY

GLY

MET

-MET

MET

MET

MET

1604 1605 1605 1605 1605 1605 1605 1605 1605 1605 1605 1605 1605 1606 1606 1606 1606 1606 1606 1606 1606 1606 1607 1607 1607 1607 1607 1607 1607 1608 1608 1608 1608 1608 1609 1609 1609 1609 1609 1609 1609 1609 1609 1609 1609 1610 1610 .1610 1610 1611 1611 1611 1611 1611 17.788 18.119 17.152 17.080 15.974 16.111 15.088 14.790 13.775 13.930 12.923 15.748 15. 147 15.244 13.921 13.589 13.357 13.151 12.202 14.056 13.835 12.831 14.904 14.963 16. 225 16.363 16.151 14.934 14.184 15. 738 15.773 16.813 14.383 13.963 13.676 12.327 11. 840 12.407 11.537 10. 849 9.974 9.678 9.416 11. 329 10.469 11. 418 10.555 10.800 9.855 12.076 12.456 13.956 14.398 13.478 -9.631 -11.468 -12.276 -13.662 -14.515 -15. 141 -15.944 -14. 707 -15.500 -16.117 -16.928 -11.641 -11.551 -11.200 -10.581 -10.269 -11.508 -11. 167 -10.471 -11.631 -9.310 -9.058 -8.523 -7.301 -6 .485 -5.274 031 -7.641 -7.033 -8.619 -9.039 -10.117 -9.541 -9.319 -10.216 -10.708 -11.640 -13.005 -13.931 -14.874 -15.771 -15.834 -16.620 -9.569 -9.6*21 -8.565 -7.406 -6.747 -6.424 -6.589 -5.989 -5 .710 542 -3.006 12.289 13 .544 12 .827 13 .456 12 .886 11.640 11.126 13 .596 13 .097 11.867 11.417 12 .775 11.702 13 .926 14 .023 15.482 16 .332 17.791 18 .150 18 .640 13 .186 12.506 13 .216 12.435 12 .787 11.853 14 .246 10.938 10.177 10.522 9.120 8 .920 8.679 7.532 9.585 9.301 10.397 10.290 11.056 10.190 10 .632 11.928 9.784 9.124 8 .231 9.996 9.870 8 .512 7.772 8 .163 6.888 6 .849 7.729 7.426 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 25.84 25 .56 27.81 26.66 30.75 30.20 30.03 30. 73 30.71 30.93 32 .31 26 26.64 25.48 26.86 26.83 25.84 30.86 31.87 31.67 27.52 26 26.68 25.66 28 26 .04 24.45 24.89 25.86 25.24 22.95 20.24 25.71 27.48 27.10 28.55 31.53 36 40.28 42 .06 42 .08 40.32 43 .27 25.55 26.98 23 .92 22 .19 25.92 23.49 23 22.57 22.18- 22.63 25.23 SSSD/55145. vOl WO 98/07835 WO 9807835PCT/US97/14885 135 ATOM 1187 CE MET 1611 13.812 -2.688 5.675 1.00 21.38 ATOM 1188 C MET 1611 12.050 -6.848 5.681 1.00 23.96 ATOM 1189 0 MET 1611 11.673 -6.326 4.633 1.00 25.26 ATOM 1190 N GLU 1612 12.130 -8.163 5.822 1.00 24.34 ATOM 1192 CA GLU 1612 11.755 -9.043 4.733 1.00 25.56 ATOM 1193 CB GLU 1612 12.018 -10.494 5.121 1.00 24.96 ATOM 1194 CG GLU 1612 11.703 -11.488 4.009 1.00 26.79 ATOM 1195 CD GLU 1612 11.812 -12.931 4.450 1.00 26.96 ATOM 1196 OEI GLU 1612 11.557 -13.212 5.636 1.00 30.98 ATOM 1197 0E2 GLU 1612 12.154 -13.791 3.611 1.00 32.31 ATOM 1198 C GLtJ 1612 10.267 -8.829 4.415 1.00 25.70 ATOM 1199 0 GLU 1612 9.860 -8.753 3.252 1.00 24.30 ATOM 1200 N TYR 1613 9.463 -8.723 5.465 1.00 23.55 ATOM 1202 CA TYR 1613 8.037 -8.501 5.294 1.00 22.94 ATOM 1203 CB TYR 1613 7.314 -8.586 6.650 1.00 24.00 ATOM 1204 CG TYR 1613 5.841 -8.281 6-.549 1.00 22.93 ATOM 1205 CD1 TYR 1613 4.945 -9.245 6.097 1.00 21.60 ATOM 1206 CEl TYR 1613 3.582 -8.962 5.963 1.00 21.14 ATOM 1207 CD2 TYR 1613 5.347 -7.018 6.869 1.00 25.81 ATOM 1208 CE2 TYR 1613 3.979 -6.718 6 .733 1.00 24.45 ATOM 1209 CZ TYR 1613 3.112 -7.697 6.281 1.00 23.28 ATOM 1210 OH TYR 1613 1.775 -7.411 6.126 1.00 22.95 ATOM 1212 C TYR 1613 7.803 -7.138 4.637 1.00 22.57 ATOM 1213 0 TYR 1613 7.022 -7.024 3.699 1.00 24.72 ATOM 1214 N LEU 1614 8.460 -6.101 5.156 1.00 22.16 ATOM 1216 CA LEU 1614 8.334 -4.755 4.615 1.00 22.60 ATOM 1217 CB LEU 1614 9.175 -3.772 5.440 1.00 22.56 ATOM 1218 CG LEU 1614 8.577 -3.415 6 .802 1.00 24.92 ATOM 1219 CD1 LEU 1614 9.535 -2.541 7.580 1.00 21.46 ATOM 1220 CD2 LEU 1614 7.218 -2.711 6.611 1.00 21.87 ATOM 1221 C LEU 1614 8.699 -4.683 3.124 1.00 23.76 ATOM 1222 0 LEU 1614 7.975 -4.077 2.326 1.00 23.84 ATOM 1223 N ALA 1615 9.809 -5.314 2.744 1.00 23.48 ATOM 1225 CA ALA 1615 10.232 -5.340 1.352 1.00 22.70 ATOM 1226 CB ALA 1615 11.591 -609 1.215 1.00 21.52 ATOM 1227 C ALA 1615 9.188 -6.063 0.505 1.00 22.87 ATOM 1228 0 ALA 1615 8.854 -5.591 -0.581 1.00 24.23 ATOM 1229 N SER 1616 8.652 -7.176 1.015 1.00 22.76 ATOM 1231 CA SER 1616 7.638 -7.954 0.295 1.00 22.88 ATOM 1232 CB SER 1616 7.315 -9.251 1.039 1.00 21.39 ATOM 1233 OG SER 1616 6.400 -9'>036 2.102 1.00 26.24 ATOM 1235 C SER 1616 6.360 -7.131 0.044 1.00 24.88 ATOM 1236 0 SER 1616 5.635 -7.358 -0.927 1.00 24.73 ATOM 1237 N LYS 1617 6.104 -6.173 0.927 1.00 23.82 ATOM 1239 CA LYS 1617 4.970 -5.287 0.810 1.00 22.47 ATOM 1240 CB LYS 1617 4.455 -4.914 2.199 1.00 23.62 ATOM 1241 CG LYS 1617 3.792 -6 .072 2 .927 1.00 27.16 ATOM 1242 CD LYS 1617 2.551 -6.487 2.169 1.00 30.84 ATOM 1243 CE LYS 1617 1.810 -7.602 2.852 1.00 33.57 ATOM 1244 NZ LYS 1617 2.484 -8.894 2.653 1.00 44.30 ATOM 1248 C LYS 1617 5.346 -4.034 0.035 1.00 23.56 ATOM 1249 0 LYS 1617 4.639 -3.030 0.091 1.00 25.16 ATOM 1250 N LYS 1618 6.495 -4.066 -0.638 1.00 24.69 ATOM 1252 CA LYS 1618 6.953 -2.943 -1.468 1.00 24.04 145. vOl WO 98/07835 PCT/US97/14885 136

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1253 1254 1255 1256 1257 1261 1262 1263 1265 1266 1267 1268 1269 1270 1272 1273 1274 1275 1276 1277 1278 1279 1281 1282 1283 1284 1285 1287 1288 1290 1291 1292 1294 1295 1296 1297 1298 1300 1301 1304 1307 1308 1309 1311 1312 1313 1314 1315 1316 1317 1318 1320 1321 1322

CB

CG

CD

CE

NZ

C

0

N

CA

CB

SG

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

CG

CD2 NDl CEl NE2

C

0

N

CA

CB

CG

CD

NE

Cz NH1 NH2

C

0

N

CA

CB

CG

OD1 0D2

C

0

N

CA

CB

CG

LYS

LYS

LYS

LYS

LYS

LYS

LYS

CYS

CYS

CYS

CYS

CYS

CYS

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ASP

ASP

ASP

AS P AS P AS P

ASP

ASP

LEU

LEU

LEU

LEU

1618 1618 1618 1618 1618 1618 1618 1619 1619 1619 1619 1619 1619 1620 1620 1620 1620 1620 1620 1620 1620 1621 1621 1621 1621 1621 1621 1621 1621 1621 1621 1622 1622 1622 1622 1622 1622 1622 1622 1622 1622 1622 1623 1623 1623 1623 1623 1623 1623 1623 1624 1624 1624 1624 5.863 5.775 5 .567 5.662 4.431 7.406 7 .557 7 .689 8 .108 7 .444 7 .941 9.631 10.304 10.170 11.604 12.202 13 .670 12 .108 12 .171 11.633 10.981 12.348 12.427 13 .181 13 .004 12 .356 13.474 13 .119 12.439 13 .073 12 .528 14.271 15.082 14.268 13 .709 13.089 12.684 11.606 10.801 11.366 15.877 16.787 15.555 16.315 15.777 16 .733 16.276 17.937 16.408 16.118 16.783 16. 941 16 .996 17.082 581 491 942 858 821 686 606 842 731 -0.885 0.313 628 -1.630 0.573 0.841 1.607 1. 995 0. 739 1. 544 1. 729 2. 763 1.297 2. 041 1.237 1. 773 1.260 3. 011 3.233 2. 187 3.401 4.405 3.406 4.608 5. 766 5. 444 6.656 6.300 5. 577 5. 137 5.239 5. 058 5.863 4.527 4.899 6.173 6.735 7.520 6.385 3.766 3.937 2.592 1.428 0.168 -2.492 -3.709 -3.345 558 -5.380 -0.713 -1.302 0. 573 1 .418 2. 792 4 .064 1 .573 1. 809 1. 363 1. 524 0 .276 0. 506 -0.987 -2.286 2 .771 2 .806 3 .804 5 .057 6 .132 7 .528 8 .601 7. 927 9.179 9 .616 4 .914 5 .370 4 .341 4 .140 3 .540 2 .175 1.488 0.131 -0.166 0.797 -1.425 5.379 5.268 6.552 7.748 8.410 9.469 10.321 9.463 8.766 9.956 8 .278 9 .132 8.265 1.00 1 .00 1 .00 1.00 1 .00 1 .00 1.00 1 .00 1 .00 1 .00 1.00 1.00 1 .00 1 .00 1 .00 1 .00 1.00 1 .00 1 .00 1.00 1.00 1 .00 1 .00 1 .00 1.00 1.00 1 .00 1 .00 1 .00 1 .00 1.00 1.00 1.00 1 .00 1 .00 0.50 0.50 0 .50 0 .50 0 .50 1 .00 1 .00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1 .00 26. 96 29.14 33.91 32. 98 36.73 24.01 23.73 25.91 25.65 24 .93 28 .14 23 .07 20.98 22.95 23.81 24.36 17.24 23 .13 25.37 24 25.21 25.62 25.53 22.76 26.42 24.74 26.62 25.70 26.23 .26.36 25.89 25.35 25.05 20.89 19.03 14 .06 11.96 11.83 10.20 8.63 24.37 25.17 24.61 28.82 32.33 36.67 43.56 36.29 28.22 26.87 26.34 26.59 24.59 -1.175 8.978 1.00 24.72 145. vOl WO 98/07835 PCTfUS97/14885 137 ATOM 1323 CD1 LEU 1624 15.844 -1.408 9.856 1.00 24.35 ATOM 1324 CD2 LEU 1624 17.258 -2.261 7.931 1.00 24.63 ATOM 1325 C LEU 1624 18.210 1.595 10.004 1.00 26.87 ATOM 1326 0 LEtI 1624 19.322 1.777 9.497 1.00 28.19 ATOM 1327 N ALA 1625 18.009 1.570 11.317 1.00 27.77 ATOM 1329 CA ALA 1625 19.069 1.741 12.309 1.00 24.54 ATOM 1330 CB ALA 1625 19.355 3.210 12.494 1.00 19.81 ATOM 1331 C ALA 1625 18.498 1. 173 13.592 1.00 26.44 ATOM 1332 0 ALA 1625 17.289 0.961 13.679 1.00 27.58 ATOM 1333 N ALA 1626 19.342 0.940 14.594 1.00 25.38 ATOM 1335 CA ALA 1626 18.872 0.397 15.865 1.00 24.65 ATOM 1336 CB ALA 1626 20.054 0.023 16.774 1.00 23.35 ATOM 1337 C ALA 1626 17.929 1.373 16.578 1.00 25.54 ATOM 1338 0 ALA 1626 17.057 0.951 17.325 1.00 27.70 ATOM 1.339 N ARG 1627 18.104 2.671 16.344 1.00 25.06 ATOM 1341 CA ARO 162-7 17.242 3.675 16.959 1.00 25.48 ATOM 1342 CB ARG 1627 17.706 5.089 16.597 1.00 28.15 ATOM 1343 CG ARG 1627 17.759 5.370 15.084 1.00 33.13 ATOM 1344 CD ARG 1627 18.157 6.811 14.774 1.00 33.29 ATOM 1345 NE ARG 1627 18.442 7.011 13.351 1.00 35.74 ATOM 1347 CZ ARG 1627 19.652 6.889 12.813 1.00 37.40 ATOM 1348 NI 1 ARG 1627 20.695 6.585 13.575 1.00 39.73 ATOM 1351 NH2 ARG 1627 19.817 7.012 11.507 1.00 36.90 ATOM 1354 C ARG 1627 15.812 3.491 16.479 1.00 24.81 ATOM 1355 0 ARG 1627 14.871 3.853 17.173 1.00 24.05 ATOM 1356 N ASN 1628 15.667 2.910 15.293 1.00 24.80 ATOM 1358 CA ASN 1628 14.368 2.686 14.685 1.00 25.97 ATOM 1359 CB ASN 1628 14.383 3.132 13.225 1.00 30.08 ATOM 1360 CG ASN 1628 14.417 4.640 .13.096 1.00 33.62 ATOM 1361 ODi ASN 1628 13.775 5.347 13.864 1.00 35.11 ATOM 1362 ND2 ASN 1628 15.212 5.141 12.169 1.00 36.31 ATOM 1365 C ASN 1628 13.802 1.288 14.824 1.00 26.03 ATOM 1366 0 ASN 1628 12.951 0.869 14.031 1.00 26.87 ATOM 1367 N VAL 1629 14.330 0.550 15.797 1.00 26.04 ATOM 1369 CA VAL 1629 13.854 -0.783 16.128 1.00 25.09 ATOM 1370 CB VAL 1629 14.924 -1.876 15.959 1.00 27.00 ATOM 1371 CG1 VAL 1629 14.390 -3.197 16.546 1.00 20.99 ATOM 1372 CG2 VAL 1629 15.295 -2.051 14.462 1.00 23.26 ATOM 1373 C VAL 1629 13.504 -0.671 17.600 1.00 27.59 ATOM 1374 0 VAL 1629 14.340 -0.285 18.418 1.00 25.81 ATOM 1375 N LEU 1630 12.245 -0.929 17.923 1.00 28.17 ATOM 1377 CA LEU 1630 11.768 -0.845 19.296 1.00 30.20 ATOM 1378 CB LEU 1630 10.445 -0.077 19.332 1.00 30.26 ATOM 1379 CG LEU 1630 10.484 1.285 18.626 1.00 29.81 ATOM 1380 CD1 LEU 1630 9.119 1.983 18.745 1.00 28.46 ATOM 1381 CD2 LEU 1630 11.576 2.141 19.233 1.00 28.37 ATOM 1382 C LEU 1630 11.639 -2.242 19.904 1.00 29.32 ATOM 1383 0 LEU 1630 11.414 -3.219 19.189 1.00 30.84 ATOM 1384 N VAL 1631 11.800 -2.342 21.221 1.00 28.90 ATOM 1386 CA VAL 1631 11.732 -3.629 21.905 1.00 26.84 ATOM 1387 CB VAL 1631 13.067 -3.919 22.670 1.00 28.88 ATOM 1388 CG1 VAL 1631 13.077 -5.341 23.236 1.00 21.54 ATOM 1389 CG2 VAL 1631 14.259 -3.699 21.744 1.00 24.30 ATOM 1390 C VAL 1631 10.561 -3.645 22.881 1.00 29.02 145. vOl WO 98/07835 PCT/US97/14885 138 ATOM 1391 ATOM 1392 ATOM 1394 ATOM 1395 ATOM 1396 ATOM 1398 ATOM 1399 ATOM 1400 ATOM 1401 ATOM 1403 ATOM 1404 ATOM 1405 ATOM 1406 ATOM 1407 ATOM 1408 ATOM 1409 ATOM 1410 ATOM 1411 ATOM 1413 ATOM 1414 ATOM 1415 ATOM 1416 ATOM 1417 ATOM 1418 ATOM 1419 ATOM 1420 ATOM 1422 ATOM 1423 ATOM 1424 ATOM 1425' ATOM 1426 ATOM 1429 ATOM 1430 ATOM 1431 ATOM 1433 ATOM 1434 ATOM 1435 ATOM 1436 ATOM 1437 ATOM 1438 ATOM 1439 ATOM 1441 ATOM 1442 ATOM 1443 ATOM 1444 ATOM 1445 ATOM 1446 ATOM 1447 ATOM 1448 ATOM 1450 ATOM 1451 ATOM 1452 ATOM 1453 ATOM 1454 5SSD/55145. vOl 0

N

CA

CB

OG1 CG2

C.

0

N

CA

CB

CG

CD

OE 1 0E2

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

ODi ND2

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

CD

CE

VAL 1631 10.406 -2.737 *THR 1632 9.733 -4.674 THR 1632 8.562 -4.830 THR 1632 7.488 -5.685 THR 1632 7.896 -7.064 THR 1632 7.268 -5.194 THR 1632 8.919 -5.493 THR 1632 10.017 -6.019 GLU 1633 7.959 -5.524 GLtJ 1633 8.155 -G.138 GLU 1633 6.865 -6.063 GLU 1633 6.957 -6.649 GLU 1633 8.035 -6.000 GLU 1633 8.124 -4.753 GLU 1633 8.788 -6.750 GLU 1633 8.600 -7.585 GLU 1633 9.347 -8.085 ASP 1634 8.185 -8.240 ASP 1634 8.550 -9.637 ASP 1634 7.408 -10.378 ASP 1634 6.041 -10.106 ASP 1634 5.865 -10.367 ASP 1634 5.137 -9.631 ASP 1634 9.826 -9.776 ASP 1634 10.127 -10.865 ASN 1635 10.569 -8.683 ASN 1635 11.819 -8.662 ASN 1635 12.888 -9.587 ASN 1635 13.226 -9.226 ASN 1635 13.275 -8.058 ASN 1635 13.423 -10.235 ASN 1635 11.632 8.980 ASN 1635 12.446 -9.677 VAL 1636 10.533 -8.498 VAL 1636 10.279 -8.711 VAL 1636 8.778 -8.946 VAL 1636 8.538 -9.081 VAL 1636 8.315 -10.209 VAL 1636 10.768 -7.449 VAL 1636 10.506 -6.351 MET 1637 11.575 -7.624 MET 1637 12.119 -6.508 MET 1637 13.366 -6.953 MET 1637 14.479 -7.554 MET 1637 15.124 -6.410 MET 1637 15.120 -7.459 MET 1637 11.040 -6.087 MET 1637 10.480 -6.9.29 LYS 1638 10.755 -4.791 LYS 1638 9.746 -4.258 LYS 1638 8.486 -3.888 LYS 1638 7.715 -5.092 LYS 1638 6.406 -4.683 LYS 1638 5.486 -5.897 23 .706 22 .764 23.616 22 .912 22 .910 21.470 24.943 25.105 25.866 27.177 27.996 29.414 30.301 30.352 30.968 27.042 27.874 25.964 25 .737 25.027 25.657 26 .867 24 .933 24 .905 24.430 24 .739 23 .945 24 .548 25.978 26.340 26 .806 22 .451 21 .834 21 .880 20.469 20.181 18.675 20.897 19 .781 20.254 18 .738 17.980 17 .204 18 .051 19.288 20.689 16 .993 16 .303 16 .931 16 .029 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1 .00 1.00 29.31 30.84 32.24 31.45 30.86 28-.04 34 .17 35.02 36.16 36.34 37.07 44 .57 49.38 51.03 51.63 36.42 38.56 37.70 38.53 44. 08 51.60 52 .37 57.23 36. 56 36 .74 36 .56 37.10 36.92 36.54 38.84 39.58 34 .78 34 .00 31.35 29.76 30.60 30.38 28.51 28.02 25.87 28.15 26.01 27.82 29.73 29.96 27.19 24 .77 24 25.74 23.67 21.78 24.60 23.87 23.06 16 799 1.00 17.298 1.00 18.005 1.00 18.256 1.00 WO 98/07835 PTU9148 PCTIUS97/14889 139

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

A-TOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1455 1459 1460 1461 1463 1464 '1465 1466 1467 1468 1469 1470 1472 1473 1474 1475 1476 1478 1479 1480 1481 1482 1483 1484 1485 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497 1499 1500 1501 1502 1504 1505 1506 1507 1508 1509 1510 1511 1513 1514 1515 1516 1517 1519

NZ

C

0

N

CA

CB

CG2

CGI

CD1

C

0

N

CA

CB

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD1 CD2 CEl CE2

CZ

C

0

N

CA

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

C

0

N

CA

LYS

LYS

LYS

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ALA

ALA

ALA

ALA

ALA

ASP

ASP

AS P

ASP

ASP

ASP

ASP

ASP

PE

PHE

PHE

PHE

PE

PHE

PHE

PHE

PHE

PE

PHE

15LY

GLY

GLY

GLY

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

ALA

ALA

ALA

ALA

ALA

ARG

ARG

1638 1638 1638 1639 1639 1639 1639 1639 1639 1639 1639 1640 1640 1640 1640 1640 1641 1641 1641 1641 1641 1641 1641 1641 1642 1642 1642 1642 1642 1642 1642 1642 1642 1642 1642 1643 1643 1643 1643 1644 1644 1644 1644 1644 1644 1644 1644 1645 1645 1645 1645 1645 1646 1646 4 .871 10.260 10.658 10.271 10.721 10. 935 11.218 12 .103 12.120 9.675 8 .466 10.156 9.321 9.557 9.641 10.691 8.716 .8.862 a9.993 9.668 10.477 8 .633 9. 049 9.598 8 .569 8.680 8.462 7.156 5.986 7.089 4.761 5.872 4 .705 7 .729 7 .983 6.661 5.710 5.805 4.945 6.872 7.124 8.387 8 .414 7.301 9.779 7.259 7.895 6 .607 6 .677 5.463 7.966 8.240 8. 766 10.015 -6 .398 -3-.042 -2-.055 -3.119 -2 .005 -2 .447 -1.236 -3 .433 -4 .232 -0.892 -1 133 0. 320 1 .499 2 .133 2 .510 2 .446 3 .440 4 .526 5 .484 6 .310 7 .203 6 076 4 .107 4 .861 2.-920 2 .426 0'.909 0 .470 0-.495 0 .026 0. 088 -0.383 -0 .354 3 139 3 165 3 746 4 .419 5. 927 6 .636 6 .407 7. 828 8.011 9. 120 8. 887 9. 127 8 .580 8 107 9 .732 10 .569 11.493 11. 388 11. 994 11 .389 12 .140 16 976 15 .293 15 .901 13 .971 13 148 11 .668 10 .762 11 .604 10 .355 13 .242 13 .103 13 .498 13 .632 15 .006 12 .538 11 .896 12 .328 11 .349 11 .753 12 9'99 13 .334 13 .648 9 .898 9 .102 9 .553 8 .191 8 .159 8 .750 7 .988 10 .066 8 .532 10.624 9. 855 7 .219 6 .018 7 .736 6 .863 6 .910 6 .399 7 .525 7 .684 8 .514 9 .549 10 .563 10. 243- 6 .357 5 .414 6 .267 5 .082 5. 028 5 .186 6 .228 4 .129 4 .138 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 1.00 1*.00 1.00 1.00 1.00 1.00 24.60 24.37 26 .58 25.69 25. 94 26.49 21.19 27.58 32.96 27.32 25.45 27.43 26.96 25.21 26.80 27.5 27 .06 30.54 33.12 36.17 42.24 33.22 29. 94 30.13 30.22 30.91 26.24 27.82 27.08 26.70 25.18 27.59 28.05 33.35 36 .19 32.76 31.44 32.94 33 35.45 39.04 37.80 '42. 51 44 .08 44.47 42.20 44.14 43 .89 45.62 45.06 45.82 45.85 45.16 47. 06 SSSD/55145. vOl WO 98/07835 MS718 140 ATOM 1520 CB ARG 1646 11.126 11.318 4.794 1.00 48.00 ATOM 1521 C ARG 1646 10.445 12.546 2.742 1.00 46.83 ATOM 152 2 0 ARG 1646 10.429 11.729 1.823 1.00 45.76 ATOM 1523 N ASP 1647 10.807 13.814 2.578, 1.00 48.96 ATOM 1525 CA ASP 1647 11.278 14.291 1.288 1.00 50.93 ATOM 1526 CB ASP 1647 10.938 15.769 1.073 1.00 52.33 ATOM 1527 CG ASP 1647 11.191 16.228 -0.360 1.005.9 ATM 1528 OD. ASP 1647 12.231 15.850 -0.956 1.00 52.58 ATOM 1529 0D2 ASP 1647 10.340 16.980 -0.896 1.00 59.54 ATOM 1530 C ASP 1647 12.789 14.104 1.336 1.00 50.78 ATOM 1531 0 ASP 1647 13.491 14.803 2.077 1.00 48.32 ATOM 1532 N ILE 1648 13.274 13.144 056 10 08 ATM 13 A ILE 1648 14.696 12.833 0.516 1.00 52.58 ATOM 1535 CB ILE 1648 14.984 11.571 -0.324 1.00 50.85 ATOM 1536 CG2 ILE 1648 14.204 10.386 0.241 1.00 49.34 ATOM 1537 CG1 ILE 1648 14.638 11.813 -1.801 1.00 48.22 ATOM 1538 CD1 ILE 1648 15.233 10.806 -2.754 1.00 42.86 ATOM 1539 C ILE 1648 15.523 13.999 -0.018 1.00 55.57 ATOM 1540 0 ILE 1648 16.648 14.222 0.423 1.00 57.24 ATOM 1541 N HIS 1649 14.944 14.766 -0.936 1.00 56.80 ATOM 1543 CA HIS 1649 15.650 15.895 -1.520 1.00 58.03 ATOM 1544 CB HIS 1649 15.013 16.302 -2.859 1.00 58.71 ATOM 1545 CG HIS 1649 15.221 15.308 -3.958 1.00 60.28 ATOM 1546 CD2 HIS 1649 16.303 14.566 -4.306 1.00 60.74 ATOM 1547 ND1 HIS 1649 14.241 14.986 -4.874 1.00 61.70 ATOM 1549 CEl HIS 1649 14.708 14.104 -5.742 1.00 61.86 ATOM 1550 NE2 HIS 1649 15.959 13.833 -5.417 1.00 60.98 ATOM 1552 C HIS 1649 15.721 17.093 -0.591 1.00 58.49 ATOM 1553 0 HIS 1649 16.129 18.175 -1.004 1.00 60.56 ATOM 1554 N HIS 1650 15.285 16.916 0.654 1.00 59.58 ATOM 1556 CA HIS 1650 15.306 18.001 1.635 1.00 61.38 ATOM 1557 CB HIS 1650 13.898 18.540 1.863 1.00 65.28 ATOM 1558 CG HIS 1650 13.404 19.433 0.738 1.00 72.62 ATOM 1559 CD2 HIS 1650 13.492 20.752 0.536 1.00 76.23 ATOM 1560 ND1 HIS 1650 12.710 18.904 -0.339 1.00 77.05 ATOM 1562 CEl HIS 1650 12.402 19.907 -1.157 1.00 78.51 ATOM 1563 NE2 HIS 1650 12.863 21.015 -0.647 1.00 78.82 ATOM 1565 C HIS 1650 15.925 17.575 2.972 1.00 60.63 ATOM 1566 0 HIS 1650 15.796 18.271 3.969 1.00 60.20 ATOM 1567 N ILE 1651 16.584 16.419 2.987 1.00 60.22 ATOM 1569 CA ILE 1651 17.197 15.920 4.204 1.00 60.03 ATOM 1570 CB ILE 1651 17.574 14.434 4.069 1.00 62.54 ATOM 1571 CG2 ILE 1651 18.280 13.920 5.323 1.00 63.48 ATOM 1572 CG1 ILE 1651 16.329 13.584 3.800 1.00 65.18 ATOM 1573 CD1 ILE 1651 16.635- 12.124 3.603 1.00 67.18 ATOM 1574 C ILE 1651 18.457 16.698 4.557 1.00 59.16 ATOM 1575 0 ILE 1651 19.326 16.907 3.716 1.00 59.25 ATOM 1576 N ASP 1652 18.532 17.176 5.793 1.00 58.91 ATOM 1578 CA ASP 1652 19.702 17.915 6.260 1.00 58.25 ATOM 1579 CB ASP 1652 19.312 18.788 7.444 1.00 61.14 ATOM 1580 CG ASP 1652 20.-506 19.569 8.028 1.00 65.33 ATOM 1581 ODi ASP 1652 21.614 19.574 7.411 1.00 67.11 ATOM 1582 0D2 ASP 1652 20.337 20.191 9.126 1.00 69.04 ATOM 1583 C ASP 1652 20.786 16.922 6.676 1.00 56.75 145. vOl WO 98/07835 WO 9807835PCT1US97/14885 ATOM 1584 ATOM 1585 ATOM 1587 ATOM 1588 ATOM 1589 ATOM 1590 ATOM 1591 ATOM 1592 ATOM 1593 ATOM 1594 ATOM 1595 ATOM 1597 ATOM 1598 ATOM 1599 ATOM 1601 ATOM 1602 ATOM 1603 ATOM 1604 ATOM 1605 ATOM 1606 ATOM 1607 ATOM 1608 ATOM 1609 ATOM 1611 ATOM 1612 ATOM 1613 ATOM 1615 ATOM 1616 ATOM 1617 ATOM 1618 ATOM 1619 ATOM 1620 ATOM 1624 ATOM 1625 ATOM 1626 ATOM 1628 ATOM 1629 ATOM 1630 ATOM 1631 ATOM 1632 ATOM 1633 ATOM 1637 ATOM 1638 ATOM .1639 ATOM 1641 ATOM 1642 ATOM 1643 ATOM 1645 ATOM 1646 ATOM .1647 ATOM 1648 ATOM 1650 ATOM 1651 ATOM 1652 0

N

CA

CB

CG

CD1 CEl CD2 CE2 Cz

OH

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2 Cz

OH

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

001 CG2

C

0

N

CA

CB

C

AS P

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

THR

THR

THR

THR

THR

THR

THR

THR

THR

THR

THR

1652 1653 1653 1653 1653 1653 1653 1653 1653 1653 1653 1653 1653 1654 1654 1654 1654 1654 1654 1654 1654 1654 1654 1654 1654 1655 1655 1655 1655 1655 1655 1655 1655 1655 1656 1656 1656 1656 1656 1656 1656 1656 1656 1657 1657 1657 1657 1657 1657 1657 1658 1658 1658 1658 20.699 21.794 22 .900 23.825 23.334 24.123 23 .701 22.099 21.664 22.469 22.049 23.717 24.381 23.673 24.421 24.978 26 .068 25.760 26.769 27.412 28.425 28.102 29.117 23.628 24.173 22.348 21.493 20.019 19.054 17.644 16 .626 15.230 21.754 21.902 21.822 22.069 23.027 24.474 25.320 26.803 27.619 20.774 19.714 20.875 -19.743 19.973 21.150 20.152 19.664 20.513 18.678 18 .548 17.318 19.811 16 .307 16 .762 15 .849 15 .783 14 .854 14 .566 13 .658 14 .214 13 .302 13 .025 12 .107 16 .158 15 .284 17.409 17 .826 19 .235 19 .269 19 .301 19 .289 19 .227 19 .216 19 .248 19 .248 17 .732 17 .935 17 393 17 .277 17 .382 17 .346 17 .608 17 .243 17 .494 15 .976 14 .907 16 .084 14 .933 15 .310 15.489 15 .889 15 .666 16 .007 14 .381 15 .007 13 .198 12 .541 11 .012 10 .730 10.431 13 .102 13 .899 12 .667 13 .140 12 .517 12 .779 7 .741 5 .826 6 .088 4 .872 3 .796 2.685 1 .724 3 .917 2 .966 1 .870 0 .933 7 .339 7 .900 7 .773 8 .947 8 .733 7 .685 6.325 5 .356 8 .053 7 .099 5 .753 4 .817 10.245 11 .335 10 .133 11 .306 10 .910 12 .079 11 .602 12 .660 12 .186 12 .057 11.454 13.380 14.236 15 .372 14 .957 16.157 15.908 17 .109 14 .824 14.733 15 .420 16 .053 16.121 16 .896 14.731 17 .472 17 .870 18.249 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1 .00 1 .00 1 .00 1.00 1.00 1 .00 1 .00 1.00 1.00 1 .00 1.00 1.00 1.00 1 .00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 1. 00 56.06 55.40 54 52 52 51.50 53 .52 52 .88 54 .63 54 53 .23 55.40 54.47 56.72 58.87 57.91 60.49 61.37 63 .72 61 .74 64.08 65.12 64 .17 60.17 61.09 60. 54 62 .12 64.32 67.17 73 77.36 81.10 62.19 61.36 62.26 62.28 62.05 62.62 66.45 67.28 68.45 61.86 62 60.10 57.73 56 .04 55.21 53.07 57.74 57.76 58.80 60.33 61.37 60.43 19.627- 1.00 20.290 1.00 20.406 1.00 145. vOl WO 98/07835 PCTUS97/14885.

142 ATOM 1653 0 ATOM 1654 N ATOM 1656 CA ATOM 1657 CB ATOM 1658 CC ATOM 1659 ODI ATOM 1660 ND2 ATOM 1663 C ATOM 1664 0 ATOM 1665 N ATOM 1667 CA ATOM 1668 C ATOM 1669 0 ATOM 1670 N ATOM 1672 CA ATOM 1673- CB ATOM 1674 CG ATOM 1675 CD ATOM 1676 NE ATOM 1678 CZ ATOM 1679 NH1 ATOM 1682 NH2 ATOM 1685 C ATOM 1686 0 ATOM 1687 N ATOM 1689 CA ATOM 1690 CB ATOM 1691 -CC ATOM 1692 CD1 ATOM 1693 CD2 ATOM 1694 C ATOM 1695 0 ATOM 1696 N ATOM 1697 CD ATOM 1698 CA ATOM 1699 CB ATOM 1700 CG ATOM 1701' C ATOM 1702 0 ATOM 1703 N ATOM 1705 CA ATOM 1706 CB ATOM 1707 CG1 ATOM 1708 CG2 ATOM 1709 C ATOM 1710 0 ATOM 1711 N ATOM 1713 CA ATOM 1714 CB ATOM 1715 CG ATOM 1716 CD ATOM "1717 CE ATOM 1718 NZ ATOM 1722 C THR 1658 ASN 1659 ASN 1659 ASN 1659 ASN 1659 ASN '1659 ASN 1659 ASN 1659 ASN 1659 GLY 1660 CLY 1660 GLY 1660 CLY 1660 ARG 1661 ARC 1661 ARC 1661 ARC 1661 ARG 1661 ARG 1661 ARG 1661 ARC 1661 ARC 1661 ARC 1661 ARC 1661 LEU 1662 LEU 1662 LEU 1662 LEU 1662 LEU 1662 LEU 1662 LETJ 1662 LEU 1662 PRO 1663 PRO 1663 PRO 1663 PRO 1663 PRO 1663 PRO 1663 PRO 1663 VAL 1664 VAL 1664 VAL 1664 VAL 1664 VAL 1664 VAL 1664 VAL 1664 LYS 1665 LYS 1665 LYS 1665 LYS 1665 LYS 1665 LYS 1665 LYS 1665 LYS 1665 20.350 20.311 21.508 21.607 22 .444 22.382 23.210 22 .781 23 .868 22 .643 23. 781 24.539 25.716 23 .879 24.536 24.283 24.848 24.492 25. 013 24. 902 24.286 25.426 24.076 23.031 24.839 24.546 25.823 26.408 27.853 25.591 23 .946 24.647 22.632 21.717 21.894 20.535 20.343 22.556 22.362 23.333 24. 020 24.831 23.898 25.670 24.957 25.328 25.303 26.189 26. 815 27.'967 28.283 29.543 29.826 25.546 13 .599 11-.567 11. 058 9. 545 8 .883 9 .265 7. 867 11. 717 11 .418 12. 570 13 .276 12 .570 12 .855 11 .659 10. 930 9 .428 8 796 7. 325 6 .614 5 .299 4 .560 4 .717 11 .422 12 .029 11. 094 11. 503 12 .031 13 .332 13 .478 14 .536 10. 362 9.436 10.428 11.475 9.424 10. 098 10. 856 9. 045 7 .933 9. 960 9.669 10. 886 11. 906 11 .523 8 .469 7. 864 8 .116 6 .991 7 .100 8 .089 8 .619 9.478 10. 128 5 .637 21.155 1.00 20.161 1.00 20.827 1.00 20.645 1.00 21.723 1.00 22 .891 1.00 21.341 1.00 20.311 1.00 20.793 1.*00 19.299 1.00 18.733 1.00 17.623 1.00 17.394 1.00 16.918 1.00 15.833 1.00 15.961 1.00 17.215 1.00 17.234 1.00 18.396 1.00 18.566 1.00 17.645 1.00 19.643 1.00 14.459 1.00 14.325 1.00 13.432 1.00 12.076 1.00 11 .399 1.00 11.*965 1.00 11.537 1.00 11.514 1.00 11.258 1.00 10.862 1.00 10.987 1.00 11.489 1.00 10.207 1.00 9.983 1.00 11.258 1.00 8.876 1.00 8.378 1.00 8.299 1.00 7.034 1.00 6.477 1.00 5.864 1.00 7.571 1.00 7.171 1.00 6.175 1.00 8.409 1.00 8.673 1.00 10.065 1.00 10.079 1.00 11.466 1.00 11.426 1.00 12.737 1.00 8.465 1.00 60.59 59.97 58.28 59.95 60.10 61.26 57.09 57.13 57.34 56 .48 54-8 7 53 .04 54 .11 51.37 48-.96 48.48 50 .03 50 .78 50.11 50.08 46.57 47.88 46.53 45 .01 42.39 40.71 40.25 42 .44 40.42 41 .16 38.45 36 .67 37.09 38.18 35.59 35.90 39.13 33 31.16 32 .07 32.49 32 .68 32.25 33 .22 29. 57 27.39 28.82 27.87 26 .99 29.23 30 .64 30.94 31 .63 26.76 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 143 ATOM 1723 ATOM 1724 ATOM 1726 ATOM 1727 ATOM 1728 ATOM 1729 ATOM 1730 ATOM 1731 ATOM 1732 ATOM 1733 ATOM 1735 ATOM 1736 ATOM 1737 ATOM 1738 ATOM 1739.

ATOM 1740 ATOM 1742 ATOM 1743 ATOM 1744 ATOM 1745 ATOM 1746 ATOM 1747 ATOM 1748 ATOM 1749 ATOM 1751 ATOM 1752 ATOM 1753 ATOM 1754 ATOM 1755 ATOM 1756 ATOM 1757 ATOM 1758 ATOM 1759 ATOM 1760 ATOM 1761 ATOM 1762 ATOM 1764 ATOM 1765 ATOM 1766 ATOM 1767 ATOM 1768 ATOM 1769 ATOM 1770 ATOM 1771 ATOM 1772 ATOM 1774 ATOM 1775 ATOM 1776 ATOM 1777 ATOM 1778 ATOM 1780 ATOM 1781 ATOM 1782 ATOM 1783 SSSD/55145. vOl 0

N

CA

CB

CG

CD2 CE2 CE3 CD1 NE 1 CZ2 CZ3 CH2

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

C

0~

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD1

LYS

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

MET

MET

MET

MET

MET

MET

MET

MET

ALA

ALA

ALA

ALA

ALA

PRO

PRO

PRO

PRO

PRO

PRO

PRO

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ALA

ALA

ALA

ALA

ALA

LEU

LEU

LEU

LEU

LEU

1665 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1667 1667 1667 1667 1667 1667 1667 1667 1668 1668 1668 1668 1668 1669 1669 1669 1669 1669 1669 1669 1670 1670 1670 1670 1670 1670 1670 1670 1670 1671 1671 1671 1671 1671 1672 1672 1672 1672 1672 26.211 24.260 23.561 22.299 22 .564 23 .052 2-3.134 23.433 22.376 22.716 23.575 23 .870 23.939 23.188 22.754 23.404 23. 046 22.894 21.823 21.795 21.019 23 .991 25.205 23.420 24.217 23.339 24.805 24.181 26. 006 26.899 26.611 27.864 28.225 25.686 25.617 24.951 24.057 23 .597 22. 588 23.M1 22.429 24.458 22.864 22.358 22.451 21.347 20.751 21.899 21.298 23.068 23.715 2-4.931 25.783 25.010 4.615 8.589 1.00 5.630 -8.137 1.00 4.381 7.865 1.00 4.273 8.724 1.00 3.872 10.174 1.00 4.717 11.232 1.00 3.920 12.398 1.00 6.062 11.306 1.00 2.636 10.730 1.00 2.660 12.063 1.00 4.433 13 .627 1.00 G .569 12.523 1.00 5. 754 13.665 1.00 4.263 6.386 1.00 3.214 5.931 1.00 5.330 5.631 1.00 5.361 4.215 1.00 6.802 3.744 1.00 7.621 4.434 1.00 9.276 3 .706 1.00 8. 904 2 .238 1.00 4.693 3.239 1.00 4.894 3.294 1.00 3.963 2.286 1.00 3.337 1.237 1.00 2.495 0.340 1.00 4.495 0.430 1.00 5.551 0.316 1.00 4.314 -0.153 1.00 3.144 -0.095 1.00 5.390 -0.942 1.00 4.731 -1.518 1.00 3.741 -0.471 1.00 5.900 -2.057 1.00 7.099 -2.288 1.00 5.010 -2.724 1.00 5.459 -3.796 1.00 4.293 -4.693 1.00 3.325 -4.065 1.00 2.184 -3.255 1.00 1.297 -2.822 1.00 2.157 -3.069 1.00 6.274 -3.294 1.00 7.146 -4.001 1.00 6.028 -2.053 1.00 6.779 -1.465 1.00 6.031 -0.287 1.00 8.125 -1.013 1.00 9.167 -1.249 1.00 8.096 -0.387 1.00 9.304 0.100 1.00 8.935 0.940 1.00 10.071 1.502 1.00 10.800 2.581 1.00 26.78 25.79 26 .56 25.63 26 24 .83 24 .49 24.54 20.10 21.86 25.71 26 .00 26 .04 23 .62 24 .87 22 .78 23.73 26 .24 35 42 .23 40.57 22.77 24.25 22 .73 23 .54 21.80 25.53 23 .66 26 .86 26.35 27.78 25.51 25.36 26.47 28.42 26 .88 29.03 31.79 32.47 32.43 25.01 28.75 28.37 25.72 30.08 31.24 26.42 31.36 33 .11 32 .73 33 .96 33.89 37.62 39.57 WO 98/07835 PCT1US97/14885 144 ATOM 1784 CD2 LEU 1672 27.054 9.491 2.087 1.00 32.30 ATOM 1785 C LEU 1672 24.157 10.207 -1.042 1.00 36.83 ATOM 1786 0 LEU 1672 23.769 11.369 -1.102 1.00 37.87 ATOM 1787 N PHE 1673 24.959 9.669 -1.954 1.00 35.82 ATOM 1789 CA PHE 1673 25.466 10.449 -3.071 1.00 35.82 ATOM 1790 CB PHE 1673 26.738 9.802 -3.639 1.00 34.66 ATOM 1791 CG PHE 1673 27.850 9.642 -2.634 1.00 33.84 ATOM 1792 CD1 PHE 1673 28.503 8.422 -2.494 1.00 32.65 ATOM 1793 CD2 PHE 1673 28.242 10.709 -1.827 1.00 36.98 ATOM 1794 CEl PHE 1673 29.540 8 .257 -1.555 1.00 37.95 ATOM 1795 CE2 PHE 1673 29.279 10.557 -0.881 1.00 39.90 ATOM 1796 CZ PHE 1673 29.927 9.325 -0.748 1.00 37.09 ATOM 1797 C PHE 1673 24.483 10 .'692 -4.210 1.00 36.34 -ATOM 1798 0 PHE 1673 24.430 11 .788 -4.754 1.00 37.18 ATOM 1799 N ASP 1674 23.705 9.677 -4.568 1.00 38.22 ATOM 1801 CA ASP 1674 22.780 9.777 -5.693 1.00 38.51 ATOM 1802 CB ASP 1674 23.008 8.597 -6.633 1.00 40.34 ATOM 1803 CG ASP 1674 24.439 8.511 -7.122 1.00 43.87 ATOM 1804 ODi ASP 1674 25.092 9.571 -7.254 1.00 42.79 ATOM 1805 0D2 ASP 1674 24.906 7 .376 -7.369 1.00 47.94 ATOM 1806 C ASP 1674 21.298 9.853 -5.360 1.00 40.21 ATOM 1807 0 ASP 1674 20.457 9.872 -6.271 1.00 39.07 ATOM 1808 N ARG 1675 20.975 9.836 -4.072 1.00 39.83 ATOM 1810 CA ARO 1675 19.589 9.900 -3.631 1.00 42.25 ATOM 1811 CB ARG 1675 18.992 11.271 -3.964 1.00 48.19 ATOM 1812 CG ARG 1675 19.691 12.420 -3 .267 1.00 59.20 ATOM 1813 CD ARG 1675 19.462 13.729 -4.019 1.00 67.81 ATOM 1814 NE ARG 1675 20.079 14.876 -3.352 1.00 75.11 ATOM 1816 CZ ARG 1675 19.688 16.136 -3.525 1.00 78.74 ATOM 1817 NHl ARG 1675 18.680 16.429 -4.341 1.00 79.91 ATOM 1820 NH2 ARG 1675 20.311 17.115 -2.890 1.00 81.24 ATOM 1823 C ARG 1675 18.730 8.777 -4.221 1.00 39.00 ATOM 1824 0 ARG 1675 17.544 8.956 -4.488 1.00 39.71 ATOM 1825 N ILE 1676 19.345 7.624 -4.434 1.00 35.50 ATOM 1827 CA ILIE 1676 18.636 6.471 -4.958 1.00 33.51 ATOM 1828 CB ILE 1676 19.434 5.759 -6.039 1.00 34.59 ATOM 1829 CG2 ILE 1676 18.582 4.678 -6.649 1.00 33.90 ATOM 1830 CG1 ILE 1676 19.848 6.752 -7.120 1.00 37.60 ATOM 1831' CD1 ILE 1676 20.861 6-197 -8.109 1.00 42.67 ATOM 1832 C ILE 1676 18.390 5.501 -3.809 1.00 30.94 ATOM 1833 0 ILE 1676 19.326 4.926 -3.2 52 1.00 28.62 ATOM 1834 N TYR 1677 17.124 5.351 -3.443 1.00 30.60 ATOM 1836 CA TYR 1677 16.724 4.467 -2.359 1.00 25.87 ATOM 1837 CE TYR 1677 15.781 5.197 -1.413 1.00 26.40 ATOM 1838 CG TYR 1677 16.483 6.220 -0.555 1.00 27.67 ATOM 1839 CD1 TYR 1677 16.663 7.533 -0.999 1.00 27.45 ATOM 1840 CEl TYR 1677 17.269 8.483 -0.191 1.00 26.55 ATOM 1841 CD2 TYR 1677 16.935 5.883 0.721 1.00 24.58 ATOM 1842 CE2 TYR 1677 17.536 6.828 1.538 1.00 26.35 ATOM 1843 CZ TYR 1677 17.698 8 .122 1.080 1.00 28.80 ATOM 1844 OH TYR 1677 18.270 9.059 1.914 1.00 34.97 ATOM 1846 C TYR 1677 16.055 3.235 -2.911 1.00', 22.70 ATOM 1847 0 TYR 1677 15.144 3.335 -3.728 1.00 26.22 ATOM 1848 N THR 1678 16.477 2.076 -2.420 1.00 21.83 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 145 ATOM 1850 CA THR 1678 15.968 0.791 -2.865 1.00 22.14 ATOM 1851 CB THR 1678 16.907 0.191 -3.928 1.00 23.91 ATOM 1852 OGi THR 1678 18.229 0.105 -3.373 1.00 27.47 ATOM 1854 CG2 THR 1678 16.949 1.053 -5.188 1.00 24.94 ATOM 1855 C THR 1678 15.999 -0.176 -1.692 1.00 22.79 ATOM 1856 0 THR 1678 16.427 0.170 -0.592 1.00 23.39 ATOM 1857 N HIS 1679 15.563 -1.402 -1.929 1.00 21.98 ATOM 1859 CA HIS 1679 15.613 -2.417 -0.888 1.00 22.97 ATOM 1860 CB HIS 1679 14.872 -3.671 -1.351 1.00 22.04 ATOM 1861 CG HIS 1679 13.421 -3.444 -1.621 1.00 25.41 ATOM 1862 CD2 HIS 1679 12.674 -3.611 -2.740 1.00 26.60 ATOM 1863 ND1 HIS 1679 12.556 -2.954 -0.663 1.00 26.13 ATOM 1865 CE1 HIS 1679 11.348 -2.830 -1.178 1.00 28.66 ATOM 1866 NE2 HIS 1679 11.394 -3.221 -2.441 1.00 29.66 ATOM 1868 C HIS 1679 17.097 -2.719 -0.650 1.00 23.14 ATOM 1869 0 HIS 1679 17.511 -3.074 -0.459 1.00 21.69 ATOM 1870 N GLN 1680 17.895 -2.506 -1.697 1.00 22.38 ATOM 1872 CA GLN 1680 19.335 -2.726 -1.658 1.00 22.33 ATOM 1873 CB GLN 1680 19.948 -2.594 -3.058 1.00 22.52 ATOM 1874 CG GLN 1680 19.895 -3.872 -3.879 1.00 29.15 ATOM 1875 CD GLN 1680 18.865 -3.847 -4.991 1.00 33.60 ATOM 1876 OE1 GLN 1680 17.819 -3.212 -4.871 1.00 38.43 ATOM 1877 NE2 GLN 1680 19.159 -4.542 -6.085 1.00 33.44 ATOM 1880 C GLN 1680 20.007 -1.740 -0.732 1.00 22.61 ATOM 1881 0 GLN 1680 20.943 -2.093 -0.027 1.00 22.00 ATOM 1882 N SER 1681 19.562 -0.490 -0.745 1.00 22.06 ATOM 1884 CA SER 1681 20.184 0.479 0.137 1.00 23.41 ATOM 1885 CB SER 1681 19.886 1.923 0.306 1.00 20.06 ATOM 1886 OG SER 1681 18.503 2.166 -0.479 1.00 22.90 ATOM 1888 C SER 1681 19.778 0.206 1.583 1.00 23.08 ATOM 1889 0 SER 1681 20.528 0.531 2.506 1. 00 24.13 ATOM 1890 N ASP 1682 18.608 -0.412 1.770 1.00 23.19 ATOM 1 892 CA ASP 1682 18.107 -0.775 3.104 1.00 22.37 ATOM 1893 CB ASP 1682 16.660 -1.275 3.018 1.00 24.55 ATOM 1894 CG ASP 1682 15.616 -0.172 3.222 1.00 24.22 ATOM 1895 ODi ASP 1682 14.428 -0.479 3.005 1.00 25.02 ATOM 1896 0D2 ASP 1682 15.949 0.968 3.625 1.00 24.82 ATOM 1897 C ASP 1682 18.980 -1.888 3.690 1.00 20.47 ATOM 1898 0 ASP 1682 19.172 -1.984 4.906 1.00 21.83 ATOM 1899 N VAL 1683 19.480 -2.746 2.806 1.00 20.14 ATOM 1901 CA VAL 1683 20.340 -3.856 3.179 1.00 20.49 ATOM 1902 CB VAL 1683 20.493 -4.842 2.003 1.00 22.38 ATOM 1903 CG1 VAL 1683 21.757 -5.691 2.159 1.00 19.57 ATOM 1904 CG2 VAL 1683 19.264 -5.740 1.942 1.00 22.35 ATOM 1905 C VAL 1683 21.677 -3.315 3.683 1.00 20.22 ATOM 1906 0 VAL 1683 22.202 -3.789 4.684 1.00 21.41 ATOM 1907 N TRP 1684 22.210 -2.311 3.003 1.00 21.33 ATOM 1909 CA TRP 1684 23.440 -1.666 3.449 1.00 22.21 ATOM 1910 CB TRP 1684 23.768 -0.473 2.540 1.00 18.78 ATOM 1911 CG TRP 1684 24.924 0.391 3.037 1.00 22.80 ATOM 1912 CD2 TRP 1684 26.237 0.477 2.472 1.00 24.60 ATOM -1913 CE2 TRP' 1684 26.989 1.364 3.286 1.00 24.34 ATOM 1914 CE3 TRP 1684 26.853 -0.099 1.352 1.00 24.32 ATOM 1915 CD1 TRP 1684 24.933 1.208 4.138 1.00 22.28 145. vOl WO 98/07835 PCT/US97/14885 146 ATOM 1916 NEl TRP 1684 26.169 1.791 ATOM 1918 CZ2 TRP 1684 28.324 1.669 ATOM 1919 CZ3 TRP 1684 28.193 0.213 ATOM 1920 CH2 TRP 1684 28.906 1.088 ATOM 1921 C TRP 1684 23.198 -1.183 ATOM 1922 0 TRP 1684 23.982 -1.475 ATOM 1923 N SER 1685 22.108 0.447 ATOM 1925 CA SER 1685 21.744 0.057 ATOM 1926 CB SER 1685 20.398 0.783 ATOM 1927 OG SER 1685 20.424 1.787 ATOM 1929 C SER 1685 21.659 -1.087 ATOM 1930 0 SER 1685 22.077 -0.933 ATOM 1931 N PHE 1686 21.099 -2.221 ATOM 1933 CA PHE 1686 20.993 -3.393 ATOM 1934 CB PHE 1686 20.216 -4.519 ATOM 1935 CG PHE 1686 20.062 -5.734 ATOM 1936 CD1 PHE 1686 19.240 -5.701 ATOM 1937 CD2 PHE 1686 20.773 -6.899 ATOM 1938 CEI PHE 1686 19.125 -6.801 ATOM 1939 CE2 PHE 1686 20.663 -8.012 ATOM 1940 CZ PHE 1686 19.842 -7.961 ATOM 1941 C PHE 1686 22.389 -3.890 ATOM 1942 0 PHE 1686 22.579 -4.424 ATOM 1943 N GLY 1687 23.354 -3.726 ATOM 1945 CA GLY 1687 24.718 -4.110 ATOM 1946 C GLY 1687 25.230 -3.247 ATOM 1947 0 GLY 1687 25.901 -3.749 ATOM 1948 N VAL 1688 24.928 -1.947 ATOM 1950 CA VAL 1688 25.331 -1.009 ATOM 1951 CB VAL 1688 25.020 0.481 ATOM 1952 CG1 VAL 1688 25.547 1.438 ATOM 1953 CG2 VAL 1688 25.675 0.832 ATOM 1954 C VAL 1688 24.598 -1.400 ATOM 1955 0 VAL 1688 25.199 -1.479 ATOM 1956 N LEU 1689 23.31,0 -1.706 ATOM 1958 CA LEU 1689 22.534 -2.111 ATOM 1959 CB LEU 1689 21.064 -2.357 ATOM 1960 CG LEU 1689 20.006 -2.491 ATOM 1961 CD1 LEU 1689 18.643 -2.109 ATOM 1962 CD2 LEU 1689 19.959 -3.895 ATOM 1963 C LEU 1689 23.158 -3.375 ATOM 1964 0 LEU 1689 23.249 -3.483 ATOM 1965 N LEU 1690 23.588 -4.323 ATOM 1967 CA LEU 1690 24.221 -5.544 ATOM 1968 CB LEU 1690 24.669 -6.444 ATOM 1969 CG LEU 1690 23.672 -7.309 ATOM 1970 CD1 LEU 1690 24.415 -7.962 ATOM 19.71 CD2 LEU 1690 23.042 -8.380 ATOM 1972 C LEU 1690 25.430 -5.168 ATOM 1973 0 LEU 1690 25.646 -5.706 ATOM 1974 N TRP 1691 26.211 -4.227 ATOM 1976 CA TRP 1691 27.405 -3.728 ATOM 1977 CB TRP 1691 28.072 -2.659 ATOM 1978 CG TRP 1691 29.394 -2.195 4.297 1.00 3.022 1.00 1.090 1.00 1.918 1.00 4.899 1.00 5.805 1.00 5.113 1.00 6.444 1.00 6.385 1.00 5.388 1.00 7.464 1.00 8.625 1.00 7.037 1.00 7.898 1.00 7.216 1.00 8.075 1.00 9.203 1.00 7.793 1.00 10.033 1.00 8.623 1.00 9.743 1.00 8.300 1.00 9.407 1.00 7.401 1.00 7.721 1.00 8.867 1.00 9.778 1.00 8.817 1.00 9.877 1.00 9.488 1.00 10.543 1.00 8.160 1.00 11.182 1.00 12.255 1.00 11.082 1.00 12.253 1.00 11.866 00 12.976 1.00 12.408 1.00 13.553 1.00 12.871 1.00 14.099 1.00 12.031 1.00 12.523 1.00 11.377 1.00 10.604 1.00 9.446 1.00 11.502 1.00 13.349 1.00 14.435 1.00 12.826 1.00 13.504 1.00 12.631 1.00 13.154 1.00 22.32 24.77 24.46 24.00 23.26 24.52 22.88 24.01 21.90 24.75 24.28 23.94 23.20 23.87 19.56 22.19 21.55 21.94 21.66 22.47 23.14 22.62 23.09 23.50 23.83 21.95 23.76 20.60 22.34 20.94 21.65 22.71 22 .71 22 .78 22.81 25.21 25.78 29.18 28.57 26.77 25.88 26.50 25.84 24.43 26.35 26.57 26.33 24.66 25.22 24 .84 -26 .92 25.77 24 .82 27.98 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 147

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1979 1980 1981 1982 1983 1985 1986 1987 1988 1989 1990 1992 1993 1994 1995 1996 1997 1998 1999 2000 2002 2003 2004 2005 2006 2007 2008 2009 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2023 2024 2025 2027 2028 2029 2030 2032 2033 2034 2035 2036 2037 2038 2039 CD2 CE2 CE3 CD1 NE1 CZ2 CZ3 CH2

C

0

N

CA

CB

CG

CD

OE1 OE2

C

0

N

CA

CB

CG2 CG1

CDI

C

0

N

CA

CB

CG

CD1 CD2 CEl CE2

CZ

C

0

N

CA

CB

OGI

CG2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PRE

PHE

THR

THR

THR

THR

THR

THR

THR

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

GLY

1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1692 1692 1692 1692 1692 1692 1692 1692 1692 1693 1693 1693 1693 1693 1693 1693 1693 1694 1694 1694 1694 1694 1694 1694 1694 1694 1694 1694 1695 1695 1695 1695 1695 1695 1695 1696 1696 1696 1696 1696 1696 1696 1696 1697 29.623 31.022 28.783 30.634 31.609 31.599 29.356 30.753 27.025 27.686 25.926 25.442 24.193 24.345 23.046 22.238 22.803 25.092 25.333 24.500 24.118 23.279 23.144 21.897 21.017 25.345 25.424 26.329 27.518 28.140 27.197 26.627 26.743 25.622 25.737 25.170 28.512 29.469 28.275 29.101 29.532 28.373 30.450 28.240 28.617 27.078 26.113 26.633 26.899 27.473 25.602 25.717 25.792 25.251 -1.104 -1.015 -0.191 715 009 -0.045 0. 769 0. 835 -3.147 -3.414 -2.393 -1.790 963 0.236 0. 992 0. 694 1. 837 856 673 956 054 -6 .144 -7.445 -5.563 -6.479 -5.698 864 017 674 -7.556 -8.611 -8.526 -9.601 -9.409 -10.490 -10. 387 -5.796 -6.299 -4.489 575 351 -1.685 767 -3.128 -2.233 766 -3.490 985 -5.482 777 -6.233 031 -1.431 -1.472 14.056 14.259 14.708 12.856 13. 518 15.086 15.533 15.713 14.876 15.883 14.916 16.162 15.919 15.028 14.962 14.058 15.850 17.191 18.379 16.734 17.618 16.858 17.704 16 .496 15 .642 18 .239 19.452 17. 414 17. 925 16. 843 16. 353 15. 088 17.224 14 .701 16 .844 15. 592 18. 689 19.276 18.698 19.473 18.657 18.150 17. 510 20.664 21.427 20. 797 21. 862 23 .216 23 .339 24.711 23.126 21.958 23.018 20.853 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00.

1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 .1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 26.95 27.64 26.28 28.38 29.56 27.78 27.63 30.68 26.38 24.82 27.62 27.02 29.27 24.77 25.98 22.29 25.12 27.88 30.18 26.65 26.14 25.37 21.48 24.80 22.40 27.17 27.30 29.98 30.61 28.30 30.91 34.46 32 .71 34.24 32 .44 32 31.74 35.15 31.12 29.96 28. 09 30.65 23.37 30.01 31.14 27.96 30.25 33.54 32.61 33.54 36.37 28.19 29.18 28.24 SSSD/55145. vOl WO 98/07835 PCTIUS97/1488 148 ATOM 2041 CA GLY 1697 24.851 -0.082 20.858 1.00 28.29 ATOM 2042 C GLY 1697 25.990 0-845 20.499 1.00 27.68 ATOM 2043 0 GLY 1697 25.960 2.022 20.846 1.00 29.79 ATOM 2044 N GLY 1698 26.986 0.324 19.790 1.00 29.23 ATOM 2046 CA GLY 1698 28.115 1.143 19.396 1.00 30.79 ATOM 2047 C GLY 1698 27.743 2.212 18.388 1.00 32.38 ATOM 2048 0 'GLY 1698 26.817 2.044 17.601 1.00 33.26 ATOM 2049 N SER 1699 28.480 3.314 18.411 1.00 30.81 ATOM 2051 CA SER 1699 28.268 4.437 17.510 1.00 32.03 ATOM 2052 CB SER 1699 28.528 5.728 18.288 1.00 34.81 ATOM 2053 OG SER 1699 28.559 6.862 17.440 1.00 40.03 ATOM 2055 C SER 1699 29.198 4.325 16.282 1.00 32.20 ATOM 2056 0 SER 1699 30.428 4.325 16.408 1.00 31.67 ATOM 2057 N PRO 1700 28.620 4.148 15.082 1.00 32.62 ATOM 2058 CD PRO 1700 27.178 4.142 14.773 1.00 34.19 ATOM 2059 CA PRO 1700 29.422 4.028 13.856 1.00 31.76 ATOM 2060 CB PRO 1700 28.357 3.830 12.759 1.00 32.04 ATOM 2061 CG PRO 1700 27.145 3.351 13.502 1.00 33.17 ATOM 2062 C PRO 1700 30.214 5.309 13.609 1.00 28.70 ATOM 2063 0 PRO 1700 29.715 6.391 13.871 1.00 28.57 ATOM 2064 N TYR 1701 31.459 5.181 13.164 1.00 28.61 ATOM 2066 CA TYR 1701 32.311 6.338 12.870 1.00 29.92 ATOM 2067 CB TYR 1701 31.920 6.946 11.510 1.00 30.15 ATOM 2068 CG TYR 1701 31.965 5-994 10.339 1.00 36.17 ATOM 2069 CD1 TYR 1701 30.799 5.630 9.664 1.00 39.26 ATOM 2070 CEl TYR 1701 30.839 4.767 8.571 1.00 41.51 ATOM 2071 CD2 TYR 1701 33.176 5.467 9.893 1.00 37.48 ATOM 2072 CE2 TYR 1701 33.229 4.607 8.805 1.00 42.94 ATOM 2073 CZ TYR 1701 32.059 4.263 8.146 1.00 45.72 ATOM 2-074 OH TYR 1701 32.110 3.431 7.043 1.00 53.99 ATOM 2076 C TYR 1701 32.279 7.448 13.941 1.00 31.09 ATOM 2077 0 TYR 1701 31.935 8.592 13.649 1.00 31.93 ATOM 2078 N PRO 1702 32.649 7.135 15.189 1.00 34.66 ATOM 2079 CD PRO 1702 33.212 5.879 15.708 1.00 36.83 ATOM 2080 CA PRO 1702 32.631 8.173 16.231 1.00 33.54 ATOM 2081 CB PRO 1702 33.116 7.432 17.479 1.00 32.18 ATOM 2082 CG PRO 1702 32.903 6.001 17.175 1.00 40.82 ATOM 2083 C PRO 1702 33.628 9.274 15.883 1.00 34.78 ATOM 2'084 0 PRO 1702 34.750 8.981 15.455 1.00 33.97 ATOM 2085 N GLY 1703 33.220 10.528 16.074 1.00 36.45 ATOM 2087 CA GLY 1703 34.085 11.667 15.788 1.00 34.40 ATOM 2088 C GLY 1703 34.245 12.006 14.317 1.00 34.34 ATOM 2089 0 GLY 1703 34.977 12.933 13.969 1.00 34.20 ATOM 2090 N VAL 1704 33.552 11.275 13.445 1.00 35.02 ATOM 2092 CA VAL 1704 33.641 11.512 12.007 1.00 32.77 ATOM 2093 CB VAL 1704 33.614 10.176 11.221 1.00 31.32 ATOM 2094 CG1 VAL 1704 33.628 10.435 9.709 1.00 31.46 ATOM 2095 CG2 VAL 1704 34.796 9.297 11.637 1.00 27.62 ATOM 2096 C VAL 1704 32.510 12.410 11.513 1.00 33.35 ATOM 2097 0 VAL 1704 31.337 12.070 11.640 1.00 33.94 ATOM 2098 N PRO 1705 32.849 13.589 10 .974 1.00 32.43 ATOM 2099 CD PRO 1705 34.181 14.221 10-.949 1.00 32.77 ATOM 2100 CA PRO 1705 31.826 14.505 10.472 1.00 33.61 ATOM 2101 CB PRO 1705 32.545 15.853 10.509 1.00 33.21 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 149 ATOM 2102 CG PRO 1705 33.935 15.482 10.141 1.00 35.53 ATOM 2103 C PRO 1705 31.395 14.138 9.052 1.00 33.91 ATOM 2104 0 PRO 1705 32.113 13.409 8.354 1.00 32.65 ATOM 2105 N VAL 1706 30.255 14.684 8.619 1.00 33.82 ATOM 2107 CA VAL 1706 29.689 14.447 7.280 1.00 33.97 ATOM 2108 CB VAL 1706 28.617 15.513 6.943 1.00 37.41" ATOM 2109 CGl VAL 1706 28.045 15.282 5.556 1.00 41.12 ATOM 2110 CG2 VAL 1706 27.507 15.484 7.971 1.00 38.89 ATOM 2111 C VAL 1706 30.712 14.428 6.135 1.00 32.32 ATOM 2112 0 VAL 1706 30.819 13.450 5.398 1.00 32.58 ATOM 2113 N GLU 1707 31.477 15.504 6.004 1.00 31.15 ATOM 2115 CA GLU 1707 32.478 15.630 4.956 1.00 29.82 ATOM 2116 CB GLU 1707 33.172 16.989 5.048 1.00 30.05 ATOM 2117 C GLU 1707 33.531 14.541 4.959 1.00 28.52 ATOM 2118 0 GLU 1707 33.995 14.134 3.896 1.00 30.85 ATOM 2119 N GLU 1708 33.958 14.110 6.143 1.00 28.70 ATOM 2121 CA GLU 1708 34.978 13.073 6.235 1.00 29.50 ATOM 2122 CB GLU 1708 35.590 13.010 7.641 1.00 31.28 ATOM 2123 CG GLU 1708 36.281 14.289 8.103 1.00 41.63 ATOM 2124 CD GLU 1708 37.454 14.718 7.237 1.00 49.91 ATOM 2125 OE1 GLU 1708 38.020 13.876 6.498 1.00 53.57 ATOM 2126 0E2 GLU 1708 37.821 15.916 7.308 1.00 58.45 ATOM 2127 C GLU 1708 34.365 11.730 5.878 1.00 30.00 ATOM 2128 0 GLU 1708 35.016 10.874 5.257 1.00 28.43 ATOM 2129 N LEU 1709 33.103 11.559 6.257 1.00 30.08 ATOM 2131 CA LEU 1709 32.392 10.324 5.964 1.00 29.19 ATOM 2132 CB LEU 1709 30.995 10.347 6.592 1.00 28.97 ATOM 2133 CG LEU 1709 30.109 9.186 6.137 1.00 30.66 ATOM 2134 CD1 LEU 1709 30.664 7.866 6.659 1.00 29.24 ATOM 2135 CD2 LEU 1709 28.684 9.403 6.593 1.00 29.29 ATOM 2136 C LEU 1709 32.294 10.130 4.449 1.00 28.26 ATOM 2137 0 LEU 1709 32.450 9.011 3.948 1.00 28.86 ATOM 2138 N PHE 1710 32.016 11.220 3.735 1.00 26.86 ATOM 2140 CA PEE 1710 31.903 11.192 2.285 1.00 28.86 ATOM 2141 CB PHE 1710 31.632 12.593 1.743 1.00 31.88 ATOM 2142 CG PHE 1710 30.249 13.095 2.014 1.00 37.62 ATOM 2143 CD1 PHE 1710 29.265 12.247 2.509 1.00 42.63 ATOM 2144 CD2 PHE 1710 29.931 14.424 1.792 1.00 43.53 ATOM 2145 CEl PHE 1710 27.977 12.718 2.783 1.00 45.99 ATOM 2146 CE2 PHE 1710 28.648 14.905 2.061 1.00 46.25 ATOM 2147 CZ PEE 1710 27.670 14.045 2.559 1.00- 44.45 ATOM 2148 C PHE 1710 33.193 10.660 1.681 1.00 30.42 ATOM 2149 0 PEE 1710 33.174 9.807 0.792 1.00 29.01 ATOM 2150 N LYS 1711 34.309 11.152 2.212 1.00 30.64 ATOM 2152 CA LYS 1711 35.650 10.762 17786 1.00 32.89 ATOM 2153 CB LYS 1711 36.670 11.655 2.502 1.00 37.91 ATOM 2154 CG LYS 1711 38.108 11.479 2.088 1.00 42.99 ATOM.- 2155 CD LYS 1711 38.976 12.528 2.752 1.00 47.45 ATOM 2156 CE LYS 1711 40.380 12.505 2.182 1.00 52.35 ATOM 2157 NZ LYS 1711 41.104 11.272 2.587 1.00 58.47 ATOM 2161 C LYS 1711 35.913 9.273 2.071 1.00 32.23 ATOM 2162 0 LYS 1711 36.445 8.559 1.216 1.00 30.79 ATOM 2163 N LEU 1712 35.533 8.807 3.264 1.00 31.37 ATOM 2165 CA LEU 1712 35.704 7.399 3.630 1.00 29.46 SSSD/55145. vOl WO 98/07835 PCT/US9714885 150 ATOM 2166 CB LEU 1712 35.220 7.117 5.065 1.00 28.57 ATOM 2167 CG LEU 1712 36.045 7.662 6.242 1.00 30.18 ATOM 2168 CD1 LEU 1712 35.395 7.349 7.569 1.00 26.92 ATOM 2169 CD2 LEU 1712 37.452 7.083 6.210 1.00 30.88 ATOM 2170 C LEU 1712 34.922 6.539 2.651 1.00 28.99 ATOM 2171 0 LEU 1712 35.438 5.551 2.136 1.00 30.73 ATOM 2172 N LEU 1713 33.675 6.915 2.388 1.00 30.13 ATOM 2174 CA LEU 1713 32.851 6.158 1.456 1.00 32.10 ATOM 2175 CB LEU 1713 31.411 6.685 1.443 1.00 35.23 ATOM 2176 CG LEU 1713 30.612 6.292 2.691 1.00 37.47 ATOM 2177 CD1 LEU 1713 29.265 6.982 2.720 1.00 40.85 ATOM 2178 CD2 LEU 1713 30.447 4.788 2.723 1.00 39.61 ATOM 2179 C LEU 1713 33.441 6.147 0.047 1.00 32.70 ATOM 2180 0 LEU 1713 33.548 5.090 -0.578 1.00 31.86 ATOM 2181 N LYS 1714 33.859 7.309 -0.444 1.00 32.42 ATOM 2183 CA LYS 1714 34.440 7.387 -1.776 1.00 32.56 ATOM 2184 CB LYS 1714 34.826 8.824 -2.112 1.00 33.02 ATOM 2185 CG LYS 1714 33.640 9.736 -2.297 1.00 35.56 ATOM 2186 CD LYS 1714 32.736 9.235 -3.396 1.00 37.94 ATOM 2187 CE LYS 1714 31.635 10.246 -3.682 1.00 42.57 ATOM 2188 NZ LYS 1714 30.727 9.805 -4.779 1.00 47.40 ATOM 2192 C LYS 1714 35.664 6.488 -1.885 1.00 35.36 ATOM 2193 0 LYS 1714 35.927 5.898 -2.937 1.00 36.68 ATOM 2194 N GLU 1715 36.376 6.338 -0.775 1.00 34.51 ATOM 2196 CA GLU 1715 37.577 5.527 -0.749 1.00 35.31 ATOM 2197 CB GLU 1715 38.566 6.125 0.250 1.00 37.07 ATOM 2198 CG GLU 1715 38.967 7.537 -0.163 1.00 43.62 ATOM 2199 CD GLU 1715 39.735 8.310 0.893 1.00 49.75 ATOM 2200 OE1 GLU 1715 39.906 7.814 2.029 1.00 49.71 ATOM 2201 OE2 GLU 1715 40.163 9.442 0.572 1.00 55.13 ATOM 2202 C GLU 1715 37.321 4.048 -0.487 1.00 34.08 ATOM 2203 0 GLU 1715 38.259 3.260 -0.438 1.00 34.82 ATOM 2204 N GLY 1716 36.049 3.674 -0.366 1.00 31.53 ATOM 2206 CA GLY 1716 35.695 2.288 -0.133 1.00 27.58 ATOM 2207 C GLY 1716 35.966 1.765 1.262 1.00 28.60 ATOM 2208 0 GLY 1716 36.069 0.560 1.464 1.00 27.81 ATOM 2209 N HIS 1717 36.062 2.663 2.236 1.00 29.10 ATOM 2211 CA HIS 1717 36.319 2.263 3.617 1.00 29.30 ATOM 2212 CB HIS 1717 36.501 3.510 4.486 1.00 30.54 ATOM 2213 CG HIS 1717 36.788 3.213 5.930 1.00 32.88 ATOM 2214 CD2 HIS 1717 37.961 3.023 6.586 1.00 32.21 ATOM 2215 ND1 HIS 1717 35.798 3.108 6.881 1.00 34.22 ATOM 2217 CEI HIS 1717 36.342 2.865 8.061 1.00 31.51 ATOM 2218 NE2 HIS 1717 37.651 2.809 7.907 1.00 31.94 ATOM 2220 C HIS 1717 35.180 1.416 4.183 1.00 28.42 ATOM 2221 0 HIS 1717 34.017 1.666 3.885 1.00 30.71 ATOM 2222 N ARG 1718 35.526 0.450 5.028 1.00 27.75 ATOM 2224 CA ARG 1718 34.559 -0.423 5.688 1.00 27.58 ATOM 2225 CB ARG 1718 34.562 -1.813 5.048 1.00 29.07 ATOM 2226 CG ARG 1718 34.078 -1.860 3.597 1.00 28.39 ATOM 2227 CD ARG 1718 32.609 -1.412 3.475 1.00 27.64 ATOM 2228 NE ARG 1718 32.091 -1.467 2.096 1.00 24.37 ATOM 2230 CZ ARG 1718 32.173 -0.476 1.210 1.00 24.26 ATOM 2231 NH1 ARG 1718 32.768 0.668 1.532 1.00 23.98 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 151

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2234 2237 2238 2239 2241 2242 2243 2244 2245 2246 2247 2248 2250 2251 2252 2253 2254 2255 2256 2257 2259 2260 2261 2262 2263 2264 2268 2269 2270 2271 2272 2273 2274 2275 2276 2277 2279 2280 2281 2283 2284 2285 2287 2288 2289 2290 2291 2294 2295 2296 2298 2299 2300 2301 NH2

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

OD1 ND2

C

0

N

CA

CB

SG

C

ARG

ARG

ARG

MET

MET

MET

MET

MET

MET

MET

MET

ASP

ASP

ASP

ASP

ASP

ASP

ASP

AS P

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

PRO

PRO

PRO

PRO

PRO

PRO

PRO

SER

SER

SER

SER

SER

SER

ASN

ASN

ASH

ASH

ASH

ASH

ASN

ASH

CYS

CYS

CYS

CYS

CYS

1718 1718 1718 1719 1719 1719 1719 1719 1719 1719 1719 1720 1720 1720 1720 1720 1720 1720 1720 1721 1721 1721 1721 1721 1721 1721 1721 1721 1722 1722 1722 1722 1722 1722 1722 1723 1723 1723 1723 1723 1723 1724 1724 1724 1724 1724 1724 1724 1724 1725 1725 1725 1725 1725 31.595 35.005 36.201 34.056 34.350 33 .072 32.408 31.015 29.797 34 .998 34 .802 35.778 36.473 37.593 38.628 38.442 39.632 35.524 34.466 35.943 35.133 35.726 34 .854 35.392 36 .054 36.354 35.039 36.064 33.807 32.504 33.630 32.107 31.603 34.246 34.274 34.777 35.336 36.152 35.327 34.088 32.982 34.237 33.092 32.559 33.679 34.531 33 .712 32.015 30.859 32.454 31.600 31.526 30.693 32 .341 -0.603 -0.521 -0.623 -0.430 -0.490 -0.302 1.060 1.307 0.338 -1.810 -2.802 -1.809 -3.008 -2.630 -1.688 -1.223 -1.398 -3.977 -3.581 -5.231 -6.261 -7.649 -8.773 -10.126 -10.749 -12 .189 -6.051 -5.926 -6.017 -6.105 -S.827 -5.846 -5.375 -7.026 -8.136 -6.820 -7.954 -7.508 -7.027 -8.731 -8.172 -10.025 -10.826 -10.319 -10.091 -10.959 -8.899 -10.779 -10.423 -11.087 11. 136 -9.771 -9.816 -12.13 5 0.019 7.148 7.428 8.074 9.501 10.3 35 -10.194 11.314 10.544 9. 854 9.169 10.926 11.385 12.358 11.747 10.596 12 .443 12.079 12.561 12.191 12.825 12.575 13.125 12.784 13 .988 13.756 14.315 14.986 14.861 14 .179 16.305 16.465 15.122 17.023 16.477 18.222 18.940 20.160 21.208 19. 359 19. 417 19.590 19.999 21.355 22.370 22.585 22.953 18 .893 19.108 17.683 16.508 15 .811 14.194 15.640 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 21.60 30.11 30.60 30.69 31.77 34. 56 36 .71 38.66 36. 99 30.20 31.41 32.49 33 37.65 44.69 50. 97 48.67 31.26 32 .69 32. 76 32.28 33 .63 35.68 36.22 42.65 46.15 35. 37. 78 36 .91 34 .43 37. 77 36 .32 34 .53 39.31 38 .78 42 .72 45. 01 46.88 53 .47 46 .67 46.21 47.80 52 .78 57. 86 61. 99 63 .17 63 .56 51.43 51.56 48.91 45.62 44 .83 41.83 42 SSSD/55145. vOl WO 98/07835 PCT[US97/14885 152

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2302 2303 2305 2306 2307 2309 2310 2311 2312 2314 2315 2316 2317 2318 2321 2322 2323 2325 2326 2327 2328 2329 2330 2331 2332 2333 2335 2336 2337 2338 2339 2340 2341 2342.

2344 2345 2346 2347 2348 2349 2350 2351 2352 2354 2355 2356 2358 2359 2360 2361 2362 2363 2364 2365 0

N

CA

CB

OG1 CG2

C

0

N

CA

CB

CG

ODi ND2

C

0

N

CA

CB

CG

CD

QEl 0E2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2 Cz

OH

C

0

N

CA

CB

CG

SD

CE

C

0

N

CYS

THR

THR

THR

THR

THR

THR

THR

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

MET

MET

MET

MET

MET

MET

MET

MET

MET

1725 1726 1726 1726 1726 1726 1726 1726 1727 1727 1727 1727 1727 1727 1727 1727 1728 1728 1728 1728 1728 1728 1728 1728 1728 1729 1729 1729 1729 1729 1729 1729 1729 1730 1730 1730 1730 1730 1730 1730 1730 1730 1730 1730 1730 1731 1731 1731 1731 1731 1731 1731 1731 1732 33.566 31. 627 32.259 31. 339 30.109 31.070 32.668 32.158 33.619 34.030 35.166 36.463 37.047 36.931 32.824 32.681 31.969 30.778 30.064 28.836 28.187 28.200 27.654 29.814 29.309 29. 559 28.670 28.225 27. 208 27.119 25.844 29.316 28.619 30.648 31.343 32.804 33.537 33.037 33.688 34.716 35.386 34.861 35.485 31. 260 31.078 31. 390 31. 298 31.526 31.158 31. 441 32.603 29. 917 29. 782 28. 893 -12.045 -13 .134 -14.153 -15.367 -14.952 -16.019 -13.622 -12.593 -14 .294 -13.867 -14.724 -14.533 -13 .453 -15.592 -14.006 -13 .236 -14 .997 -15 .235 -16.504 -16.866 -18.169 -18 .463 -18.896 -14.049 -13 .602 -13.544 -12 .408 -12.272 -13 .350 -13.483 -13.021 -11.133 -10 .229 -11.063 -9.893 -9 .861 -8.639 -7.358 -6.227 -8.757 -7 .620 -6.362 -5 .227 943 -8 .920 -11.138 -11.315 -12..778 -13.087 -14 .804 -14-.550 -10 .858 -10 .227 -11.191 15.493 15.141 14.320 14 .132 13.523 15.454 12.963 12 .518 12.319 10.983 10.422 11 .168 11 .158 11 .814 10.058 9.116 10.326 9.510 9.975 9 .15.6 9.608 10.824 8 .742 9 .549 8 .512 10.750 10.911 12.364 12 .748 14 .262 12.139 10.390 9 .938 10.435 9 .912 10.359 9.857 10.103 9.626 9.119 8.632 8.889 8.405 8.379 7.726 7 .813 6 .372 5 .989 4 .545 4.064 2.678 5 .912 4.871 6.688 1.00 1 .00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 44 .63 37.46 35.29 33.44 34 .77 30.22 33 .53 32 .93 32 .72 35.91 40.64 46 .52 49.98 49.04 34.27 32 .96 32.49 31.99 34.15 35.63 39.72 42.25 39.87 30.76 29.58 30.01 30.21 30.13 33.61 33.71 30.31 30.26 28.89 28.91 28.91 29.09 30.15 29.97 28.99 29.24 28.25 28.41 31 .64 27.10 27.46 26 .68 28.68 35.43 46.19 60.10 58.31 27.42 30.80 28.53 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 153 ATOM 2367 CA ATOM 2368 GB ATOM 2369 CG ATOM 2370 SD ATOM 2371 CE ATOM 2372 C ATOM 2373 0 ATOM 2374 N ATOM 2376 CA ATOM 2377 CB ATOM 2378 CG ATOM 2379 SD ATOM 2380 CE ATOM 2381 C ATOM 2382 0 ATOM 2383 N ATOM 2385 CA ATOM 2386 CB ATOM 2387 CG ATOM 2388 CD ATOM 2389 NE ATOM 2391 CZ ATOM 2392 NH1 ATOM 2395 NH2 ATOM 2398 C ATOM 2399 0 ATOM 2400 N ATOM 2402 CA ATOM 2403 CB ATOM 2404 CG ATOM 2405 OD.

ATOM 2406 0D2 ATOM 2407 C ATOM 2408 0 ATOM 2409 N ATOM 2411 CA ATOM 2412 GB ATOM 2413 SG ATOM 2414 C ATOM 2415 0 ATOM 2416 N ATOM 2418 CA ATOM 2419 GB ATOM 2420 CG -ATOM 2421 CD2 ATOM 2422 CE2 ATOM 2423 CE3 ATOM 2424 CD1 ATOM 2425 NEl ATOM 2427 CZ2 ATOM 2428 CZ3 ATOM 2429 GH2 ATOM 2430 C ATOM 2431 0 MET 1732 MET 1732 MET 1732 MET 1732 MET 1732 MET 1732 MET -1732 MET 1733 MET 1733 MET 1733 MET 1733 MET 1733 MET 1733 MET 1733 MET 1733 ARG 1734 ARG 1734 ARG 1734 ARG 1734 ARG 1734 ARG 1734 ARG 1734 ARG 1734 ARG 1734 ARG 1734 ARG 1734 ASP 1735 ASP 1735 ASP 1735 ASP 1735 ASP 1735 ASP 1735 ASP 1735 ASP 1735 CYS 1736 CYS 1736 CYS 1736 CYS 1736 CYS 1736 CYS 1736 TRP 1737 TRP 1737 TRP 1737 TRP 1737 TRP 1737 TRP 1737 TRP 1737 TRP 1737 TRP 1737, TRP 1737 TRP 1737 TRP 1737 TRP 1737 TRP 1737 27.522 26..562 25.116 24 .004 23 .787 27.445 26.886 28 .024 28 .057 28 .903 28.235 29.442 28.886 28.720 28.185 29.891 30.642 32.007 32 .927 33.229 33.922 35.238 36.023 35.760 29.859 29 .992 29.071 28.254 27 .669 28.724 29.842 28.432 27.139 26 .777 26.611 25 .561 25 .007 23 .934 26.129 25.403 27.438 28 .123 29.162 28.601 29.268 28.371 30.534 27 .359 27.213 28.710 30.873 29.959 28.788 29.737 -10.777 -11.308 10.838 -11.550 -13.195 -9.243 -8.691 -8.564 -7.104 -6.594 -6.556 -6.111 -7.126 -6.613 -5.753 -7.169 -6.783 -7.488 -7.154 -5.672 -5.256 -5.361 -5.853 -5.048 -7.037 -6 .290 -8.107 -8.420 -9.830 -10.913 -10.632 -12.051 -7.396 -6.996 965 -5.952 -5.767 -7.126 -4.633 -3.797 -4.461 -3.247 -2 .810 -2.520 -2.688 -2.278 -3.165 -2 .024 -1.876 -2.305 -3.198 -2.774 -3.372 -2.646 6.389 1.00 26.47 7.458 1.00 25.79 7.274 1.00 26.01 8.469 1.00 26.22 7.783 1.00 23.74 6.319 1.00 25.15 5.379 1.00 25.41 7.308 1.00 26.48 7.331 1.00 27.09 8.488 1.00 25.91 9.824 1.00 31.64 11.094 1.00 29.59 12.420 1.00 28.14 6.056 1.00 28.43 5.372 1.00 31.37 5.747 1.00 28.57 4.551 1.00 27.00 4.510 1.00 25.98 5.707 1.00 28.13 5.765 1.00 29.97 4.553 1.00 40.49 4.363 1.00 43.95 5.318 1.00 41.81 3.184 1.00 46.20 3.268 1.00 24.57 2.314 1.00 24.94 3.235 1.00 24.79 2.061 1.00 231.88 2.150 1.00 25.95 2.024 1.00 27.60 1.529 1.00 27.75 2.430 1.00 28.90 1.941 1.00 22.61 0.833 1.00 22.66 3.085 1.00 20.61 3.109 1.00 23.63 4.534 1.00 21.98 5.111 1.00 22.95 2.599 1.00 23.62 2.047 1.00 22.15 2.775 1.00 24.37 2.342 1.00 23.77 3.371 1.00 19.38 4.718 1.00 21.62 5.971 1.00 24.81 6.980 1.00 25.95 6.340 1.00 29.02 5.007 1.00 23.21 6.362 1.00 21.80 8.347 1.00 26.68 7.699 1.00 31.06 8.685 1.00 30.18 0.978 1.00 24.88 0.689 1.00 25.11 SSSD/55145. vOl WO 98/07835 WO 9807835PCT/US97/14885 154 ATOM 2432 N HIS 1738 28.303 -4.278 0.132 1.00 25.27 ATOM 2434 CA HIS 1738 28.888 -4.406 -1.191 1.00 24.27 ATOM 2435 CB HIS 1738 28.280 -5.573 -1.986 1.00 25.24 ATOM 2436 CG HIS 1738 29.179 -6.073 -3.081 1.00 26.28 ATOM 2437 CD2 HIS 1738 29.727 -5.437 -4.147 1.00 25.67 ATOM 2438 ND1 HIS 1738 29.697 -7.352 -3.098 1.00 27.55 ATOM 2440 CEl HIS 1738 30.528 -7.478 -4.117 1.00 27.51 ATOM 2441 NE2 HIS 1738 30.564 -6.329 -4.770 1.00 30.93 ATOM 2443 C HIS 1738 28.715 -3.087 -1.953 1.00 25.59 ATOM 2444 0 HIS 1738 27.659 -2.451 -1.905 1.00 22.01 ATOM 2445 N ALA 1739 29.784 -2.651 -2.612 1.00 23.84 ATOM 2447 CA ALA 1739 29.759 -1.418 -3.388 1.00 24.93 ATOM 2448 CB ALA 1739 31.131 -1.177 -4.024 1.00 26.39 ATOM 2449 C ALA 1739 28.671 -1.508 -4.462 1.00 25.35 ATOM 2450 0 ALA 1739 27.963 -0.535 -4.727 1.00 28.20 ATOM 2451 N VAL 1740 28.543 -2.680 -5.073 1.00 22.68 ATOM 2453 CA VAL 1740 27.528 -2.904 -6.101 1.00 26.46 ATOM 2454 CB VAL 1740 27.995 -3.968 -7.117 1.00 29.70 ATOM 2455 CG1 VAL 1740 27.063 -4.003 -8.334 1.00 26.01 ATOM 2456 CG2 VAL 1740 29.433 -3.686 -7.537 1.00 31.22 ATOM 2457 C VAL 1740 26.213 -3.358 -5.443 1.00 25.07 ATOM 2458 0 VAL 1740 26.138 -4.474 -4.903 1.00 23.55 ATOM 2459 N PRO 1741 25.155 -2.519 -5.514 1.00 25.30 ATOM 2460 CD PRO 1741 25.133 -1.190 -6.153 1.00 22.43 ATOM 2461 CA PRO 1741 23.844 -2.833 -4.921 1.00 24.09 ATOM 2462 CB PRO 1741 22.962 -1.675 -5.402 1.00 2.3.12 ATOM 2463 CG PRO 1741 23.928 -0.527 -5.491 1.00 22.04 ATOM 2464 C PRO 1741 23.272 -4.191 -5.313 1.00 22.18 ATOM 2465 0 PRO 1741 22.727 -4.900 -4.466. 1.00 21.23 ATOM 2466 N SER 1742 23.437 -4.570 -6.580 1.00 23.87 ATOM 2468 CA SER 1742 22.928 -5.847 -7.088 1.00 24.36 ATOM 2469 CB SER 1742 23.071 -5.907 -8.612 1.00 27.39 ATOM 2470 OG SER 1742 24.436 -6.025 -8.986 1.00 29.25 ATOM 2472 C SER 1742 23.636 -7.058 -6.488 1.00 23.96 ATOM 2473 0 SER 1742 23.145 -8.179 -6.575 1.00 24.30 ATOM 2474 N GLN 1743 24.810 -6.839 -5.915 1.00 24.39 ATOM 2476 CA GLN 1743 25.558 -7.934 -5.345 1.00 23.15 ATOM 2477 CB GLN 1743 27.046 -7.755 -5.638 1.00 23.83 ATOM 2478 CG GLN 1743 27.359 -7.784 -7.126 1.00 22.84 ATOM 2479 CD GEM 1743 26.816 -9.036 -7.808 1.00 24.20 ATOM 2480 OE1 GEM 1743 27.318 -10.135 -7.590 1.00 21.50 ATOM 2481 NE2 GLN 1743 25.775 -8.871 -8.628 1.00 22.45 ATOM 2484 C GLN 1743 25.309 -8.171 -3.868 1.00 23.12 ATOM 2485 0 GLN 1743 25.816 -9.135 -3.317 1.00 24.96 ATOM 2486 N ARG 1744 24.557 -7.280 -3.225 1.00 23.67 ATOM 2488 CA ARG 1744 24.242 -7.424 -1.806 1.00 22.11 ATOM 2489 CB ARG 1744 23.659 -6.110 -1.231 1.00 19.70 ATOM 2490 CG ARG 1744 24.672 -4.959 -1.338 1.00 21.26 ATOM 2491 CD ARG 1744 24.049 -3.640 -0.890 1.00 20.68 ATOM 2492 NE ARG 1744 24.923 .2.552 -1.305 1.00 25.21 ATOM 2494 CZ ARG 1744 24.540 -1.313 -1.583 1.00 24.30 ATOM 2495 NH1 ARG 1744 23.257 -0.955 -1.481 1.00 22.04 ATOM 2498 NH2 ARG 1744 25.450 -0.448 -2.036 1.00 21.29 ATOM 2501 C ARG 1744 23.184 -8.505 -1.640 1.00 22.53 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 155 ATOM 2502 0 ARG 1744 22.437 -8.800 -2.588 1.00 23.08 ATOM 2503 N PRO 1745 23.162 -9.170 -0.467 1.00 20.76 ATOM 2504 CD PRO 1745 24.087 -9.078 0.681 1.00 21.71 ATOM 2505 CA PRO 1745 22.160 -10.207 -0.243 1.00 '22.34 ATOM 2506 CB PRO 1745 22.632 -10.859 1.057 1.00 20.58 ATOM 2507 CG PRO 1745 23.298 -9.727 1.783 1.00 20.36 ~ATOM 2508 C PRO 1745 20.814 -9.512 -0.048 1.00 23.62 ATOM 2509 0 PRO 1745 20.759 -8.318 0.255 1.00 25.29 ATOM 2510 N THR 1746 19.731 -10.235 -0.275 1.00 23.39 ATOM 2512 CA THR 1746 18.404 -9.675 -0.080 1.00 22.77 ATOM 2513 CB THR 1746 17.386 -10.368 -1.004 1.00 23.24 ATOM 2514 OGi THR 1746 17.409 -11.783 -0.763 1.00 23.11 ATOM 2516 CG2 THR 1746 17.724 -10.103 -2.475 1.00 24.96 ATOM 2517 C THR 1746 18.009 -9.954 1.365 1.00 24.98 ATOM 2518 0 THR 1746 18.664 -10.758 2.043 1.00 24.30 ATOM 2519 N PHE 1747 16.944 -9.318 1.853 1.00 24.95 ATOM 2521 CA PHE 1747 16.501 -9.596 3.221 1.00 25.16 ATOM 2522 CB PHE 1747 15.395 -8.628 .3.661 1.00 23.64 ATOM 2523 CG PHE 1747 15.916 -7.283 4.089 1.00 24.34 ATOM 2524 CD1 PHE 1747 16.715 -7.167 5.226 1.00 21.21 ATOM 2525 CD2 PHE 1747 15.649 -6.137 3.334 1.00 21.42 ATOM 2526 CEl PHE 1747 17.252 -5.932 5.597 1.00 20.99 ATOM 2527 CE2 PHE 1747 16.178 -4.907 3.699 1.00 20.36 ATOM 2528 CZ PHE 1747 16.985 -4.807 4.840 1.00 19.30 ATOM 2529 C PHE 1747 16.034 -11.049 3.311 1.00 23.57 ATOM 2530 0 PHE 1747 16.182 -11.702 4.344 -1.00 25.32 ATOM 2531 N LYS 1748 15.520 -11.573 2.202 1.00 23.19 ATOM 2533 CA LYS 1748 15.066 12.95 8 2.167 1.00 23.67 ATOM 2534 CB LYS 1748 14.462 -13.285 0.799 1.00 .26.67 ATOM 2535 CG LYS 1748 14.018 -14.739 0.622 1.00 30.49 ATOM 2536 CD LYS 1748 13.642 -14.996 -0.837 1.00 38.98 ATOM 2537 CE LYS 1748 13.182 -16.432 -1.087 1.00 44.52 ATOM 2538 NZ LYS 1748 11.997 -16.790 -0.245 1.00 52.75 ATOM 2542 C LYS 1748 16.264 -13.865 2.445 1.00 25.65 ATOM 2543 0 LYS 1748 16.184 -14.778 3.270 1.00 27.19 ATOM 2544 N GLN 1749 17.378 -13.603 1.762 1.00 24.56 ATOM 2546 CA GLN 1749 18.588 -14.397 1.950 1.00 26.33 ATOM 2547 CE GLN 1749 19.702 -13.953 0.993 1.00 27.97 ATOM 2548 CG GLN 1749 19.416 -14.066 -0.484 1.00 37.31 ATOM 2549 CD GLN 1749 20.518 -13.415 -1.315 1.00 40.24 ATOM 2550 OE1 GLN 1749 20.296 -12.408 -1.970 1.00 38.83 ATOM 2551 NE2 GLN 1749 21.726 -13.983 -1.259 1.00 47.83 ATOM 2554 C GLN 1749 19.099 -14.223 3.377 1.00 23.92 ATOM 2555 0 GLN 1749 19.459 -15.196 4.040 1.00 25.27 ATOM 2556 N LEU 1750 19.155 -12.976 3.829 1.00 23.12 ATOM 2558 CA LEU 1750 19.641 -12.662 5.175 1.00 24.34 ATOM 2559 CB LEU 1750 19.607 -11.149 5.427 1.00 23.08 ATOM 2560 CG LEU 1750 20.633 -10.311 4.665 1.00 23.84 ATOM 2561 CD1 LEU 1750 20 .274 -8.806 4.724 1.00 22.10 ATOM 2562 CD2 LEU 1750 22.013 -10.586 5.246 1.00 24.91 ATOM 2563 C LEU .1750 18.840 13.400 6.236 1.00 27.40 ATOM 2564 0. LETJ 1750 19.408 -13.915 7.211 1.00 27.11 ATOM 2565 N VAL 1751 17.527 -13.482 6.031 1.00 26.83 ATOM 2567 CA VAL 1751 16.665 -14.174 6.970 1.00 25.31 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 156 ATOM 2568 CB VAL 1751 15.176 -13.994 6.599 1.00 25.87 ATOM 2569 CGI VAL 1751 14.304 -14.975 7.382 1.00 28.43 ATOM 2570 CG2 VAL 1751 14.746 -12.593 6.934 1.00 21.52 ATOM 2571 C VAL 1751 17.047 -15.642 7.025 1.00 25.87 ATOM 2572 0 VAL 1751 17.178 -16.218 8.106 1.00 23.41 ATOM 2573 N GLU 1752 17.253 -16.243 5.858 1.00 29.98 ATOM 2575 CA GLU 1752 17.631 -17.651 5.799 1.00 33.12 ATOM 2576 CB GLU 1752 17.653 -18.134 4.346 1.00 35.99 ATOM 2577 CG GLU 1752 16.284 -18.077 3.670 1.00 43.58 ATOM 2578 CD GLU 1752 16.300 -18.575 2.230 1.00 48.64 ATOM 2579 OE1 GLU 1752 15.453 -18.124 1.431 1.00 48.99 ATOM 2580 OE2 GLU 1752 17.157 -19.426 1.902 1.00 55.41 ATOM 2581 C GLU 1752 18.995 -17.891 6.467 1.00 33.15 ATOM 2582 0 GLU 1752 19.173 -18.847 7.236 1.00 30.71 ATOM 2583 N ASP 1753 19.951 -17.011 6.186 1.00 31.12 ATOM 2585 CA ASP 1753 21.279 -17.131 6.770 1.00 30.51 ATOM 2586 CB ASP 1753 22.243 -16.108 6.155 1.00 29.15 ATOM 2587 CG ASP 1753 22.488 -16.344 4.672 1.00 33.53 ATOM 2588 ODI ASP 1753 22.361 -17.494 4.215 1.00 34.92 ATOM 2589 OD2 ASP 1753 22.815 -15.371 3.955 1.00 38.26 ATOM 2590 C ASP 1753 21.215 -16.968 8.287 1.00 28.54 ATOM 2591 0 ASP 1753 21.739 -17.800 9.025 1.00 28.95 ATOM 2592 N LEU 1754 20.537 -15.926 8.753 1.00 27.25 ATOM 2594 CA LEU 1754 20.421 -15.673 10.193 1.00 28.08 ATOM 2595 CB LEU 1754 19.754 -14.328 10.455 1.00 23.31 ATOM 2596 CG LEU 1754 20.733 -13.199 10.160 1.00 24.47 ATOM 2597 CD1 LEU 1754 20.007 -11.863 10.094 1.00 19.58 ATOM 2598 CD2 LEU 1754 21.846 -13.207 11.216 1.00 21.17 ATOM 2599 C LEU 1754 19.688 -16.789 10.921 1.00 31.61 ATOM 2600 0 LEU 1754 20.037 -17.135 12.048 1.00 32.64 ATOM 2601 N ASP 1755 18.690 -17.367 10.259 1.00 32.61 ATOM 2603 CA ASP 1755 17. 931 -18.460 10.833 1.00 34.20 ATOM 2604 CB ASP 1755 16.823 -18.883 9.872 1.00 37.70 ATOM 2605 CG ASP 1755 15.808 -19.780 10.526 1.00 44.,27 ATOM 2606 ODI ASP 1755 15.445 -19.521 11.692 1.00 47.16 ATOM 2607 OD2 ASP 1755 15.370 -20.745 9.876 1.00 51.35 ATOM 2608 C ASP 1755 18.894 -19.616 11.073 1.00 34.63 ATOM 2609 0 ASP 1755 18.858 -20.273 12.119 1.00 36.24 ATOM 2610 N ARG 1756 19.782 -19.826 10.108 1.00 32.60 ATOM 2612 CA ARG 1756 20.784 -20.870 10.190 1.00 33.69 ATOM 2613 CB ARG 1756 21.548 -20.939 8.867 1.00 35.42 ATOM 2614 CG ARG 1756 22.639 -22.003 8.800 1.00 40.87 ATOM 2615 CD ARG 1756 23.212 -22.094 7.395 1.00 42.73 ATOM 2616 NE ARG 1756 23.739 -20.813 6.926 1.00 48.45 ATOM 2618 CZ ARG 1756 24;882 -20.274 7.340 1.00 49.90 ATOM 2619 NH1 ARG 1756 25.634 -20.905 8.243 1.00 49.63 ATOM 2622 NH2 ARG 1756 25.276 -19.105 6.844 1.00 50.86 ATOM 2625 C ARG 1756 21.748 -20.598 11.345 1.00 34.78 ATOM 2626 0 ARG 1756 21.929 -21.436 12.228 1.00 36.24 ATOM 2627 N ILE 1757 22.325 -19.402 11.363 1.00 35.35 ATOM 2629 CA ILE 1757 23.281 -19.018 12.392 1.00 35.54 ATOM 2630 CB ILE 1757 23.905 -17.631 12.103 1.00 34.99 ATOM 2631 CG2 ILE 1757 24.955 -17.303 13.159 1.00 32.06 ATOM 2632 CGI ILE 1757 24.547 -17.626 10.711 1.00 33.77 SSSD/55145. vOl WO 98/07835 WO 9807835PCT/US97/14885' 157 ATOM 2633 CD1 ILE 1757 24.908 -16.247 10.185 1.00 31.44 ATOM 2634 C ILE 1757 22.698 -19.036 13.803 1.00 36.49 ATOM 2635 0 ILE 1757 23.337 -19.548 14.716 1.00 36.40 ATOM 2636 N VAL 1758 21.487 -18.515 13.988 1.00 36'.91 ATOM 2638 CA VAL 1758 20.881 -18.498 15.322 1.00 38.68 ATOM 2639 CB VAL 1758 19.425 -17.962 15.312 1.00 37.77 ATOM 2640 CG1 VAL 1758 18.806 -18.059 16.708 1.00 38.39 ATOM 2641 CG2 VAL 1758 19.392 -16.524 14.854 1.00 36.69 ATOM 2642 C VAL 1758 20.891 -19.908 15.895 1.00 41.38 ATOM 2643 0 VAL 1758 21.405 -20.138 16.997 1.00 42.41 ATOM 2644 N ALA 1759 20.379 -20.851 15.111 1.00 40.59 ATOM 2646 CA ALA 1759 20.325 -22.247 15.508 1.00 40.84 ATOM 2647 CB ALA 1759 19.741 -23.074 14.384 1.00 40.20 ATOM 2648 C ALA 1759 21.703 -22.787 15.897 1.00 42.52 ATOM 2649 0 ALA 1759 21.822 -23.594 16.809 1.00 44.78 ATOM 2650 N LEU 1760 22.740 -22.339 15.208 1.00 43.16 ATOM 2652 CA LEU 1760 24.095 -22.800 15.493 1.00 46.98 ATOM 2653 CB LEU 1760 24.921 -22.761 14.203 1.00 47.66 ATOM 2654 CG LEU 1760 24.286 -23.545 13.060 1.00 52.77 ATOM 2655 CD1 LEU 1760 24.973 -23.222 11.745 1.00 56.58 ATOM 2656 CD2 LEU 1760 24.343 -25.038 13.369 1.00 53.06 ATOM 2657 C LEU 1760 24.811 -21.986 16.573 1.00 47.43 ATOM 2658 0 LEU 1760 25.917 -22.335 16.989 1.00 46.58 ATOM 2659 N THR 1761 24.183 -20.914 17.034 1.00 48.65 ATOM 2661 CA THR 1761 24.814 -20.055 18.021 1.00 49.69 ATOM 2662 CB THR 1761 24.382 -18.570 17.831 1.00 50.15 ATOM 2663 OGi THR 1761 24.783 -18.127 16.529 1.00 49.87 ATOM 2665 CG2 TFIR 1761 25.063 -17-.671 18.843 1.00 48.64 ATOM 2666 C THR 1761 24.673 -20.497 19.475 1.00 .50.33 ATOM 2667 0 TER 1761 23.584 -20.825 19.947 1.00 48.81 ATOM 2668 N SER 1762 25.811 -20.511 20.166 1.00 50.25 ATOM 2670 CA SER 1762 25.891 -20.890 21.566 1.00 50.98 ATOM 2671 CB SER 1762 27.362 -20.887 22.002 1.00 54.71 ATOM 2672 OG SER 1762 27.537 -21.423 23.308 1.00 57.99 ATOM 2674 C SER 1762 25.083 -19.914 22.425 1.00 49.39 ATOM 2675 0 SER 1762 25.297 -18.694 22.370 1.00 48.00 ATOM 3474 N SER 461 79.623 25.766 14.533 1.00 48.84 ATOM 3476 CA SER 461 79.566 24.645 13.593 1.00 46.93 ATOM 3477 CB SER 461 78.276 23.838 13.809 1.00 46.66 ATOM 3478 C SER 461 79.676 25.114 12.138 1.00 43.02 ATOM 3479 0 SER 461 79.692 24.301 11.210 1.00 40.19 ATOM 3480 N GLU 462 79.791 26.427 11.956 1.00 41.48 ATOM 3482 CA GLU 462 79.904 27.034 10.628 1.00 39.59 ATOM 3483 CB GLU 462 80.021 28.560 10.744 1.00 40.66 ATOM 3484 C GLU 462 81.054 26.480 9.796 1.00 36.60 ATOM 3485 0 GLU 462 80.852 26.121 8.641 1.00 35.10 ATOM 3486 N TYR 463 82.252 26.416 10.380 1.00 36.07 ATOM 3488 CA TYR 463 83.430 25.916 9.673 1.00 35.60 ATOM 3489 CB TYR 463 84.597 26.906 9.755 1.00 38.15 ATOM 3490 CG TYR 463 84.372 28.104 8.861 1.00 44.08 ATOM 3491 CD1 TYR 463 84.137 29.368 9.406 1.00 44.99 ATOM 3492 CEl TYR 463 83 .813 30.451 8.593 1.00 46.88 ATOM 3493 CD2 TYR 463 84.305 27.959 7.464 1.00 43.95 ATOM 3494 CE2 TYR 463 84.003 29.044 6.642 1.00 41.86 SSSD/55145. vOl WO 98/07835 P2IJ9I48 PCTIUS97/14885 158

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3495 3496 3498 3499 3500 3502 3503 3504 3505 3506 3507 3508 3509 3510 3512 3513 3514 3515 3516 3517 3518 3519 3520 3521 3522 3523 3524 3525 3526 3528 3529 3530 3531 3532 3533 3534 3535 3536 3538 3539 3540 3541 3542 3543 3544 3545 3546 3547 3548 3*550 3551 3552 3554 Cz

OH

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CD

CA

CB

CG

C

0-

N

CA

CB

CG

CD

OE1 0E2

C

0

.N

CA

CB

CG

ODi 0D2

C

0

N

CD

CA

CB

CG

C

0

N

CA

TYR

TYR

TYR

TYR

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PRO

PRO

PRO

PRO

PRO

PRO

PRO

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ASP

ASP

ASP

ASP

ASP

AS P

ASP

ASP

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ARG

ARG

463 463 463 463 464 464 464 464 464 464 464 464 464 465 465 465 465 465 465 465 465 466 466 466 466 466 466 466 467 467 467 467 467 467 467 467 467 468 468 468 468 4.68 468 468 468 469 469 469 469 469 469 469 470 470 83.768 83.468 83 .903 84.440 83 .742 84.167 85.663 .86.075 87.552 87.920 88.344 83.426 83 .083 83.147 82.462 81. 484 80.510 79.355 80.021 83 .511 84.641 83 .150 81.865 84 .074 83.247 82.274 84 .419 83 .626 85.611 86 .030 87.493 87.922 89.276 90.013 89 .592 85.825 85 .938 85.472 85 .273 83 .793 83.566 82.429 84 .514 85.803 85 .068 87.100 88.001 87 .801 89.091 89-.366 87 .033 87.032 86.361 85.600 30.282 31.364 24 .520 23. 828 24. 098 22.753 22. 727 23.633 23. 987 24. 996 23.271 22.296 23.119 21.001 20.463 19.341 19.433 18.492 20. 846 19.889 19.574 19. 734 20.104 19. 185 19. 196 20.326 17. 765 17.077 17.330 15. 987 15.987 14.682 14.769 15.767 13 .823 15.037 15.430 13. 802 12. 776 12.640 11.697 11.670 10. 992 11.470 10. 701 11.209 12. 062 10.011 10.042 11. 505 8 .720 7. 822 8.639 7.446 7.215 6.431 10. 014 9.147 11.260 11.633 11.919 13.049 13.015 13.659 12.351 12. 858 13.705 12.943 14.114 13.747 12.577 12.858 12.359 15.059 14.642 16.349 16.967 17.346 18.626 18.394 16.950 16.2 97 17.315 16. 976 16. 540 15.891 15.213 15.426 14.458 18.146 19.309 17.831 18.851 19.224 20.397 20.919 20.807 18.278 17.650 18.481 19.276 18 .012 18 .831 18.938 18.260 17.414 19.411 19.779 1. 00 1.00 1.00 1. 00 1.00 1.00 1. 00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 43 .89 44.37 33 33 32 .81 34.64 37.48 45.48 55.80 61. 78 58.34 33-.05 34.54 32.59 33 .74 31.20 32.77 26.22 31.59 35.64 33.77 36.71 36 .97 36 .17 36 .83 40.80 37.39 34 .71 38.40 42 .59 49.21 58 .93 64 .76 63 .57 69.03 40.74 41.52 38.57 40.86 40.27 41.36 42.50 38 40.75 41-.80 41.71 41.87 40.07 40.42 39.42 41.00 41.75 40.70 41.03 145. vOl WO 98/07835 WO 9807835PCTIUJS97/14885 159 ATOM 3555 CB ARG 470 84.827 7.677 21.075 1.00 44.18 ATOM 3556 CG ARG 470 85.628 8.240 22.218 1.00 47.89 ATOM 3557 CD ARG 470 84.719 8.5i8 23.400 1.00 50.56 ATOM 3558 NE ARG 470 83.576 9.345 23.023 1.00 51.20 ATOM 3560 CZ ARG 470 82.695 9.845 23.881 1.00 52.24 ATOM 3561 NH1 ARG 470 82.818 9.608 25.183 1.00 51.31 ATOM 3564 NH2 ARG 470 81.672 10.564 23.432 1.00 52.73 ATOM 3567 C ARG 470 84.596 7.004 18.723 1.00 39.03 ATOM 3568 0 ARG 470 84.401 5.813 18.518 1.00 40.72 ATOM 3569 N TRP 471 83.972 7.965 18.050 1.00 37.77 ATOM 3571 CA TRP 471 82.948 7.656 17.059 1.00 36.73 ATOM 3572 CB TRP 471 81.672 8.401 17.432 1.00 35.05 ATOM 3573 CG TRP 471 81.044 7.862 18.673 1.00 34.85 ATOM 3574 CD2 TRP 471 80.235 6.687 18.766 1.00 34.96 ATOM 3575 CE2 TRP 471 79.831 6.564 20.116 1.00 35.12 ATOM 3576 CE3 TRP 471 79.810 5.721 17.838 1.00 33.25 ATOM 3577 CD1 TRP 471 81.106 8.390 19.933 1.00 29.97 ATOM 3578 NEl TRP 471 80.377 7.616 20.805 1.00 32.18 ATOM 3580 CZ2 TRP 471 79.017 5.512 20.560 1.00 33.98 ATOM 3581 CZ3 TRP 471 79.002 4.673 18.282 1.00 33.71 ATOM 3582 CH2 TRP 471 78.618 4.580 19.632 1.00 33.28 ATOM 3583 C TRP 471 83.275 7.930 15.599 1.00 37.27 ATOM 3584 0 TRP 471 82.580 7.445 14.695 1.00 36.61 ATOM 3585 N GLU 472 84.341 8.680 15.361 1.00 37.93 ATOM 3587 CA GLU 472 84.706 9.054 14.004 1.00 37.08 ATOM 3588 CB GLU 472 85.865 10.049 14.045 1.00 36.30 ATOM 3589 CG GLU 472 86.026 10.851 12.773 1.00 33.51 ATOM 3590 CD GLU 472 84.931 11.895 12.580 1.00 33.80 ATOM 3591 OE1 GLU 472 84.385 12.408 13.581 1.00 35.19 ATOM 3592 0E2 GLU 472 84.641 12.226 11.412 1.00 32.51 ATOM 3593 C GLU 472 85.021 7.923 13.032 1.00 37.88 ATOM 3594 0 GLU 472 85.774 7.000 13.351 1.00 38.20 ATOM 3595 N LEU 473 84.422 7.992 11.846 1.00 37.55 ATOM 3597 CA LEU 473 84.678 7.004 10.813 1.00 36.93 ATOM 3598 CB LEU 473 83.404 6.244 10.443 1.00 37.08 ATOM 3599 CG LEU 473 83.680 5.086 9.470 1.00 39.14 ATOM 3600 CD1 LEU 473 84.196 3.877 10.250 1.00 38.39 ATOM 3601 CD2 LEU 473 82.433 4.716 8.672 1.00 39.46 ATOM 3602 C LEU 473 85.207 7.732 9.577 1.00 38.52 ATOM 3603 0 LEU 473 84.660 8.764 9.182 1.00 38.67 ATOM 3604 N PRO 474 86.334 7.259 9.005 1.00 39.02 ATOM 3605 CD PRO 474 87.259 6.259 9.571 1.00 38.39 ATOM 3606 CA PRO 474 86.918 7.877 7.809 1.00 38.24 ATOM 3607 CB PRO 474 88.188 7.049 7.590 1.00 38.40 ATOM- 3608 CG PRO 474 88.580 6.680 8.979 1.00 35'.50 ATOM 3609 C PRO 474 85.942 7.727 6.642 1.00 37.56 ATOM 3610 0 PRO 474 85.415 6.641 6.400 1.00 37.88 ATOM 3611 N ARG 475 85.720 8.809 5.907 1.00 37.73 ATOM 3613 CA ARG 475 84.779 8.790 4.795 1.00 40.01 ATOM 3614 CB ARG 475 84.655 10.183 4.182 1.00 38.31 ATOM 3615 CG ARG 475 84.217 11.236 5.198 1.00 35.15 ATOM 3616 CD ARG 475 84.069 12.631 4.586 1.00 33-.92 ATOM 3617 NE ARG 475 83.718 13.603 5.616 1.00 30.45 ATOM 3619 CZ ARG 475 82.475 13.880 5.993 1.00 26.48 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 160 ATOM 3620 NH1 ARG 475 81.444 13.284 5.407 1.00 24.80 ATOM 3623 NH2 ARC 475 82.271 14.650 7.056 1.00 25.16 ATOM 3626 C ARG 475 .85.054 7.735 3.728 1.00 42.18 ATOM 3627 0 ARG 475 84.125 7.197 3.128 1.00 41.43 ATOM 3628 N ASP 476 86.322 7.391 3.535 1.00 45.44 ATOM 3630 CA ASP 476 86.676 6.387 2.541 1.00 49.80 ATOM 3631 CB ASP 476 88.192 6.343 2.329 1.00 50.95 ATOM 3632 CC ASP 476 88.944 5.975 3.585 1.00 53.89 ATOM 3633 ODi ASP 476 89.303 4.789 3.731 1.00 59.71 ATOM 3634 0D2 ASP 476 89.176 6.867 4.427 1.00 57.39 ATOM 3635 C ASP 476 86.149 5.010 2.950 1.00 51.23 ATOM 3636 0 ASP 476 86.051 4.102 2.121 1.00 53.54 ATOM 3637 N ARC 477 85.814 4.864 4.230 1.00 50.49 ATOM 3639 CA ARC 477 85.285 3.610 4.753 1.00 49.32 ATOM 3640 CB ARC 477 85.8B34 3.364 6.152 1.00 49.79 ATOM 3641 CC ARC 477 87.237 2.806 6.112- 1.00 53.06 ATOM 3642 CD ARC 477 87.960 2.981 7.420 1.00 56.76 ATOM 3643 NE ARC 477 87.310 2.293 8.529 1.00 59.35 ATOM 3645 CZ ARC 477 87.728 2.371 9.789 1.00 62.23 ATOM 3646 NH1 ARC 477 88.793 3.103 10.101 1.00 63.66 ATOM 3649 NH2 ARC 477 87.067 1.741 10.745 1.00 64.35 ATOM 3652 C ARC 477 83.755 3.547 4.750 1.00 48.04 ATOM 3653 0 ARG 477 83.160 2.693 5.404 1.00 48.09 ATOM 3654 N LEU 478 83.129 4.412 3.958 1.00 45.38 ATOM 3656 CA LEU 478 81.685 4.469 3.870 1.00 41.60 ATOM 3657 CB LEU 478 81.168 5.578 4.790 1.00 38.39 ATOM 3658 CC LEU 478 79.651 5.699 4.894 1.00 36.38 ATOM 3659 CD1 LEU 478 79.113 4.595 5.802 1.00 33.98 ATOM 3660 CD2 LEU 478 79.293 7.068 5.441 1.00 40.06 ATOM' 3661 C LEU 478 81.279 4.774 2.433 1.00 41.92 ATOM 3662 0 LEU 478 81.696 5.780 1.870 1.00 43.99 ATOM 3663 N VAiL 479 80.466 3.904 1.844 1.00 42.29 ATOM, 3665 CA VAL 479 79.992 4.082 0.471 1.00 41.07 ATOM 3666 CB VAL 479 80.227 2.816 -0.397 1.00 41.13 ATOM 3667 CC1 VAL 479 79.719 3.057 -1.810 1.00 40.19 ATOM 3668 CG2 VAL 479 81.700 2.448 -0.420 1.00 41.36 ATOM 3669 C VAL 479 78.500 4.345 0.540 1.00 40.44 ATOM 3670 0 VAiL 479 77.719 3.451 0.885 1.00 39.86 ATOM 3671 N LEU 480 78.112 5.582 0.253 1.00 41.37 ATOM 3673 CA LEU 480 76.706 5.973 0.293 1.00 41.63 ATOM 3674 CB LEU 480 76.568 7.492 0.166 1.00- 39.91 ATOM 3675 CC LEU 480 77.236 8.332 1.261 1.00 39.23 ATOM 3676 CD1 LEU 480 76.890 9.800 1.039 1.00 37.73 ATOM 3677 CD2 LETJ 480 76.791 7.877 2.647 1.00 35.18 ATOM 3678 C LEU 480 75.899 5.273 -0.788 1.00 42.21 ATOM 3679 0 LEU 480 76.395 5.048 -1.890 1.00 45.27 ATOM 3680 N CLY 481 74.650 4.947 -0.476 1.00 41.51 ATOM 3682 CA GLY 481 73.812 4.257 -1.433 1.00 40.19 ATOM 3683 C CLY 481 72.446 4.872 -1.640 1.00 41.58 ATOM 3684 0 CLY 481 72.262 6.091 -1.550 1.00 41.35 ATOM 3685 N LYS 482 71.474 4.009 -1.908 1.00 42.65 ATOM 3687 CA LYS 482 70.105 4.429 -2.166 1.00 44.17 ATOM 3688 CB LYS 482 69.240 3.221 -2.542 1.00 45.66 ATOM 3689 C LYS 482 69.475 5.148 -0.994 1.00 44.86 SSSD/55145. vOl WO 98/07835 PTU9148 PCT/US97/14885' 161

ATOM

ATOM

ATOM

ATOM

,ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3690 3691 3692 3693 3694 3695 3696 3697 3698 3700 3701 3702 3703 3704 3705 3706 3707 3709 3710 3711 3712 3714 3715 3716 3717 3718 3720 3721 3722 3723 3725 3726 3727 3728 3729 3731 3732 3733 3734 3735 3737 3738 3739 3740 3742 3743 3744 3745 3746 3747 3750 3751 3752 3754 0

N

CD

CA

CB

CG

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

C

0

N

CA

CB

C

0

N

CA

C

0

N

CA

CB

C

0

N

CA

CB

C

0

N

CA

C

0

N

CA

CB

CG

CD

OE1 NE2

C

N

CA

LYS

PRO

PRO

PRO

PRO

PRO

PRO

PRO

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

GLY

GLY

GLY

GLY

GLU

GLU

GLU

GLU

GLU

GLY

GLY

GLY

GLY

ALA

ALA

ALA

ALA

ALA

PHE

PE

PE

PE

PE

GLY

GLY

GLY

GLY

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

VAL

VAL

482 483 483 483 483 483 483 483 484 484 484 484 484 484 484 484 485 485 485 485 486 486 486 486 486 487 487 487 487 488 488 488 488 488 489 489 489 489 489 490 490 490 490 491 491 491 491 491 491 491 491 491 492, 492 69.638 68 .749 68 .518 68 .099 67.542 67.269 .66 .991 66 .314 66 .858 65.837 6.6.433 67.517 68 .226 66 .906 64 .715 63 .571 65.027 63 .998 64.445 65.643 63.471 63.733 63.873 62 .618 61.481 62 .943 61.960 62 .373 63 .040 61.979 62.304 61.637 63 .817 64.413 64.429 65.877 66.277 66.749 67.924 66.171 66.852 66.787 65.765 67.874 68.000 68 .891 69.286 70.155 70.483 70.529 68 '623 69.511 68.148 68.676 4.752 6.234 6.880 6.983 8.200 7.666 6.151 5.376 6.268 5.547 4.883 3.844 3.460 2.630 6.501 6.075 7.788 8.737 10. 183 10. 468 11. 090 12.525 13.084 13. 249 12.775 14.415 15. 188 16.635 17. 172 17. 265 18.661 19. 121 18.830 18.597 19. 155 19. 364 20.699 18. 207 18.399 17.005 15. 803 14.760 14.624 14.015 12.984 13.520 12. 518 13.143 14. 330 12.341 11.720 11. 792 10. 561 9.3 04 0.155 -1.273 -2.576 -0.206 -0.947 -2.307 0.429 -0.251 1.742 2.477 3 .720 3.445 4.731 2 .784 2.878 3.055 3.006 3.397 3 .476 3.577 3.458 3 .508 2.091 4.245 4.295 4 .791 5.520 5.634 4.747 6.735 6.992 8.283 7.085 8.141 5.946 5.831 6.467 6.368 6 .731 6 .349 6.797 5.692 5 .013 5.528 4 .504 3.371 2.289 1.202 1.255 0.202 5.114 5.959 4.693 5.193 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1. 00 1 .00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 45.23 45. 94 46. 96 47.79 47.02 46.65 48.74 48.01 49.91 53 .93 50.17 48 .93 49. 47.03 58. 61. 60.35 64.00 66 .09 65.26 67.18 68.69 69.88 68.80 69.26 68.47 67.56 66.71 66.48 67.22 67.78 68. 97 67.38 67 .14 66 .22 65.49 66 .11 64.07 61.56 60.79 54 .72 51.78 49.17 49. 97 48 .06 51.02 56.00 58.93 60.31 60.19 45.59 45.22 43.19 41.54 SSSD/551 45. vOl WO 98107835 PCTIUS97/14885 162 ATOM 3755 CE VAL 492 67.655 8.584 6.087 1.00 41.74 ATOM 3756 CG1 VAL 492 68.217 7.248 6.561 1.00 43.70 ATOM 3757 CG2 VAL 492 67.283 9.463 7.269 1.00 44.07 ATOM 3758 C VAL 492 68.971 8.424 3.993 1.00 39.72 ATOM 3759 0 VAL 492 68.125 8.271 3.108 1.00 39.81 ATOM 3760 N VAL 493 70.176 7.872 3.942 1.00 36.38 ATOM 3762 CA VAL 493 70.545 7.001 2.844 1.00 35.88 ATOM 3763 CE VAL 493 71.580 7.666 1.869 1.00 36.92 ATOM 3764 CG1 VAL 493 71.142 9.069 1.485 1.00 36.64 ATOM 3765 CG2 VAL 493 72.978 7.670 2.469 1.00 38.29 ATOM 3766 C VAL 493 71.131 5.689 3.351 1.00 36.03 ATOM 3767 0 VAL 493 71.693 5.617 4.443 1.00 36.57 ATOM 3768 N LEU 494 70.947 4.6G37 2.571 1.00 34.91 ATOM 3770 CA LEU 494 71.500 3.344 2.909 1.00 36.04 ATOM 3771 CB LEU 494 70.809 2.244 2.094 1.00 37.43 ATOM 3772 CG LEU 494 71.312 0.814 2.269 1.00 36.62 ATOM 3773 CD1 LEU 494 71.327 0.437 3.735 1.00 36.37 ATOM 3774 CD2 LEU 494 70.419 -0.118 1.479 1.00 40.70 ATOM 3775 C LEU 494 72.967 3.451 2.510 1.00 37.08 ATOM 3776 0 LEU 494 73.308 4.160 1.560 1.00 34.90 ATOM 3777 N ALA 495 73.839 2.779 3.243 1.00 37.18 ATOM 3779 CA ALA 495 75.246 2.830 2.918 1.00 39.84 ATOM 3780 CE ALA 495 75.885 4.066 3.541 1.00 39.29 ATOM 3781 C ALA 495 75.949 1.578 3.400 1.00 41.68 ATOM 3782 0 ALA 495 75.400 0.808 4.189 1.00 41.53 ATOM 3783 N GLU 496 77.149 1.348 2.881 1.00 43.44 ATOM 3785 CA GLU 496 77.936 0.202 3.297 1.00 42.86 ATOM 3786 CE GLU 496 78.328 -0.663 2.101 1.00 44.63 ATOM 3787 CG GLU 496 77.120 -1.167 1.320 1.00 53.31 ATOM 3788 CD GLU 496 77.386 -2.450 0.545 1.00 59.48 ATOM 3789 OE1 GLU 496 76.494 -3.332 0.534 1.00 62.39 ATOM 3790 0E2 GLU 496 78.477 -2.580 -0.053 1.00 62.15 ATOM 3791 C GLU 496 79.150 0.750 4.006 1.00 40.96 ATOM 3792 0 GLU 496 79.889 1.568 3.455 1.00 40.81 ATOM 3793 N ALA 497 79.267 0.411 5.280 1.00 40.79 ATOM 3795 CA ALA 497 80.381 0.857 6.096 1.00 41.84 ATOM 3796 CE ALA 497 79.888 1.240 7.478 1.00 38.80 ATOM 3797 C ALA 497 81.394 -0.280 6.181 1.00 44.72 ATOM 3798 0 ALA 497 81.019 -1.445 6.215 1.00 44.78 ATOM 3799 N ILE 498 82.678 0.054 6.183 1.00 48.03 ATOM 3801 CA ILE 498 83.729 -0.952 6.255 1.00 48.78 ATOM 3802 CE ILE 498 84.654 -0.894 5.014 1.00 50.57 ATOM 3803 CG2 ILE 498 85.748 -1.954 5.119 1.00 51.32 ATOM 3804 CG1 ILE 498 83.851 -1.103 3.726 1.00 51.90 ATOM 3805 CD1 ILE 498 83.139 0.146 3.198 1.00 55.47 ATOM 3806 C ILE 498 84.573 -0.754 7.511 1.00 48.31 ATOM 3807 0 ILE 498 85.005 0.359 7.805 1.00 47.90 ATOM 3808 N GLY 499 84.754 -1.829 8.271 1.00 49.29 ATOM 3810 CA GLY 499 85.563 -1.774 9.479 1.00 53.17 ATOM 3811 C GLY 499 85.076 -0.944 10.657 1.00 57.22 ATOM 3812 0 GLY 499 85.885 -0.341 11.364 1.00 59.20 ATOM 3813 N LEU 500 83.768 0. 948 10 .909 1.00 58.51 ATOM 3815 CA LEU 500 83.193 -0.189 12.025 1.00 57.80 ATOM 3816 CE LEU 500 81.705 -0.519 12.181 1.00 55.67 SSSD/55145. vOl WO 98/07835 WO 9807835PCT/US97/14885 :163 ATOM 3817 CG LEU 500 80.789 0.036 11.086 1.00 54.81 ATOM 3818 CD1 LEU 500 79.361 -0.445 11.293 1.00 53.00 ATOM 3819 CD2 LEU 500 80.854 1.561 11.089 1.00 53.27 ATOM 3820 C LEU 500 83.926 -0.466 13.333 1.00 58.15 ATOM 3821 0 LEU 500 84.461 -1.560 13.529 1.00 60.29 ATOM 3822 N PRO 505 87.397 -6.022 10.511 1.00 77.18 ATOM 3823 CD PRO 505 88.509 -6.651 11.242 1.00 78.26 ATOM 3824 CA PRO 505 87.755 -4.660 10.097 1.00 75.62 ATOM 3825 CB PRO 505 89.166 -4.487 10.669 1.00 75.77 ATOM 3826 CG PRO 505 89.696 -5.884 10.715 1.00 77.07 ATOM 3827 C PRO 505 87.709 -4.440 8.583 1.00 73.15 ATOM 3828 0 PRO 505 87.772 -3.308 8.105 1.00 72.63 ATOM 3829 N ASN 506 87.595 -5.524 7.830 1.00 71.27 ATOM 3831 CA ASN 506 87.518 -5.421 6.380 1.00 69.14 ATOM 3832 CB ASN 506 88.577 -6.313 5.728 1.00 70.76 ATOM 3833 C ASN 506 86.119 -5.840 5.940 1.00 67.30 ATOM 3834 0 ASN 506 85.834 -5.957 4.750 1.00 67.03 ATOM 3835 N ARG 507 85.250 -6.064 6.921 1.00 65.27 ATOM 3837 CA ARG 507 83.876 -6.479 6.669 1.00 62.86 ATOM 3838 CB ARG 507 83.335 -7.267 7.864 1.00 65.45 ATOM 3839 C ARG 507 82.991 -5.274 6.443 1.00 59.56 ATOM 3840 0 ARG 507 83.161 -4.247 7.100 1.00 59.70 ATOM 3841 N VAL 508 82.057 -5.397 5.509 1.00 56.65 ATOM 3843 CA VAL 508 81.135 -4.310 5.226 1.00 55.48 ATOM 3844 CB VAL 508 80.850 -4.157 3.719 1.00 55.71 ATOM 3845 CG1 VAL 508 82.146 -3.962 2.962 1.00 58.18 ATOM 3846 CG2 VAL 508 80.096 -5.356 3.188 1.00 58.76 ATOM 3847 C VAL 508 79.833 -4.537 5.979 1.00 53.10 ATOM 3848 0 VAL 508 79.352 -5.665 6.091 1.00 54.25 ATOM 3849 N THR 509 79.282 -3.460 6.514 1.00 50.06 ATOM 3851 CA THR 509 78.041 -3.512 7.260 1.00 45.70 ATOM 3852 CE THR 509 78.256 -3.029 8.715 1.00 45.59 ATOM 3853 OGI THR 509 79.395 -3.696 9.279 1.00 43.86 ATOM 3855 CG2 THR 509 77.028 -3.328 9.573 1.00 44.19 ATOM 3856 C THR 509 77.064 -2.574 6.564 1.00 43.57 ATOM 3857 0 THR 509 77.416 -1.444 6.221 1.00 41.15 ATOM 3858 N LYS 510 75.871 -3.073 6.268 1.00 42.96 ATOM 3860 CA LYS 510 74.847 -2.253 5.640 1.00 41.91 ATOM 3861 CB LYS 510 73.740 -3.144 5.091 1.00 44.74 ATOM 3862 CG LYS 510 72.864 -2.461 4.069 1.00 51.83 ATOM 3863 CD LYS 510 73.392 -2.645 2.659 1.00 55.00 ATOM 3864 CE LYS 510 72.769 -3.879 2.020 1.00 58.36 ATOM 3865 NZ LYS 510 73.069 -5.131 2.769 1.00 58.57 ATOM 3869 C LYS 510 74.322 -1.367 6.789 1.00 40.74 ATOM 3870 0 LYS 510 73.909 -1.874 7.837 1.00 40.26 ATOM 3871 N VAL 511 74.413 -0.052 6.624 1.00 37.21 ATOM 3873 CA VAL 511 73.989 0.877 7.661 1.00 33.44 ATOM 3874 CE VAL 511 75.227 1.515 8.362 1.00 34.53 ATOM 3875 CG1 VAL 511 76.100 0.436 9.014 1.00 31.98 ATOM 3876 CG2 VAL 511 76.048 2.322 7.358 1.00 34.82 ATOM 3877 C VAL 511 73.134 1.989 7.087 1.00 31.34 ATOM 3878 0 VAL 511 73.025 2.130 5.871 1.00 31.33 ATOM 3879 N ALA 512 72.485 2.748 7.961 1.00 30.70 ATOM 3881 CA ALA 512 71.671 3.876 7.523 1.00 30.81 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885' 164 ATOM 3882 CB ALA 512 70.305 3.879 8.206 1.00 29.85 ATOM 3883 C ALA 512 72.453 5.124 7.904 1.00 31.30 ATOM 3884 0 ALA 512 73.036 5.197 8.996 1.00 30.24 ATOM 3885 N VAL 513 72.480 6.096 6.999 1.00 30.86 ATOM 3887 CA VAL 513 73.208 7.332 7.238 1.00 30.58 ATOM 3888 CB VAL 513 74.358 7.525 6.223 1.00 31.11 ATOM 3889 CG1 VAL 513 75.132 8.788 6.547 1.00 29.63 ATOM 3890 CG2 VAL 513 75.290 6.317 6.223 1.00 28.70 ATOM 3891 C VAL 513 72.300 8.556 7.189 1.00 31.28 ATOM 3892 0 VAL 513 71.645 8.824 6.167 1.00 30.12 ATOM 3893 N LYS 514 72.229 9.257 8.321 1.00 31.03 ATOM 3895 CA LYS 514 71.439 10.479 8.451 1.00 32.56 ATOM 3896 CB LYS 514 70.881 10.635 9.870 1.00 34.31 ATOM 3897 CG LYS 514 69.977 9.516 10.326 1.00 38.25 ATOM 3898 CD LYS 514 69.513 9.774 11.753 1.00 47.74 ATOM 3899 CE LYS 514 68.514 8.719 12.230 1.00 51.60 ATOM 3900 NZ LYS 514 67.226 8.755 11.468 1.00 58.53 ATOM 3904 C LYS 514 72.357 11.659 8.137 1.00 30.29 ATOM 3905 0 LYS 514 73.485 11.736 8.628 1.00 28.14 ATOM 3906 N MET 515 71.867 12.580 7.320 1.00 30.67 ATOM 3908 CA MET 515 72.643 13.747 6.920 1.00 29.94 ATOM 3909 CB MET 515 73.435 13.442 5.648 1.00 30.64 ATOM 3910 CG MET 515 72.557 13.038 4.464 1.00 32.16 ATOM 3911 SD MET 515 73.525 12.522 3.036 1.00 37.59 ATOM 3912 CE MET 515 74.015 10.933 3.563 1.00 29.11 ATOM 3913 C MET 515 71.675 14.869 6.635 1.00 29.71 ATOM 3914 0 MET 515 70.462 14.664 6.598 1.00 30.04 ATOM 3915 N LEU 516 72.212 16.060 6.445 1.00 29.56 ATOM 3917 CA LEt) 516 71.381 17.206 6.136 1.00 30.76 ATOM 3918 CB LEt) 516 72.093 18.508 6.526 1.00 28.20 ATOM 3919 CG LEt) 516 72.396 18.724 8.011 1.00 28.48 ATOM 3920 CD1 LEt) 516 73.202 19.983 8.185 1.00 27.55 ATOM 3921 CD2 LEU 516 71.114 18.814 8.794 1.00 25.49 ATOM 3922 C LEt) 516 71.081 17.225 4.647 1.00 30.97 ATOM 3923 0 LEU 516 71.728 16.534 3.851 1.00 29.93 ATOM 3924 N LYS 517 70.030 17.946 4.291 1.00 31.57 ATOM 3926 CA LYS 517 69.677 18.117 2.899 1.00 31.44 ATOM 3927 CB LYS 517 68.169 18.310 2.752 1.00 34.79 ATOM 3928 CG LYS 517 67.375 17.098 3.194 1.00 38.42 ATOM 3929 CD LYS 517 66.148 16.888 2.343 1.00 46.52 ATOM 3930 CE LYS 517 65.087 17.950 2.582 1.00 53.77 ATOM 3931 NZ LYS 517 63.901 17.740 1.690 1.00 56.38 ATOM 3935 C LYS 517 70.457 19.377 2.499 1.00 30.18 ATOM 3936 0 LYS 517 70.892 20.134 3.370 1.00 27.47 ATOM 3937 N SER 518 70.646 19.594 1.201 1.00 31.13 ATOM 3939 CA SER 518 71.394 20.747 0.693 1.00 32.11 ATOM 3940 CB SER 518 71.518 20.652 -0.824 1.00 33.45 ATOM 3941 OG SER 518 70.242 20.567 -1.428 1.00 34.51 ATOM 3943 C SER 518 70.814 22.103 1.073 1.00 32.81 ATOM 3944 0 SER 518 71. 515 23.123 1.027 1.00 34.03 ATOM 3945 N ASP 519 69.540 22.117 1.449 1.00 29.80 ATOM 3947 CA ASP 519 68.886 23.354 1.836 1.00 28.94 ATOM 3948 CB ASP 519 67.473 23.421 1.237 1.00 33.90 ATOM 3949 CG ASP 519 66.542 22.332 1.771 1.00 34.42 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 165

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

A-TOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3950 3951 3952 3953 3954 3956 3957 3958 3959 3960 3962 3963 3964 3966 3967 3968 3969 3971 3972 3973 3974 3975 3976 3977 3978 3979 3981 3982 3983 3984 3985 3986 3990 3991 3992 3994 3995 3996 3997 3998 3999 4000 4001 4003 4004 4005 4006 4007 4008 4009 4010 4012 4013 4014 OD1 0D2

C

0

N

CA

CB

C

0

N

CA

CB

OG1 CG2

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

OG

ASP

ASP

AS P

ASP

ALA

ALA

ALA

ALA

ALA

THR

THR

THR

THR

THR

THR

THR

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LYS

LYS_

LYS

LYS

LYS

LYS

LYS

LYS

LYS

ASP

AS P

ASP

ASP

AS P AS P

ASP

AS P

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

SER

SER

SER

SER

67.020 65.313 68.829 68 .177 69.514 69.488 70. 174 70.122 70.880 69.800 70.357 69.254 68 .547 68.275 71.251 71.348 71.876 72 .745 73.404 74.414 75. 769 76.798 75.806 71.932 72.428 70.670 69.805 68.481 67 .560 66.360 65.443 64. 31~3 69.572 69.589 69.374 69.182 68 .928 67.586 66.568 67.549 70.424 70.317 71.603 72.873 74 .064 75.462 75.597 76.530 72.909 73.249 72.560 72.500 71.980 71.793 21.328 22.485 23 .559 24.485 22 .710 22 .824 21.639 24-108 24.741 24.491 25.692 26.635 25.968 27.074 25.263 24.072 26.241 25. 978 27.282 27 .130 26.579 27.261 25.461 25.345 24.480 25.750 2 5.210 25.970 25.541 24.776 24.312 23.509 23.733 22 .922 23.383 21.980 21.831 22.396 22 .106 23.120 21.190 20.104 21.761 21.121 21.997 21.433 19.979 22.321 20.869 19.777 21.902 21.861 23.209 23.213 2.333 1 .617 3 .342 3 .816 4.099 5.558 6.190 6.040 5.309 7 .2 72 7.885 8.463 9.520 7.379 9.048 9.369 9.696 10.832 11.299 12.450 12.009 12.231 11.452 11.969 12 .684 12 .097 13 .135 13.188 14.322 13.789 14 .914 14 .373 12.861 13.788 11.590 11.214 9.714 9.286 9. 954 8 .270 11.606 12 .162 11.347 11.700 11. 282- 11.593 11.098 10.967 13.200 13.653 13 .956 15.422 15.939 17.343 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 35.58 41.83 29.08 29.79 29.73 29. 16 28. 13 28.06 28. 84 27. 84 30.45 33.56 36.27 36 .06 30. 04 28.16 31.42 36.94 44. 74 58.34 64. 64.89 70.26 34. 02 31.11 32.53 34.06 39.54 45.55 52.08 54. 16 54 .38 31.73 31.15 29.22 28 .79 27.65 33 .89 34.66 30. 04 28.00 30.83 29.87 27.60 24.08 26.11 23 .67 21.28 26.38 26 .09 29. 72 32 .16 33.45 40.42 145. vOl WO 98/07835 PCT/US97/14885 166 ATOM 4016 C SER 526 71.572 20.728 15.902 1.00 31.64 ATOM 4017 0 SER 526 71.869 20.030 16.889 1.00 32.54 ATOM 4018 N ASP 527 70.454 20.561 15.201 1.00 27.92 ATOM 4020 CA ASP 527 69.492 19.527 15.524 1.00 28.60 ATOM 4021 CB ASP 527 68.187 19.767 14.765 1.00 29.35 ATOM 4022 CG ASP 527 67.418 20.984 15.278 1.00 31.37 ATOM 4023 ODi ASP 527 67.759 21.549 16.353 1.00 31.96 ATOM 4024 0D2 ASP 527 66.456 21.369 14.591 1.00 32.58 ATOM 4025 C ASP 527 70.038 18.131 15.246 1.00 28.82 ATOM 4026 0 ASP 527 69.854 17.212 16.047 1.00 29.65 ATOM 4027 N LEU 528 70.721 17.962 14.120 1.00 29.29 ATOM 4029 CA LEU 528 71.302 16.658 13.794 1.00 29.94 ATOM 4030 CB LEU 528 71.780 16.621 12.336 1.00 26.45 ATOM 4031 CG LEU 528 72.315 15.276 11.840 1.00 28.34 ATOM 4032 CD1 LEU 528 71.240- 14.189 12.035 1.00 27.16 ATOM 4033 CD2 LEU 528 72.756-- 15.387 10.372 1.00 25.91 ATOM 4034 C LEU 528 72.449 16.319 14.776 1.00 29.72 ATOM 4035 0 LEU 528 72.617 15.162 15.178 1.00 28.98 ATOM 4036 N ILE 529 73.224 17.329 15.168 1.00 30.15 ATOM 4038 CA ILE 529 74.305 17.131 16.134 1.00 28.88 ATOM 4039 CB ILE 529 75.188 18.382 16.268 1.00 26.91 ATOM 4040 CG2 ILE 529 76.175 18.221 17.423 1.00 24.82 ATOM 4041 CG1 ILE 529 75.960 18.613 14.984 1.00 23.98 ATOM 4042 CD1 ILE 529 76.663 19.932 14.973 1.00 28.33 ATOM 4043 C ILE 529 73.709 16.799 17.518 1.00 29.71 ATOM 4044 0 ILE 529 74.172 15.880 18.193 1.00 29.19 ATOM 4045 N SER 530 72.672 17.524 17.926 1.00 26.84 ATOM 4047 CA SER 530 72.061 17.247 19.214 1.00 31.46 ATOM 4048 CB SER 530 70.948 18.251 19.521 1.00 36.17 ATOM 4049 OG SER 530 70.045 18.363 18.431 .1.00 47.58 ATOM 4051 C SER 530 71.526 15.822 19.248 1.00 30.05 ATOM 4052 0 SER 530 71.646 15.136 20.270 1.00 29.61 ATOM 4053 N GLU 531 70.972 15.357 18.132 1.00 27.74 ATOM 4055 CA GLU 531 70.458 13.999 18.090 1.00 28.71 ATOM 4056 CB GLU 531 69.709 13.727 16.789 1.00 29.72 ATOM 4057 CG GLU 531 69.147 12.319 16.737 1.00 32.21 ATOM 4058 CD GLU 531 68.510 11.979 15.414 1.00 33.88 ATOM 4059 OE1 GLU 531 68.026 10.84G 15.281 1.00 37.60 ATOM 4060 0E2 GLU 531 68.483 12.833 14.510 1.00 34.70 ATOM 4061 C GLU 531 71.578 12.974 18.271 1.00 28.91 ATOM 4062 0 GLU 531 71.428 12.007 19.019 1.00 29.46 ATOM 4063 N MET 532 72.686 13.179 17.567 1.00 28.84 ATOM 4065 CA MET 532 73.851 12.296 17.648 1.00 29.35 ATOM 4066 CB MET 532 74.948 12.786 16.689 1.00 27.41 ATOM 4067 CG MET 532 76.299 12.117 16.872 1.00 26.71 ATOM 4068 SD MET 532 77.503 12.675 15.640 1.00 32.27 ATOM 4069 CE MET 532 77.732 14.400 16.117 1.00 24.10 ATOM 4070 C MET 532 74.389 12.280 19.078 1.00 28.80 ATOM 4071 0 MET 532 74.700 11.230 19.630 1.00 29.74 ATOM 4072 N GLU 533 74.481 13.454 19.681 1.00 28.83 ATOM 4074 CA GLU 533 74.985 13.546 21.033 1.00 29..66 ATOM 4075 CB GLU 533 78.182 15.008 21.423 1.00 32.23 ATOM 4076 CG GLU 533 76.331 15.687 20.651 1.00 34.47 ATOM 4077 CD GLU 533 77.656 14.937 20.774 1.00 38.03 145. vOl WO 98/07835 PCTIUS97/14885 167 ATOM 4078 QEl GLU 533 78.168 14.780 21.903 1.00 39.75 ATOM 4079 0E2 GLU 533 78.192 14.497 19.736 1.00 38.75 ATOM 4080 C GLU 533 74.058 12.815 22.005 1.00 31.55 ATOM 4081 0 GLU 533 74.521 12.083 22.88B9 1.00 30.63 ATOM 4082 N MET 534 72.750 12.958 21.799 1.00 31.31 ATOM 4084 CA MET 534 71.789 12.289 22.664 1 .00 30.78 ATOM 4085 CB MET 534 70.348 12.672 22.319 1.00 31.23 ATOM 4086 CG MET 534 69.453 12.648 23.551 0.50 29.35 PRT1 ATOM 4087 SD MET 534 67.688 12.563 23.246 0.50 28.79 PRT1 ATOM 4088 CE MET 534 67.290 14.230 22.875 0.50 26.96 PRT1 ATOM 4089 C MET 534 71.991 10.773 22.560 1.00 28.82 ATOM 4090 0 MET 534 72.053 10.083 23.568 1.00 30.10 ATOM 4091 N MET 535 72.149 10.271 21.339 1.00 29.16 ATOM 4093 CA MET 535 72.381 8.852 21.110 1.00 29.37 ATOM 4094 CB MET 535 72.546 8.551 19.617 1.00 27.35 ATOM 4095 CG MET 535 71.281 8.790 18.817 1.00 28.40 ATOM 4096 SD MET 535 71.255 7.955 17.255 1.00 30.26 ATOM 4097 CE MET 535 71.336 9.279 16.188 1.00 35.50 ATOM 4098 C MET 535 73.612 8.388 21.887 1.00 30.36 ATOM 4099 0 MET 535 73.626 7.287 22.460 1.00 26.13 ATOM 4100 N LYS 536 74.640 9.233 21.909 1.00 30.70 ATOM 4102 CA LYS 536 75.850 8.913 22.649 1.00 31.76 ATOM 4103 CB LYS 536 76.934 9.954 22.388 1.00 31.05 ATOM 4104 CG LYS 536 77.550 9.883 21.004 1.00 26.80 ATOM 4105 CD LYS 536 78.534 11.017 20.860 1.00 31.05 ATOM 4106 CE LYS 536 79.132 11.138 19.466 1.00 29.83 ATOM 4107 NZ LYS 536 79.957 12.377 19.440 1.00 29.32 ATOM 4111 C LYS 536 75.550 8.834 24.150 1.00 31.99 ATOM 4112 0 LYS 536 75.920 7.859 24.806 1.00 31.92 ATOM 4113 N MET 537 74.837 9.826 24.676 1.00 31.81 ATOM 4115 CA MET 537 74.517 9.835 26.090 1.00 35.37 ATOM 4116 CB MET 537 73.860 11.154 26.506 1.00 41.32 ATOM 4117 CG MET 537 74.828 12.335 26.610 1.00 51.50 ATOM 4118 SD MET 537 76.234 12.090 27.776 1.00 57.48 ATOM 4119 CE MET 537 75.460 12.637 29.334 1.00 56.91 ATOM 4120 C MET 537 73.630 8.679 26.499 1.00 36.11 ATOM 4121 0 MET 537 73.845 8.084 27.548 1.00 38.54 ATOM 4122 N ILE 538 72.652 8.347 25.661 1.00 33.69 ATOM 4124 CA ILE 538 71.704 7.277 25.954 1.00 31.62 ATOM 4125 CB ILE 538 70.492 7.314 *24.974 1.00 28.21 ATOM 4126 CG2 ILE 538 69.681 6.013 25.034 1.00 28.22 ATOM 4127 CG1 ILE 538 69.590 8.488 25.338 1.00 23.74 ATOM 4128 CD1 ILE 538 68.487 8.728 24.344 1.00 27.94 ATOM 4129 C ILE 538 72.322 5.894 26.008 1.00 31.07 ATOM 4130 0 ILE 538 71:952 5.080 26 '860 1.00 33.13 ATOM 4131 N GLY 539 73.239 5.611 25.094 1.00 29.52 ATOM 4133 CA GLY 539 73.871 4.309 25.093 1.00 28.40 ATOM 4134 C GLY 539 73.111 3.275 24.289 1.00 30.21 ATOM 4135 0 GLY 539 72.018 3.554 23.788 1.00 29.66 ATOM 4136 N LYS 540 73.679 2.074 24.199 1.00 .28.44 ATOM 4138 CA LYS 540 73.105 0.984 23.426 1.00 31.09 ATOM 4139 CB LYS 540 74.215 0.089 22.895 1.00 33.15 ATOM 4140 CG LYS 540 75.116 0.776 21.906 1.00 39.54 ATOM 4141 CD LYS 540 76.125 -0.175 21.329 1.00 43.98 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 168 ATOM 4142 CE LYS 540 77.033 0.562 20.349 1.00 50.79 ATOM 4143 NZ LYS 540 76.338 0.977 19.086 1.00 51.09 ATOM 4147 C LYS 540 72.053 0.087 24.059 1.00 32.78 ATOM 4148 0 LYS 540 72.088 -0.195 25.266 1.00 32.41 ATOM 4149 N HIS 541 71.137 -0.374 23.208 1.00 31.20 ATOM 4151 CA HIS 541 70.080 -1.304 23.591 1.00 31.53 ATOM 4152 CB HIS 541 68.911 -0.630 24.298 1.00 30.69 ATOM 4153 CG HIS 541 67.948 -1.613 24.882 1.00 31.18 ATOM 4154 CD2 HIS 541 67.938 -2.255 26.072 1.00 33.02 ATOM 4155 NDl HIS 541 66.882 -2.123 24.165 1.00 30.56 ATOM 4157 CE1 HIS 541 66.268 -3.037 24.889 1.00 32.95 ATOM 4158 NE2 HIS 541 66.886 -3.140 26.053 1.00 31.79 ATOM 4160 C HIS 541 69.590 -2.013 22.340 1.00 32.72 ATOM 4161 0 HIS 541 69.495 -1.404 21.275 1.00 30.34 ATOM 4162 N LYS 542 69.282 -3.305 22.475 1.00 32.32 ATOM 4164 CA *LYS 542 68.828 -4.131 21.359 1.00 30.29 ATOM 4165 CB LYS 542 68.637 -5.587 21.798 1.00 29.34 ATOM 4166 C LYS 542 67.560 -3.661 20.692 1.00 29.09 ATOM 4167 0 LYS 542 67.369 -3.903 19.507 1.00 29.12 ATOM 4168 N ASN 543 66.683 -3.012 21.446 1.00 28.54 ATOM 4170 CA ASM 543 65.425 -2.559 20.869 1.00 29.10 ATOM 4171 CB ASN 543 64.245 -3.047 21.712 1.00 29.69 ATOM 4172 CG ASH 543 64.253 -4.556 21.900 1.00 29.62 ATOM 4173 ODi ASN 543 64.510 -5.050 23.000 1.00 31.63 ATOM 4174 ND2 ASN 543 64.020 -5.291 20.828 1.00 28.66 ATOM 4177 C ASH 543 65.299 -1.073 20.532 1.00 29.61 ATOM 4178 0 ASN 543 64.207 -0.507 20.578 1.00 28.00 ATOM 4179 N -ILE 544 66.432 -0.442 20.222 1.00 28.39 ATOM 4181 CA ILE 544 66.466 0.958 19.804 1.00 25.73 ATOM 4182 CB ILE 544 66.903 1.952 20.935 1.00 25.98 ATOM 4183 CG2 ILE 544 66.083 1.721 22.215 1.00 22.04 ATOM 4184 CG1 ILE 544 68.41-2 1.860 21.209 1.00 24.30 ATOM 4185 CD1 ILE 544 68.901 2.846 22.274 1.00 22.83 ATOM 4186 C ILE 544 67.463 1.020 18.639 1.00 26.20 ATOM 4187 0 ILE 544 68.276 0.106 18.467 1.00 25.46 ATOM 4188 N ILE 545 67.307 2.016 17.771 1.00 26.26 ATOM 4190 CA ILE 545 68.223 2.209 16.641 1.00 27.62 ATOM 4191 CB ILE 54 5 67.647 3.195 15.585 1.00 28.33 ATOM 4192 CG2 ILE 545 68.726 3.595 14.562 1.00 28.00 ATOM 4193 CGl ILE 545 66.453 2.565 14.856 1.00 24.69 ATOM 4194 CD1 ILE 545 66.850 1.467 13.875 1.00 26.17 ATOM 4195 C ILE 545 69.492 2.794 17.267 1.00 28.23 ATOM 4196 0 ILE 545 69.468 3.872 17.846 1.00 28.97 ATOM 4197 N ASH 546 70.595 2.069 17.164 1.00 29.45 ATOM 4199 CA ASH 546 71.845 2.508 17.774 1.00 28.58 ATOM 4200 CB ASN 546 72.580 1.309 18.384 1.00 26.34 ATOM 4201 CO ASN 546 71.812 0.673 19.527 1.00 25.52 ATOM 4202 ODi ASN 546 71.634 1.277 20.580 1.00 28.82 ATOM 4203 Nfl2 ASN 546 71.341 -0.542 19.318 1.00 26.57 ATOM 4206 C ASH 546 72.810 3.264 16.881 1.00 28.74 ATOM 4207 0 ASH 546 72.858 3.041 15.675 1.00 29.26 ATOM 4208 N LEU 547 73.578 4.155 17.504 1.00 29.90 ATOM 4210 CA LEU 547 74.618 4.936 16.834 1.00 30.27 ATOM 4211 CB LEU 547 75.075 6.081 17.745 1.00 25.85 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 169 ATOM 4212 CG LEU 547 76.161 7.034 17.232 1.00 27.73 ATOM 4213 CD1 LEU 547 75.670 7.851 16.033 1.00 27.38 ATOM 4214 CD2 LEU 547 76.545 7.966 18.345 1.00 29.14 ATOM 4215 C LEU 547 75.811 .4.004 16.567 1.00 32.22 ATOM 4216 0 LEU 547 76.256 3.291 17.471 1.00 33.38 ATOM 4217 N LEU 548 76.317 4.005 15.335 1.00 32.12 ATOM 4219 CA LEU 548 77.45-2 3.159 14.960 1.00 32.94 ATOM 4220 CB LEU 548 77.103 2.310 13.740 1.00 29.97 ATOM 4221 CG LEU 548 75.839 1.458 13.840 1.00 31.55 ATOM 4222 CD1 LEU 548 75.662 0.713 12.540 1.00 27.85 ATOM 4223 CD2 LEU 548 75.917 0.500 15.025 1.00 26.34 ATOM 4224 C LEU 548 78.726 3.955 14.654 1.00 36.06 ATOM 4225 0 LEU 548 79.836 3.410 14.668 1.00 36.42 ATOM 4226 N GLY 549 78.562 5.219 14.298 1.00 35.78 ATOM 4228 CA GLY 549 79.713 6.042 13.987 1.00 36.22 ATOM 4229 C GLY 549 79.267 7.376 13.433 1.00 35.30 ATOM 4230 0 GLY 549 78.062 7.646 13.362 1.00 33.46 ATOM 4231 N ALA 550 80.232 8.206 13.042- 1.00 34.94 ATOM 4233 CA ALA 550 79.945 9.525 12.490 1.00 31.91 ATOM 4234 CB ALA 550 79.588 10.495 13.613 1.00 30.54 ATOM 4235 C ALA 550 81.128 10.077 11.715 1.00 31.58 ATOM 4236 0 ALA 550 82.281 9.832 12.080 1.00 31.23 ATOM 4237 N CYS 551 80.818 10.812 10.643 .1.00 31.13 ATOM 4239 CA CYS 551 81.805 11.503 9.804 1.00 28.28 ATOM 4240 CB CYS 551 81.621 11.180 8.316 1.00 27.27 ATOM 4241 SG CYS 551 81.771 9.449 7.839 1.00 30.33 ATOM 4242 C CYS 551 81.450 12.960 10.074 1.00 25.88 ATOM 4243 0 CYS 551 80.432 13.458 9.605 1.00 27.73 ATOM 4244 N THR 552 82.214 13.586 10.954 1.00 25.35 ATOM 4246 CA THR 552 81.988 14.967 11.353 1.00 26.79 ATOM 4247 CB THR 552 82.051 15.092 12.899 1.00 27.76 ATOM 4248 OGi THR 552 83.392 14.839 13.338 1.00 27.62 ATOM 4250 CG2 THR 552 81.119 14.086 13.575 1.00 29.17 ATOM 4251 C TRR 552 83.036 15.931 10.790 1.00 25.03 ATOM 4252 0 THR 552 82.825 17.137 10.746 1.00 25.34 ATOM 4253 N GLN 553 84.174 15.385 10.381 1.00 27.34 ATOM 4255 CA GLN 553 85.285 16.190 9.888 1.00 26.31 ATOM 4256 CB GLN 553 86.601 15.639 10.468 1.00 25.05 ATOM 4257 CG GLN 553 86.581 15.491 11.993 1.00 24.78 ATOM 4258 CD GLN 553 86.382 16.823 12.709 1.00 25.40' ATOM. 4259 OE1 GLN 553 87.175 17.748 12.546 1.00 33.74 ATOM 4260 NE2 GLN 553 85.338 16.920 13.516 1.00 25.61 ATOM 4263 C GLN 553 85.390 16.274 8.379 1.00 27.08 ATOM 4264 0 GLN 553 85.083 15.318 7.669 1.00 28.76 ATOM 4265 N ASP 554 85.804 17.438 7.899 1.00 28.63 ATOM 4267 CA ASP 554 86.015 17.677 6.471 1.00 29.70 ATOM 4268 CB ASP 554 87.335 17.050 6.051 1.00 29.73 ATOM 4269 CG ASP 554 88.480 17.587 6.857 1.00 33.38 ATOM 4270 ODi ASP 554 88.794 18.780 6.711 1.00 36.53 ATOM 4271 0D2 ASP 554 89.024 16.841 7.687 1.00 36.40 ATOM 4272 C ASP 554 84.908 .17.258 5.522 1.00 29.64 ATOM 4273 0 ASP 554 85.112 16.422 4.643 1.00 32.06 ATOM 4274 N GLY 555 83.748 17.881 5.679 1.00 28.59 ATOM 4276 CA GLY 555 82.620 17.579 4.825 1.00 26.85 145. vOl WO 98/07835 PCT/US97/14885 170

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4277 4278 4279 4280 4281 4282 4283 4284 4285 4286 4288 4289 4290 4291 4292 4293 4294 4295 4297 4298 4299 4300 4301 4302 4303 4304 4305 4307 4308 4309 4311 4312 4313 4314 4315 4316 4317 4319 4320 4321 4322 4323 4324 4325 4326 4328 4329 4330 4331 4332 4333 4334 4336 4337

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2 cz

OH

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

tG2 CG1 CD1

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

GLY

GLY

PRO

PRO

PRO

PRO

PRO

PRO

PRO

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR.

TYR

TYR

TYR

VAL

VAL

VAL

VAL

VAL

VAL

VAL

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

VAL

VAL

VAL

VAL

VAL

VAL

VAL

GLU

GLU

GLU

555 555 556 556 556 556 556 556 556 557 557 557 .557 557 557 557 557 558 558 558 558 558 558 558 558 558 558 558 558 559 559 559 559 559 559 559 560 560 560 560 560 560 560 560 561 561 561 561 561 561 561 562 562 562 81. 333 81. 319 80.229 80. 159 78 .920 78 .033 79.025 78 .885 79. 515 78 .171 78 .032 77.403 76 .922 78 .088 76 .204 77. 169 76. 060 77 .717 77. 018 77.813 77 .969 78. 966 79.121 77.122 77.271 78 .280 78 .452 76 .848 77.823 75.601 75.286 74. 102 73 .802 74.456 74. 911 73 .834 75 .824 75.638 77. 012 76.819 77. 793 79.274 74. 917 75.404 73 .743 72 .957 71.634 71.951 70 .697 72.618 72 .875 72.057 71.666 71. 199 17.434 17.593 17.113 16.850 16.942 16.494 15.881 15.941 14.875 16.314 15.452 16.217 15.414 14.733 16.340 14.246 14.385 13.065 11. 82 3 10.918 11. 414 10.893 11.315 12.386 12.815 12.272 12.681 11. 13 1 10.902 10.870 10.175 10.832 10.036 12.281 8.772 8.536 7.846 6.465 5.82 9 4.468 6.745 6.399 5.644 5.497 5.129 4.325 5.061 6.400 5.246 2.956 2.694 2.079 0.74 4 -0.086 5.607 6.834 4.920 3.472 5.550 4.386 3.398 6. 700 6 .654 7. 754 8.917 10.092 11.310 12.011 12.271 8.554 8.011 8. 807 8 .573 7.632 6 .203 5.383 4.073 5.666 4.350 3.560 2.253 9. 932 10.647 10. 313 11.564 12.329 13.607 12.687 11.137 10.593 11.371 10.966 10.619 9.979 9.657 9.525 12.034 13.160 11.681 12.606 13.047 13.701 11.874 12.006 10.825 12.834 12.399 13.589 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00o 1.00 1.00 1.00 1. 00 1. 00 1.00 1. 00 1. 00 1.00 1.00 1.00 1. 00 1 .00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 25.30 23.96 24.84 21.36 25.26 23.37 24 .44 26.50 27.38 26.25 28.25 27.09 28.35 25.54 26 .91 29.06 29.05 29.43 28.02 27.83 31.70 32.90 32.69 30.23 29.97 33.20 35.32 28.42 27.81 29.20 29.17 28.53 27.08 23.27 26.41 25. 91 26. 71 27.55 28.48 29.18 27.99 28.97 29.17 28.92 28.60 28.58 27.53 22.44 23.19 28.20 27. 99 29.17- 28.96 27.34 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885' .171 ATOM 4338 CG GLU 562 72.308 -0.331 14.583 1.00 30.12 ATOM 4339 CD GLU 562 71.838 -1.075 15.808 1.00 32.29 ATOM 4340 OE1 GLU 562 72.526 -2.030 16.217 1.00 32.45 ATOM 4341 0E2 GLU 562 70.785 -0.702 16.362 1.00 30.16 ATOM 4342 C GLU 562 70.580 0.794 11.340 1.00 29.79 ATOM 4343 0 GLU 562 69.690 1.653 11.386 1.00 29.75 ATOM 4344 'N TYR 563 70.684 -0.106 10.369 1.00 30.51 ATOM 4346 CA TYR 563 69.735 -0.209 9.267 1.00 33.76 ATOM 4347 CB TYR 563 70.494 -0.602 7.988 1.00 31.04 ATOM 4348 CG TYR 563 69.624 -0.928 6.806 1.00 33.40 ATOM 4349 CD1 TYR 563 68.693 -0.019 6.340 1.00 33.07 ATOM 4350 CEl TYR 563 67.908 -0.301 5.240 1.00 34.71 ATOM 4351 CD2 TYR 563 69.749 -2.141 6.147 1.00 34.61 ATOM 4352 CE2 TYR 563 68.970 -2.446 5.035 1.00 36.54 ATOM 4353 CZ TYR 563 68.047 -1.518 4.589 1.00 36.83 ATOM 4354 OH TYR 563 67.261 -1.805 3.50-1 1.00 38.81 ATOM 4356 C TYR 563 68.655 -1.269 9.588 1.00 36.14 ATOM 4357 0 TYR 563 68.946 -2.365 10.023 1.00 37.70 ATOM 4358 N ALA 564 67.406 -0.948 9.309 1.00 37.87 ATOM 4360 CA ALA 564 66.276 -1.832 9.534 1.00 38.49 ATOM 4361 CB ALA 564 65.278 -1.167 10.458 1.00 42.57 ATOM 4362 C ALA 564 65.645 -2.153 8.179 1.00 39.65 ATOM 4363 0 ALA 564 64.796 -1.423 7.687 1.00 39.74 ATOM 4364 N SER 565 66.039 -3.280 7.607 1.00 40.06 ATOM 4366 CA SER 565 65.567 -3.699 6.295 1.00 40.67 ATOM 4367 CB SER 565 66.267 -4.986 5.883 1.0.0 38.71 ATOM 4368 OG SER 565 66.107 -5.964 6.889 1.00 41.35 ATOM 4370 C SER 565 64.081 -3.884 6.106 1.00 42.17 ATOM 4371 0 SER 565 63.585 -3.741 4.992 1.00 44.25 ATOM 4372 N LYS 566 63.360 -4.207 7.167 1.00 41.71 ATOM 4374 CA LYS 566 61.928 -4.427 7.015 1.00 40.22 ATOM 4375 CB LYS 566 61.525 -5.,668 7.800 1.00 39.51 ATOM 4376 CG LYS 566 62.202 -6.910 7.226 1.00 41.48 ATOM 4377 CD LYS 566 62.113 -8.094 8.149 1.00 41.53 ATOM 4378 CE LYS 566 62.710 -9.312 7.491 1.00 41.18 ATOM 4379 NZ LYS 566 62.763 -10.458 8.438 1.00 46.17 ATOM 4383 C LYS 566 61.007 -3.220 7.263 1.00 40.47 ATOM 4384 0 LYS 566 59.800 -3.367 7.486 1.00 42.68 ATOM 4385 N GLY 567 61.584 -2.026 7.167 1.00 38.90 ATOM 4387 CA GLY 567 60.826 -0.799 7.336 1.00 37.13 ATOM 4388 C GLY 567 60.199 -0.592 8.694 1.00 36.72 ATOM 4389 0 GLY 567 60.644 -1.172 9.683 1.00 38.48 ATOM 4390 N ASN 568 59.191 0.273 8.753 1.00 35.77 ATOM 4392 CA ASN 568 58.518 0.549 10.015 1.00 35.36 ATOM 4393 CB ASN 568 57.883 1.957 10.045 1.00 36.30 ATOM 4394 CG ASN 568 56.635 2.088 9.169 1.00 38.06 ATOM 4395 ODi ASN 568 55.623 1.421 9.383 1.00 38.66 ATOM 4396 ND2 ASN 568 56.686 3.010 8.221 1.00 37.29 ATOM 4399 C ASN 568 57.504 -0.532 10.341 1.00 33.04 ATOM 4400 0 ASN 568 57.061 -1.265 9.461 1.00 32.10 ATOM 4401 N LEU 569 57.142 -0.612 11.617 1.00 33.59 ATOM 4403 -CA. LEU 569 56.199 -1.60 4 1i2.132 1.00 32.91 ATOM 4404 CB LEU 569 56.045 -1.428 13.647 1.00 33.84 ATOM 4405 CG LEU 569 55.088 -2.343 14.403 1.00 31.96 145. vOl WO 98/07835 PCT/US97/14885 172 ATOM 4406 CDI LEU 569 55.522 -3.797 14.216 1.00 33.20 ATOM 4407 CD2 LEU 569 55.089 -1.967 15.868 1.00 30.81 ATOM 4408 C LEU 569 54.820 -1.591 11.478 1.00 32.12 ATOM 4409 0 LEU 569 54.214 -2.645 11.300 1.00 33.08 ATOM 4410 N ARG 570 54.315 -0.409 11.148 1.00 32.05 ATOM 4412 CA ARG 570 52.999 -0.293 10.529 1.00 35.21 ATOM 4413 CB ARG 570 52.659 1.173 10.256 1.00 36.77 ATOM 4414 CG ARG 570 51.282 1.370 9.653 1.00 43.11 ATOM 4415 CD ARG 570 51.203 2.690 8.926 1.00 49.24 ATOM 4416 NE ARG 570 52.154 2.775 7.815 1.00 55.77 ATOM 4418 CZ ARG 570 52.995 3.790 7.619 1.00 58.89 ATOM 4419 NH1 ARG 570 53.016 4.820 8.463 1.00 61.61 ATOM 4422 NH2 ARG 570 53.804 3.786 6.566 1.00 59.16 ATOM 4425 C ARG 570 52.992 -1.063 9.220 1.00 35.16 ATOM 4426 0 ARG 570 52.145 -1.922 8.990 1.00 35.50 ATOM 4427 N GLU 571 53.971 -0.760 8.383 1.00 36.29 ATOM 4429 CA GLU 571 54.111 -1.400 7.089 1.00 37.51 ATOM 4430 CB GLU 571 55.219 -0.701 6.308 1.00 41.27 ATOM 4431 CG GLU 571 54.945 0.778 6.110 1.00 49.88 ATOM 4432 CD GLU 571 56.087 1.516 5.436 1.00 57.58 ATOM 4433 OE1 GLU 571 57.264 1.122 5.636 1.00 60.59 ATOM 4434 OE2 GLU 571 55.804 2.504 4.714 1.00 61.14 ATOM 4435 C GLU 571 54.399 -2.896 7.228 1.00 36.24 ATOM 4436 0 GLU 571 53.889 -3.716 6.459 1.00 34.22 ATOM 4437 N TYR 572 55.202 -3.238 8.232 1.00 35.98 ATOM 4439 CA TYR 572 55.570 -4.619 8.517 1.00 35.34 ATOM 4440 CB TYR 572 56.526 -4.656 9.714 1.00 30.94 ATOM 4441 CG TYR 572 56.959 -6.034 10.180 1.00 32.71 ATOM 4442 CD1 TYR 572 58.009 -6.714 9.547 1.00 32.33 ATOM 4443 CEI TYR 572 58.464 -7.940 10.026 1.00 30.31 ATOM 4444 CD2 TYR 572 56.369 -6.626 11.303 1.00 33.43 ATOM 4445 CE2 TYR 572 56.813 -7.851 11.791 1.00 31.46 ATOM 4446 CZ TYR 572 57.864 -8.502 11.148 1.00 33.99 ATOM 4447 OH TYR 572 58.311 -9.706 11.640 1.00 36.30 ATOM 4449 C TYR 572 54.312 -5.425 8.826 1.00 37.26 ATOM 4450 0 TYR 572 54.121 -6.530 8.314 1.00 36.91 ATOM 4451 N LEU 573 53.457 -4.850 9.665 1.00 36.82 ATOM 4453 CA LEU 573 52.208 -5.476 10.075 1.00 35.56 ATOM 4454 CB LEU 573 51.537 -4.629 11.165 1.00 34.03 ATOM 4455 CG LEU 573 52.238 -4.527 12.519 1.00 32.82 ATOM 4456 CD1 LEU 573 51.621 -3.423 13.377 1.00 28.95 ATOM 4457 CD2 LEU 573 52.168 -5.858 13.207 1.00 29.46 ATOM 4458 C LEU 573 51.237 -5.658 8.915 1.00 34.56 ATOM 4459 0 LEU 573 50.670 -6.729 8.726 1.00 34.80 ATOM 4460 N GLN -574 51.030 -4.602 8.150 1.00 37.10 ATOM 4462 CA GLN 574 50.101 -4.666 7.031 1.00 41.15 ATOM 4463 CB GLN 574 49.875 -3.278 6.457 1.00 41.63 ATOM 4464 CG GLN 574 49.089 -2.375 7.366 1.00 43.13 ATOM 4465 CD GLN 574 49.063 -0.959 6.860 1.00 47.77 ATOM 4466 OE1 GLN 574 49.655 -0.647 5.827 1.00 50.00 ATOM 4467 NE2 GLN 574 48.378 -0.086 7.582 1.00 49.67 ATOM 4470 C GLN 574 50.529 -5.627 5.934 1.00 42.38 ATOM 4471 0 GLN 574 49.685 -6.284 5.318 1.00 44.56 ATOM 4472 N ALA 575 51.835 -5.717 5.697 1.00 41.99 SSSD/55145. vOl WO 98/07835 PCT/US97114885* 173 ATOM 4474 ATOM 4475 ATOM 4476 ATOM 4477 ATOM 4478 ATOM 4480 ATOM 4481 ATOM 4482 ATOM 4483 ATOM 4484 ATOM 4486 ATOM 4487 ATOM 4490 ATOM 4493 ATOM 4494 ATOM 4495 ATOM 4497 ATOM 4498 ATOM 4499 ATOM 4500 ATOM 4501 ATOM 4503 ATOM 4504 ATOM 4507 ATOM 4510 ATOM 4511 ATOM 4512 ATOM 4514 ATOM 4515 ATOM 4516 ATOM 4517 ATOM 4518 ATOM 4520 ATOM 4521 ATOM 4522 ATOM 4523 ATOM 4524 ATOM 4525 ATOM 4526 ATOM 4527 ATOM 4529 ATOM 4530 ATOM 4531 ATOM 4533 ATOM 4534 ATOM 4535 ATOM 4537 ATOM 4538 ATOM 4539 ATOM 4541 ATOM 4542 ATOM 4543 ATOM 4545 ATOM 4546 SSSD/55145. vOl

CA

CB

C

0

N

CA

CB

CG

CD

NE

Cz NH1 NH2

C

0

N

CA

CB

CG

CD

NE

CZ

NHI

NH2

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

OG

C

0

N

CA

CB

OG-

C

0

N

CA

CB

ALA 575 ALA 575 ALA 575 ALA 575 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 GLN 594 GLN 594 GLN 594 GLN 594 GLN 594 LEU 595 LEU 595 LEU 595 LEU 595 LEU 595 LEU 595 LEU 595 LEU 595 SER 596 SER 596 SER 596 SER 596 SER 596 SER 596 SER 597 SER 597 SER 597 SER 597 SER 597 SER 597 LYS 598 LYS 598 LYS 598 52.367 53.841 52.186 52.392 51.815 51.642 52.676 54.100 55.172 56.513 56.975 56.215 58.201 50.242 50.028 -49.275 47.893 47.027 47.189 46.463 46.284 45.612 45.052 45.466 47.334 47.478 53.312 52.110 51.175 52.501 53.101 52.140 52.470 52.619 53.570 53.496 54.977 51.480 50.276 52.012 51.206 52. 004 52.945 50.853 51.470 49.888 49.462 48.386 47.574 50.666 50.735 51.607 52.798 53.558 -6.608 -6 .325 -8.058 -8.949 -8.294 -9.646 910 -9.896 -9.836 -9.783 -8.785 -7.732 -8.846 -9.931 -10.869 -9.146 -9.344 -8.170 -6.939 -5.766 -4 .683 -3.565 -3.372 -2.655 -10.649 -10.933 -14.007 -14.068 -15 .183 -14.278 -15.292 -13.313 -13.335 -11.902 -11.074 -9.609 -11.596 -14.093 -14 .046 -14.780 -15.541 -16.737 -16.345 -14.641 -13.590 -15.070 -14.315 -15.084 -15.839 -14.068 -13.045 -15.007 -14.844 -16.163 4.676 4.446 5.066 4,249 6.319 6.824 7 .920 7.377 8.460 7.874 7.120 6.851 6.622 7.326 8.098 6.866 7.292 6.845 7.696 7.080 8.039 7.793 6 .606 8.749 6 .740 5.551 7.967 8.799 8.3.19 10.258 10.619 11.092 12.505 13.020 12 .153 12.524 12.301 13.372 13.139 14 .377 15.316 15.834 16 .820 16.488 16.676 17.292 18.461 19.229 18.343 19.372 20.047 19.399 20.229 20.384 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1. 00 1.00 1. 00 1. 00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 41.29 40.43 41.42 43.65 42.56 42.51 40.14 40.32 40.78 42.13 40.73 39.21 37.62 44.48 46 .84 46.26 46 .89 46.16 44 .93 44.60 45.05 45.95 47.39 45.49 46.60 47.15 63 .97 63 .06 64 .16 61.68 60.95 58.58 55.58 54.05 56.23 58 .84 55.93 53.77 54.31 51.04 48.97 48.89 48.59 47.56 46.71 47.11 47.88 50.66 57.08 46.03 46.49 46.08 46.33 46.67 WO 98/07835 PCTIUS97/14885 174 ATOM 4547 CG LYS 598 54.449 -16.224 ATOM 4548 CD LYS 598 55.240 -17.539 ATOM 4549 CE LYS 598 55.899 -17.797 ATOM 4550 NZ LYS 598 54.891 -18.076 ATOM 4554 C LYS 598 53.706 -13.790 ATOM 4555 0 LYS 598 54.292 -12.968 ATOM 4556 N ASP '599 53.780 -13.804 ATOM 4558 CA ASP 599 54.598 -12.851 ATOM 4559 CB ASP 599 54.523 -13.098 ATOM 4560 CG ASP 599 55.288 -14.336 ATOM 4561 ODi ASP 599 56.228 -14.754 ATOM 4562 0D2 ASP 599 54.958 -14.894 ATOM 4563 C ASP 599 54.120 -11.437 ATOM 4564 0 ASP 599 54.937 -10.550 ATOM 4565 N LEU 600 52.803 -11.235 ATOM 4567 CA LEU 600 52.246 -9.918 ATOM 4568 CB LEU 600 50.747 -9.882 ATOM 4569 CG LEU 600 50.332 -10.068 ATOM 4570 CD1 LEU 600 48.814 -9.992 ATOM 4571 CD2 LEU 600 50.974 -9.012 ATOM 4572 C LEU 600 52.537 -9.452 ATOM 4573 0 LEU 600 52.910 -8.294 ATOM 4574 N VA-L 601 52.41.5 -10.348 ATOM 4576 CA VAL 601 52.692 -9.969 ATOM 4577 CB VAL 601 52.214 -11.036 ATOM 4578 CG1 VAL 601 52.331 -10.483 ATOM 4579 CG2 VA-L 601 50.766 -11.409 ATOM 4580 C VAL 601 54.198 -9.741 ATOM 4581 0 VAL 601 54.634 -8.856 ATOM 4582 N SER 602 54.981 -10.531 ATOM 4584 CA SER 602 56.421 -10.421 ATOM 4585 CB SER 602 57.045 -11.504 ATOM 4586 OG SER 602 58.453 -11.387 ATOM 4588 C SER 602 56.809 -9.038 ATOM 4589 0 SER 602 57.651 -8.363 ATOM 4590 N CYS 603 56.183 -8.614 ATOM 4592 CA CYS 603 56.438 -7.294 ATOM 4593 CB CYS 603 55.543 -7.055 ATOM 4594 SG CYS 603 55.653 -5.423 ATOM 4595 C CYS 603 56.198 -6.211 ATOM 4596 0 CYS 603 57.023 -5.316 ATOM 4597 N ALA 604 55.088 -6.321 ATOM 4599 CA ALA 604 54.743 -5.358 ATOM 4600 CB ALA 604 53.321 -5.610 -ATOM 4601 C ALA 604 55.741 -5.394 ATOM 4602 0 ALA 604 56.050 -4.358 ATOM 4603 N TYR 605 56.212 -6.592 ATOM 4605 CA TYR 605 57.189 -6.758 ATOM 4606 CB TYR 605 57.500 -8.236 ATOM 4607 CG TYR 605 58.640 -8.495 ATOM 4608 CD1 TYR 605 58.511 -8.236 ATOM 4609 CEI TYR -605 59.556 -8.507 ATOM 4610 CD2 TYR 605 59.841 -9.026 ATOM 4611 CE2 TYR 605 60.896 -9.300 21.623 21.668 23 .026 24.093 19.599 20.311 18.264 17. 513 16. 001 15. 560 16.260 14.493 17. 796 18.059 17. 776 18 .030 17. 747 16 .281 16 .190 15.373 19.439 19.636 20.419 21.808 22.827 24.252 22.560 21. 982 22 .731 21.262 21.307 20.439 20.419 20.800 21.394 19.707 19.141 17.925 17.229 20.191 20.362 20.917 21.965 22.481 23.128 23.727 23 .465 24.539 24.737 25.690 27. 053 27.943 25.230 26.109 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1 .00 1.00 1.00 1 .00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1. 00 1.00 1.00 1. 00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 0.50 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1 .00 49.61 53 .69 53.15 52. 02 45.43 44 .18 44. 16 43.46 44 .83 48.24 52. 51.43 42.71 45.00 37.69 3-4.03 34 .06 33 .13 37.38 25.63 34 .58 33.18 34 .24 35.80 37.50 38.08 40.77 35. 04 34 .33 32 .58 36.01 38.43 43 .36 35.21 35. 03 34 34.04 33.45 32.19 PRT1 32.79 33 .36 31.31 32.36 32.01 32.83 30.89 32.95 33 .34 32.58 32.51 33 37. 08 34.22 36.64 145. vOl WO 98/07935 WO 9807835PCT/US97/14885 175 ATOM 4612 CZ TYR 605 60.746 -9.042 27.464 1.00 37.56 ATOM 4613 OH TYR 605 61.776 -9.342 28.336 1.00 38.08 ATOM 4615 C TYR 605 58.480 -6.006 24.191 1.00 32.42 ATOM 4616 0 TYR 605 58.975 -5.203 24.991 1.00 33.34 ATOM 4617 N GLN 606 58.997 -6.267 22.989 1.00 30.61 ATOM 4619 CA GLN 606 60.218 -5.643 22.474 1.00 31.12 ATOM 4620 CB GLN 606 60.499 -6.143 21.058 1.00 30.57 ATOM 4621 CG GLN 606 61.044 -7.568 21.008 1.00 33.90 ATOM 4622 CD GLN 606 61.240 -8.080 19.593 1.00 32.17 ATOM 4623 OE1 GLN 606 62.155 -7.652 18.883 1.00 32.55 ATOM 4624 NE2 GLN 606 60.374 -8.998 19.171 1.00 33.10 ATOM 4627 C GLN 606 60.157 -4.114 22.487 1.00 31.69 ATOM 4628 0 GLN 606 61.111 -3.453 22.910 1.00 31.18 ATOM 4629 N VAL 607 59.035 -3.564 22.020 1.00 29.50 ATOM 4631 CA VAL 607 58.816 -2.122 22.000 1.00 27.54 ATOM 4632 CB VAL 607 57.454 -1.751 21.306 1.00 26.79 ATOM 4633 CG1 VAL 607 57.131 -0.291 21.516 1.00 24.80 ATOM 4634 CG2 VAL 607 57.505 -2.050 19.815 1.00 22.95 ATOM 4635 C VAL 607 58.827 -1.576 23.432 1.00 28.30 ATOM 4636 0 VAL 607 59.469 -0.548 23.705 1.00 28.32 ATOM 4637 N ALA 608 58.110 -2.247 24.340 1.00 27.21 ATOM 4639 CA ALA 608 58.061 -1.805 25.735 1.00 26.54 ATOM 4640 CB ALA 608 57.070 -2.649 26.550 1.00 26.70 ATOM 4641 C ALA 608 59.457 -1.850 26.368 1.00 25.97 ATOM 4642 0 ALA 608 59.802 -0.993 27.183 1.00 25.88 ATOM 4643 N ARG 609 60.250 -2.848 25.994 1.00 26.02 ATOM 4645 CA ARG 609 61.606 -2.977 26.512 1.00 30.44 ATOM 4646 CB ARG 609 62.234 -4.285 26.058 1.00 34.09 ATOM 4647 CG ARG 609 61.642 -5.516 26.682 1.00 39.24 ATOM 4648 CD ARG 609 62.659 -6.615 26.615 1.00 42.75 ATOM 4649 NE ARG 609 63.405 -6.704 27.860 1.00 45.52 ATOM 4651 CZ ARG 609 64.525 -7.405 28.019 1.00 46.24 ATOM 4652 NH1 ARG 609 65.055 -8.079 27.001 1.00 41.48 ATOM 4655 NH2 ARG 609 65.079 -7.482 29.225 1.00 47.49 ATOM 4658 C ARG 609 62.478 -1.829 26.015 1.00 34.20 ATOM 4659 0 ARG 609 63.265 -1.255 26.788 1.00 35.24 ATOM 4660 N GLY 610 62.368 -1.528 24.717 1.00 33.25 ATOM 4662 CA GLY 610 63.130 -0.439 24.138 1.00 29.57 ATOM 4663 C GLY 610 62.802 0.814 24.908 1.00 29.31 ATOM 4664 0 GLY 610- 63.695 1.543 25.335 1.00 27.46 ATOM 4665 N MET 611 61.507 1.020 25.147 1.00 31.07 ATOM 4667 CA MET 611 61.016 2.178 25.889 1.00 30.09 ATOM 4668 CB MET 611 59.493 2.280 25.782 1.00 29.51 ATOM 4669 CG MET 611 58.997 2.655 24.404 1.00 28.21 ATOM 4670 SD MET 611 59.760 4.175 23.787 1.OU 29.00 ATOM 4671 CE MET 611 59.350 5.335 25.039 1.00 25.91 ATOM 4672 C MET 611 61.439 2.189 27.361 1.00 30.47 ATOM 4673 0 MET 611 61.734 3.242 27.919 1.00 29.43 ATOM 4674 N GLU 612 61.429 1.031 28.002 1.00 31.97 ATOM 4676 CA GLU 612 61.836 0.947 29.402 1.00 35.34 ATOM 4677 CB GLU 612 61.*707 -0.490 29.904 1.00 36.17 ATOM 4678 CG GLU 612 6j2.305 -0.729 31.278 1.00 34.87 ATOM 4679 CD GLU 612 62.259 -2.185 31.705 1.00 32.68 ATOM 4680 OE1 GLU 612 62.641 -3.070 30.904 1.00 35.01 145. vOl WO 98/07835 PCT/UJS97/14885 176 ATOM 4681 0E2 GLU 612 61.848 -2.443 32.858 1.00 36.56 ATOM 4682 C GLU 612 63.296 1.425 29.490 1.00 35.26 ATOM 4683 0 GLU 612 63.677 2.162 30.417 1.00 31.21 ATOM 4684 N TYR 613 64.092 1.040 28.491 1.00 36.10 ATOM 4686 CA TYR 613 65.491 1.458 28.440 1.00 34.76 ATOM 4687 CB TYR 613 66.249 0.788 27.301 1.00 31.15 ATOM 4688 CG TYR 613 67.700 1.195 27.284 1.00 34.28 ATOM 4689 CD1 TYR 613 68.600 0.654 28.207 1.00 36.50 ATOM 4690 CEl TYR 613 69.949 1.035 28.219 1.00 38.20 ATOM 4691 CD2 TYR 613 68.179 2.135 26.366 1.00 32.99 ATOM 4692 CE2 TYR 613 69.520 2.526 26.372 1.00 33.32 ATOM 4693 CZ TYR 613 70.399 1.968 27.302 1.00 36.59 ATOM 4694 OH TYR 613 71.721 2.340 27.333 1.00 35.73 ATOM 4696 C TYR 613 65.583 2.970 28.273 1.00 34.03 ATOM 4697 0 TYR 613 66.231 3.643 29.075 1.00 35.26 ATOM 4698 N LEU 614 64.916 3.503 27.250 1.00 31.78 ATOM 4700 CA LEU 614 64.945 4.937 26.998 1.00 29.50 ATOM 4701 CB LEU 614 64.095 5.297 25.775 1.00 28.26 ATOM 4702 CG LEU 614 64.564 4.742 24.422 1.00 31.29 ATOM 4703 CD1 LEU 614 63.564 5.089 23.321 1.00 28.09 ATOM 4704 CD2 LEU 614 65.951 5.282 24.079 1.00 29.52 ATOM 4705 C LEU 614 64.489 5.715 28.224 1.00 -32.49 ATOM 4706 0 LEU 614 65.108 6.717 28.598 1.00 31.73 ATOM 4707 N ALA 615 63.431 5.232 28.872 1.00 33.06 ATOM 4709 CA ALA 615 62.906 5.870 30.070 1.00 35.16 ATOM 4710 CB ALA 615 61.598 5.192 30.511 1.00 36.64 ATOM 4711 C ALA 615 63.942 5.838 31.202 1.00 35.36 ATOM 4712 0 ALA 615 64.065 6.805 31.952 1.00 36.80 ATOM 4713 N SER 616 64.690 4.739 31.315 1.00 3.5.91 ATOM 4715 CA SER 616 65.716 4.621 32.354 1.00 35.78 ATOM 4716 CB SER 616 66.287 3.199 32.424 1.00 32.52 ATOM 4717 OG SER 616 67.133 2.899 31.324 1.00 29.64 ATOM 4719 C SER 616 66.832 5.623 32.063 1.00 37.48 ATOM 4720 0 SER 616 67.556 6.048 32.967 1.00 38.76 ATOM 4721 N LYS 617 66.971 5.980 30.790 1.00 34.74 ATOM 4723 CA LYS 617 67.973 6.931 30.357 1.00 32.44 ATOM 4724 CB LYS 617 68.540 6.520 28.998 1.00 32.94 ATOM .4725 CG LYS 617 69.330 5* *232 29.041 1.00 32.64 ATOM 4726 CD LYS 617 70.539 5.402 29.933 1.00 38.45 ATOM 4727 CE LYS 617 71.252 4.091 30.139 1.00 40.84 ATOM 4728 NZ LYS 617 72.552 4.306 30.812 1.00 46.49 ATOM 4732 C LYS 617 67.376 8.325 30.281 1.00 33.29 ATOM 4733 0 LYS 617 67.909 9.188 29.598 1.00 33.95 ATOM 4734 N LYS 618 66.245 8.528 30.952 1.00 34.87 ATOM 4736 CA LYS 618 65.569 9.822 30.997 1.00 35.44 ATOM 4737 CB LYS 618 66.512 10.868 31.581 1.00 40.44 ATOM 4738 CG LYS 618 67.192 10.446 32.877 1.00 48.19 ATOM 4739 CD LYS 618 66.234 10.363 34.037 1.00 55.47 ATOM 4740 CE LYS 618 66.962 9.939 35.310 1.00 61.56 ATOM 4741 NZ LYS 618 66.070 10.032 36.514 1.00 68.82 ATOM 4745 C LYS 618 65.015 10.327 29.663 1.00 35.62 ATOM 4746 0 LYS 618 64.557 -11.463 29.569 1.00 36.44 ATOM 4747 N CYS 619 65.006 9.472 28.647 1.00 34.24 ATOM 4749 CA CYS 619 64.525 9.848 27.323 1.00 31.62 145. vOl WO 98/07835 PCTIUS97/14885 177

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM.

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4750 4751 4752 4753 4754 4756 4757 4758 4759 4760 4761 4762 4763 4765 4766 4767 4768 4769 4771 4772 4774 4775 4776 4778 4779 4780 4781 4782 4784 4785 4788 4791 4792 4793 4795 4796 4797 4798 4799 4800 4801 4802 4804 4805 4806 4807 4808 4809 4810 4811 4813 4814 4815 4816

CB

SG

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

CG

CD2 ND1 CE 1 NE2

C

0

N

CA

CB

CG

CD

NE

CZ

NH1l NIH2

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

C

0

CYS

CYS

CYS

CYS

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

AS P

ASP

AS P

ASP

ASP

AS P

ASP

ASP

LEU

LEU

LEU

LEU

LEU

LEU

LEtJ

LEU

ALA

ALA

ALA

ALA

ALA

619 619 619 619 620 620 620 620 620 620 620 620 621 621 621 621 621 621 621 621 621 621 622 622 622 622 622 622 622 622 622 622 622 623 623 623 623 623 623 623 623 624 624 624 624 624 624 624 624 625 625 625 625 625 65.279 64.816 63.004 62 .418 62.359 60.935 60.268 58.799 60.392 60.016 60.864 61.384 60.249 60.133 59.708 59. 903 60.511 59.373 59.637 60.325 59.194 59.466 58.048 57.068 57.705 58.285 58.781 59.216 60.362 61.215 60.640 56.283 55.289 56.719 55. 986 56.443 55.535 55.980 54.376 56.094 56.406 55.895 55.964 56.013 56.01-9 57.257 55.974 54 .738 53.589 54.997 53 .946 53.447 54.618 55.839 9.033 9.306 9.701 8.649 10.798 10.822 12.040 12.116 11.957 13.236 10.961 11. 920 9.986 9.973 8.578 8.344 7.336 9.168 8.669 .7.554 11.026 11.570 11.248 12.239 13.628 14.135 15.563 16 .050 15.715 14 .891 16 .168 11.891 12 .544 10.884 10.468 11.212 10.918 11.131 10.469 8.967 8.494 8.209 6.759 6 .118 4 .592 4.020 4.177 6 .274 6.511 5.632 5.113 6.205 4.020 3.978 26.263 24.541 27.149 27.388 26.800 26.542 27.193 26.774 28.712 29.396 25.023 24.465 24 .366 22.906 22.430 20.961 20.300 19.988 18.795 18.956 22 .321 21.251 22 .960 22 .490 22.370 23.674 23 .570 24.876 25.463 24.*860 26.680 21.213 20.912 20.459 19.261 17.994 16 .772 15.624 16 .954 19.051 17.957 20.118 20.005 21. 390 21.452 20.765 22 .904 19.217 19.612 18.084 17.223 16.298 16.427 16.378 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 0.50 0.50 0.50 0.50 0.50 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 31.17 30. 02 30.45 29.24 30. 14 31.76 31.26 31.66 29.71 27.40 31.86 32 31.70 32.12 29.61 28.62 27.49 30.08 25.00 26.55 34 .51 36.79 35.26 34 .68 33.43 31.52 27.82 28.82 30.41 31.15 30.83 34.71 35.58 34.90 34.30 36 .76 43.35 47.64 43.30 32.24 31.19 32.27 33.18 31.16 32 .74 30.64 34.51 35.18 35.72 32.37 30.60 25.26 29.87 32.01 SSSD/55145. vOl WO 98/07835 PCT/IJS97/14885 178 ATOM 4817 N ALA 626 53.834 3.163 15.779 1.00 30.12 ATOM 4819 CA ALA 626 54.373 2.057 14.978 1.00 29.62 ATOM 4820 CB ALA 626 53.231 1.159 14.441 1.00 27.11 ATOM 4821 C ALA 626 55.255 2.552 13.838 1.00 26.57 ATOM 4822 0 ALA 626 56.193 1.871 13.434 1.00 26.29 ATOM 4823 N ARG 627 54.935 3.730 13.317 1.00 26.74 ATOM 4825 CA ARG 627 55.706 4.352 12.244 1.00 28.73 ATOM 4826 CB ARG 627 55.056 5.671 11.827 1.00 29.62 ATOM 4827 CG ARG 627 54.894 6.659 12.972 1.00 31.84 ATOM 4828 CD ARG 627 54.435 8.032 12.485 1.00 38.54 ATOM 4829 NE ARG 627 53.987 8.878 13.590 1.00 38.59 ATOM 4831 CZ ARG 627 52.745 8.879 14.064 1.00 39.55 ATOM 4832 NH1 ARG 627 51.822 8.094 13.525 1.00 35.96 ATOM 4835 NH2 ARG 627 52.447 9.604 15.127 1.00 41.05 ATOM 4838 C ARG 627 57.151 4.632 12.676 1.00 30.79 ATOM 4839 0 ARG 627 58.058 4.687 11.838 1.00 30.16 ATOM 4840 N ASN 628 57.347 4.822 13.985 1.00 30.31 ATOM 4842 CA ASN 628 58.661 5.109 14.550 1.00 28.50 ATOM 4843 CB ASN 628 58.587 6.257 15.549 1.00 27.84 ATOM 4844 CG ASN 628 58.369 7.571 14.868 1.00 31.41 ATOM 4845 ODI ASN 628 58.893 7.796 13.782 1.00 33.45 ATOM 4846 ND2 ASN 628 57.551 8.429 15.460 1.00 28.53 ATOM 4849 C ASN 628 59.352 3.919 15.169 1.00 28.10 ATOM 4850 0 ASN 628 60.232 4.076 16.021 1.00 28.64 ATOM 4851 N VAL 629 58.887 2.733 14.803 1.00 27.79 ATOM 4853 CA VAL 629 59.484 1.482 15.253 1.00 28.30 ATOM 4854 CB VAL 629 58.475 0.577 15.983 1.00 25.38 ATOM 4855 CG1 VAL 629 59.118 -0.753 16.284 1.00 23.07 ATOM 4856 CG2 VAL 629 57.980 1.246 17.265 1.00 22.48 ATOM 4857 C VAL 629 59.925 0.810 13.949 1.00 28.69 ATOM 4858 0 VAL 629 59.114 0.616 13.043 1.00 27.07 ATOM 4859 N LEU 630 61.220 0.542 13.823 1.00 29.54 ATOM 4861 CA LEU 630 61.749 -0.081 12.616 1.00 30.17 ATOM 4862 CB LEU 630 62.999 0.659 12.142 1.00 29.62 ATOM 4863 CG LEU 630 62.831 2.180 12.035 1.00 29.14 ATOM 4864 CD1 LEU 630 64.121 2.795 11.579 1.00 29.83 ATOM 4865 CD2 LEU 630 61.693 2.543 11.086 1.00 32.59 ATOM 4866 C LEU 630 62.036 -1.541 12.899 1.00 30.50 ATOM 4867 0 LEU 630 62.290 -1.910 14.042 1.00 31.06 ATOM 4868 N VAL 631 61.966 -2.376 11.866 1.00 33.03 ATOM 4870 CA VAL 631 62.174 -3.813 12.022 1.00 31.83 ATOM 4871 CB VAL 631 60.902 -4.605 11.582 1.00 29.48 ATOM 4872 CGI VAL 631 61.017 -6.067 11.980 1.00 29.39 ATOM 4873 CG2 VAL 631 59.644 -3.984 12.196 1.00 25.38 ATOM 4874 C VAL 631 63.379 -4.242 11.196 1.00 32.37 ATOM 4875 0 VAL 631 63.508 -3.865 10.024 1.00 33.57 ATOM 4876 N THR 632 64.285 -4.987 11.820 1.00 34.39 ATOM 4878 CA THR 632 65.504 -5.453 11.145 1.00 35.84 ATOM 4879 CB THR 632 66.659 -5.685 12.148 1.00 33.11 ATOM 4880 OG1 THR 632 66.328 -6.774 13.020 1.00 34.88 ATOM 4882 CG2 THR 632 66.922 -4.426 12.972 1.00 28.85 ATOM 4883 C THR 632 65.272 -6.738 10.350 1.00 37.63 ATOM 4884 0 THR 632 64.195 -7.347 10.439 1.00 37.20 ATOM 4885 N GLU 633 66.289 -7.163 9.600 1.00 39.78 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 179

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4887 4888 4889 4890 4891 4892 4893 4894 4895 4897 4898 4899 4900 4901 4902 4903 4904 4906 4907 4908 4909 4910 4913 491.4 491.5 4917 4918 4919 4920 4921 4922 4923 4925 4926 4927 4928 4929 4930 4931 4932 4934 4935 4936 4937 4938- 4939 4943 4944 4945 4947 4948 4949 4950 4951

CA

CB

CD

OE1 0E2

C

0

N

CA

CB

CG

OD1 0D2

C

0

N

CA

CE

CG

OD1 ND2

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG2 CG1 CD1

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ASP

ASP

ASP

ASP

ASP

AS P

ASP

ASP

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

VAL

VAL

VAL

VAL

VAL

VAL

VAL

MET

MET

MET

MET

MET

MET

MET

MET

LYS,

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

ILE

ILE

ILE

ILE

ILE

ILE

633 633 633 633 633 633 633 633 634 634 634 634 634 634 634 634 635 635 635 635 635 635 635 635 636 636 636 636 636 636 636 637 637 637 637 637 637 637 637 638 638 638 638 638 638 638 638 638 639 639 639 639 639 639 66 .182 67.437 67.336 66.490 65.859 66 .460 65.919 65.360 66.287 66 .075 67.324 68.539 68 .462 69.568 64 .848 64.737 63.937 62 .686 61 .768 61 .483 60 .868 61 .949 62 .801 61.939 63 .844 64 .016 65 .517 65.697 66 .169 63 .349 63 .531 62. 52,5 61. 860 60.642 59.559 58 .860 59.030 62 .874 63.512 62 .985 63 .915 65.161 66 .171 67.370 68.409 68.964 63 .283 62 .918 63.163 62.597 62 .580 61.896 61 .918 60.496 -8.379 -8.590 -9.729 -9.404 -8.327 -10.25 6 -9.592 -10.582 -9.494 -10.585 -10.809 11. 24 0 -12.2 92 -10.52 5 10. 340 10. 873 -9.508 -9.186 -10.417 -10. 985 -10.336 -12.192 -8.577 -8.800 -7.795 -7.164 -7.005 -6.284 -8.367 -5.797 -5.061 -5.492 -4.194 -4.241 -5.264 -5.048 -6.709 -3.209 -3.496 -2.04 1 -0.994 -0.983 -2.059 -1.984 -3.029 -2.785 0.383 0.869 1.004 2.343 2.862 4.206 1.854 1.494 8.794 7.933 6.876 5.622 5.523 4.710 9.677 9.222 10.949 11.884 12.743 11.916 11. 237 11.943 12 .751 13.847 12.257 12.939 12.992 11.624 10.786 11.383 14.331 15. 187, 14.561 15.856 16.195 17.530 16.242 15.811 14.849 16.807 16.879 17.820 1.7.455 15.803 15.116 17.454 18.479 16 .820 17. 244 16.349 16.691 15.781 16.150 17.498 17. 215 16.146 18.387 18.501 19.965 20. 017 20.926 20.599 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1. 00 1. 00 1.00.

1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 43.30 46.66 51.37 54.30 55.85 55. 42.72 45.10 42.83 43 .03 4-9.02 55.95 59.10 59.41 41.75 42 .79 42 .51 42.53 45.07 46 .54 49.77 49.29 40. 51 41. 37. 98 33 .92 32.21 31.40 30. 93 31.85 33 .47 31.69 31.44 34 .97 36.80 35.45 32.12 31.86 29.47 30.87 29.66 27.51 27.29 28 24 25 .59 27 .72 27.66 26.21 26 .27 26.52 21.50 25.70 25.62 145. vOl WO 98/07835 PCT/US97/14885 180 ATOM 4952 C ILE 639 63.505 3.288 17.718 1.00 29.56 ATOM 4953 0 ILE 639 64.730 3.281 17.906 1.00 27.74 ATOM 4954 N ALA 640 62.897 4.101 16.857 1.00 27.91 ATOM 4956 CA ALA 640 63.620 5.071 16.042 1.00 28.79 ATOM 4957 CB ALA 640 63.377 4.796 14.563 1.00 26.74 ATOM 4958 C ALA 640 63.164 6.487 16.385 1.00 28.91 ATOM 4959 0 ALA 640 62.087 6.683 16.956 1.00 28.67 ATOM 4960 N ASP 641 64.007 7.464 16.067 1.00 28.25 ATOM 4962 CA ASP 641 63.708 8.876 16.296 1.00 30.80 'ATOM 4963 CB ASP 641 62.520 9.319 15.428 1.00 33.44 ATOM 4964 CG ASP 641 62.869 9.393 13.948 1.00 38.01 ATOM 4965 ODi ASP 641 64.002 9.001 13.574 1.00 42.41 ATOM 4966 0D2 ASP 641 62.006 9.847 13.160 1.00 41.74 ATOM 4967 C ASP 641 63-501 9.311 17.745 1.00 29.07 ATOM 4968 0 ASP 641 62.847 10.309 18.020 1.00 28.42 ATOM A4969 N PEE 642 64.138 8.604 18.663 1.00 29.69 ATOM 4971 CA PEE 642 64.036 8.914 20.074 1.00 29.62 ATOM 4972 CB PHE 642 G4.347 7.656 20.890 1.00 27.18 ATOM 4973 CG PHE 642 65.702 7.058 20.603 1.00 23.96 ATOM 4974 CD1 PHE 642 66.848 7.559 21.219 1.00 23.66 ATOM 4975 CD2 PEE 642 65.828 5.974 19.742 1.00 24.08 ATOM 4976 CEl PEE 642 68.090 6.992 20.980 1.00 23.02 ATOM 4977 CE2 PEE 642 67.069 5.403 19.501 1.00 23.20 ATOM 4978 CZ PEE 642 68.200 5.909 20.121 1.00 21.68 ATOM 4979 C PEE 642 64.948 10.075 20.502 1.00 32.99 ATOM 4980 0 PEE 642 64.755 10.664 21.574 1.00 32.10 ATOM 4981 N GLY 643 65.940 10.396 19.671 1.00 34.66 ATOM 4983 CA GLY 643 66.869 11.463 20.003 1.00 35.29 ATOM 4984 C GLY 643 66.639 12.755 19.250 1.00 39.13 ATOM 4985 0 GLY 643 67.464 13.666 19.333 1.00 39.83 ATOM 4986 N LEt) 644 65.520 12.850 18.532 1.00 42.26 ATOM 4988 CA LEt) 644 65.202 14.043 17.745 1.00 46.25 ATOM -4989 CB LEt) 644 63.935 13.843 16.911 1.00 44.59 ATOM 4990 CG LEt) 644 63.911 12.839 15.763 1.00 43.00 ATOM 4991 CD1 LEU 644 62.653 13.068 14.940 1.00 42.61 ATOM 4992 CD2 LEt) 644 65.119 13.016 14.889 1.00 45.65 ATOM 4993 C LEt) 644 65.037 15.298 18.578 1.00 49.59 ATOM 4994 0 LEt) 644 64.391 15.281 19.623 1.00 51.90 ATOM 4995 N ALA 645 65.585 16.401 18.080 1.00 52.08 ATOM 4997 CA ALA 645 65.495 17.677 18.777 1.00 54.71 ATOM 4998 CB ALA 645 66.414 18.699 18.124 1.00 54.38 ATOM 4999 C ALA 645 64.053 18.184 18.790 1.00 55.44 ATOM 5000 0 ALA 645 63.534 18.582 19.832 1.00 56.69 ATOM 5001 N ASP 652 52.389 21.543 14.759 1.00 73.74 ATOM 5003 CA ASP 652 51.207 21.745 13.934 1.00 73.83 ATOM 5004 CB ASP 652 51.601 21.995 12.472 1.00 73.22 ATOM 5005 CG ASP 652 50.398 22.241 11.569 1.00 72.95 ATOM 5006 ODI ASP 652 49.354 22.715 12.065 1.00 73.71 ATOM 5007 0D2 ASP 65 ;2 50.497 21.956 10.357 1.00 73.02 ATOM 5008 C ASP 652 50.321 20.514 14.042 1.00 75.11 ATOM 5009 0 ASP 652 50.568 19.495 13.394 1.00 75.96 ATOM 5010 N TYR 653 49.272 20.628 14.849 1.00 75.57 ATOM 5012 CA TYR 653 48.348 19.524 15.064 1.00 75.68 ATOM 5013 CB TYR 653 47.274 19.914 16.088 1.00 76.85 SSSD/55145. vOl WO 98/07835 PCTIUS97/1 4885 181.

ATOM 5014 CG TYR 653 47.771 19.995 17.519 1.00 79.55 ATOM 5015 CD1 TYR 653 46.983 20.567 18.518 1.00 80.89 ATOM 5016 CEl TYR 653 47.438 20.648 19.836 1.00 83.02 ATOM 5017 CD2 TYR 653 49.032 19.503 17.874 1.00 80.87 ATOM 5018 CE2 TYR 653 49.496 19.578 19.183 1.00 81.70 ATOM 5019 CZ TYR 653 48.698 20.152 20.160 1.00 83.09 ATOM 5020 OH TYR 653 49.165 20.243 21.451 1.00 83.73 ATOM 5022 C TYR 653 47.685 19.038 13.787 1.00 75.03 ATOM 5023 0 TYR 653 47.232 17.897 13.711 1.00 75.97 ATOM 5024 N TYR 654 47.679 19.885 12.767 1.00 73.85 ATOM 5026 CA TYR 654 47.039 19.538 11.507 1.00 73.32 ATOM 5027 CB TYR 654 46.276 20.750 10.972 1.00 71.97 ATOM 5028 CG TYR 654 45.259 21.276 11.954 1.00 70.94 ATOM 5029 CD1 TYR 654 45.659 21.801 13.185 1.00 71.41 ATOM 5030 CEl TYR 654 44.733 22.234 14.121 1.00 73.60 ATOM 5031 CD2 TYR 654 43.899 21.206 11.680 1.00 71.81 ATOM 5032 CE2 TYR 654 42.956 21.642 12.610 1.00 74.81 ATOM 5033 CZ TYR 654 43.380 22.152 13.832 1.00 74.84 ATOM 5034 OH TYR 654 42.457 22.571 14.769 1.00 76.60 ATOM 5036 C TYR 654 47.975 18.967 10.446 1.00 73.82 ATOM 5037 0 TYR 654 47.545 18.671 9.329 1.00 74.25 ATOM 5038 N LYS 655 49.249 18.806 10.784 1.00 74.04 ATOM 5040 CA LYS 655 50.195 18.256 9.827 1.00 75.41 ATOM 5041 CB LYS 655 51.626 18.680 10.164 1.00 78.45 ATOM 5042 CG LYS 655 52.647 18.198 9.151 1.00 83.01 ATOM 5043 CD LYS 655 54.062 18.589 9.537 1.00 87.72 ATOM 5044 CE LYS 655 55.076 17.813 8.703 1.00 91.45 ATOM 5045- NZ LYS 655 56.489 18.133 9.074 1.00 94.17 ATOM 5049 C LYS 655 50.075 16.736 9.832 1.00 75.50 ATOM 5050 0 LYS 655 50.245 16.092 10.872 1.00 75.90 ATOM 5051 N LYS 656 49.750 16.173 8.672 1.00 75.26 ATOM 5053 CA LYS 656 49.597 14.730 8.533 1.00 74.97 ATOM 5054 CB LYS 656 48.723 14.406 7.323 1.00 75.40 ATOM 5055 CG LYS 656 47.266 14.753 759 1.00 76.87 ATOM 5056 CD LYS 656 46.489 14.535 6.239 1.00 80.75 ATOM 5057 CE LYS 656 45.001 14.655 6.483 1.00 83.60 ATOM 5058 NZ LYS 656 44.236 14.637 5.204 1.00 87.14 ATOM 5062 C LYS 656 50.939 14.016 8.414 1.00 '74.58 ATOM 5063 0 LYS 656 51.904 14.578 7.897 1.00 75.01 ATOM 5064- N GLY 660 49.137 9.764 5.736 1.00 59.18 ATOM 5066 CA GLY 660 48.106 10.781 5.848 1.00 56.19 ATOM 5067 C GLY 660 47.407 10.761 7.192 1.00 55.31 ATOM 5068 0 GLY 660 46.289 11.263 7.328 1.00 56.96 ATOM 5069 N ARG 661 48.059 10.163 8.183 1.00 53.02 ATOM 5071 CA ARG 661 47.493 10.083 9.527 1.00 49.80 ATOM 5072 CE ARG 661 47.944 8.799 10.229 1.00 51.79 ATOM 5073 CG ARG 661 47.683 7.523 .9.450 1.00 50.59 ATOM 5074 CD ARG 661 47.822 6.323 10.367 1.00 53.68 ATOM 5075 NE ARG 661 47.714 5.044 9.665 1.00 52.66 ATOM 5077 CZ ARG 661 47.928 3.863 10.236 1.00 51.73 ATOM 5078 NHi ARG 661 48.264 3.794 11.518 1.00 50.23 ATOM 5081 NH2 ARG 661 47.800 2.751 9.528 00 52.58 ATOM 5084 C ARG 661 47.915 11.297 10.346 1.00 44.80 ATOM 5085 0 ARG 661 48.865 11.998 9.986 1.00 43.61 5550/55 145. vOl WO 98/07835 PCT/US97/14885 182

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM.

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

~ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5086 5088 5089 5090 5091 5092 5093 5094 5095 5096 5097 5098 5099 5100 5101 5102 5104 5105 5106 5107 5108 5109 5110 5112 5113 5114 5115 5116 5117 5121 5122 5123 5125 5126 5127 5128 5129 5130 5131 5132 5134 5135 5136 5137 5138 5139 5141 5142 5143 5144 5145 5146 5147 5148

N

CA

CB

CG

CD1 CD2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG

CD2 CE2 CE3 CD1 NEl CZ2 CZ3 CH2

C

0

N

CA

CB

CG

SD

CE

C

0

N

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PRO

PRO

PRO

PRO

PRO

PRO

PRO

VAL

VAL

VAL

VAL

VAL

VAL

VAL

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

MET

MET

MET

MET

MET

MET

MET

MET

ALA

662 662 662 662 662 662 662 662 663 663 663 663 663 663 663 664 664 664 664 664 664 664 665 665 665 665 665 665 665 665 665 666 666 666 666 666 666 666 666 666 666 666 666 666 666 667 667 667 667 667 667 667 667 668 47.221 47.518 46.234 45.515 44.045 46.217 48.162 47.529 49.441 50.375 50.158 51.516 51.728 49. 477 49.699 48.646 47.951 47.038 47.885 46. 091 47.137 46 .908 46.803 46.040 45.456 44.324 43.927 42.664 42.296 46.801 46.230 48.080 48.886 50.204 50.078 49.531 49.630 48.982 50.473 50.206 49.190 48.548 48.658 49.203 49.688 48.905 49.180 49.150 50.487 50.*384 50.711 48.294 47-066 48.933 11.528 12.654 13.415 14.074 14.278 15.383 12.170 11.479 12.518 13.113 12.107 12.787 12.657 12.491 11.841 13.532 13.931 15.181 16.408 14.989 12.749 12.641 11.809 10.631 9.958 10.774 10.334 11.056 10.720 9.644 8.659 9.915 9.068 8.682 7.530 7.559 6.257 8.569 6.238 5.469 5.929 8.248 6.934 9.802 9.202 11.099 11.960 13.423 13.975 15.728 15.745 11.802 11.699 11.824 11.453 12.333 12.671 11.499 11.831 11.156 13 .622 14.417 13 .843 12.868 15.054 14 .885 13.401 16.371 17.392 16.362 17.583 17.376 17.160 16.186 18.120 19.318 17.23G 17.614 16.370 15.768 14.367 13.899 12.486 18.498 18 .955 18.748 19.619 18.945 18.006 16.684 16.163 15.882 18.234 17.132 14 .874 14. 599 14.107 20.913 21.873 20.929 22.069 21.641 21.226 20.919 19.183 23.289 23.183 24.456 1 .00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 40..74 37.88 36. 19 35.32 31.05 34.37 35.34 33 .06 36.39 37. 57 36.39 36. 98 38.48 35.47 35.08 34.28 34.43 36.92 37.55 38.28 33.03 34 .62 32.47 30.71 29.59 29.64 31.86 30.42 26.50 32.23 30.04 31.38 32.32 31.07 28.26 27.07 26.71 26.56 24. 97 27.38 27.22 30.14 26.64 33. 84 32.82 35.75 37.60 41.95 48.44 55.33 49.29 38.98 39.18 38.72 SSSD/55145. vOl WO 98/07835 ,cIS7I48 PCr/US97/14885 183 ATOM 5150 CA ALA 668 48.231 11.728 25.727 1.00 37.82 ATOM 5151 CB ALA 668 49.224 11.527 26.857 1.00 38.49 ATOM 5152 C ALA 668 47.497 13.051 25.891 1.00 38.16 ATOM 5153 0 ALA 668 47.937 14.072 25.363 1.00 37.21 ATOM 5154 N PRO 669 46.383 13.062 26.644 1.00 39.78 ATOM 5155 CD PRO 669 45.785 11.931 27.367 1.00 40.08 ATOM 5156 CA PRO 669 45.598 '14.281 26.858 1.00 40.68 ATOM 5157 CB PRO 669 44.474 13.806 27.782 1.00 42.15 ATOM 5158 CG PRO 669 44.346 12.352 27.446 1.00 42.56 ATOM 5159 C PRO 669 46.398 15.432 27.484 1.00 42.69 ATOM 5160 0 PRO 669 46.320 16.566. 27.019 1.00 42.14 ATOM 5161 N GLU 670 47.168 15.153 28.532 1.00 43.21 ATOM 5163 CA GLtJ 670 47.956 16.211 29.160 1.00 44.62 ATOM 5164 CB GLTJ 670 48.651 15.719 30.429 1.00 44.95 ATOM 5165 CG GLU 670 49.824 14.782 30.197 1.00 45.54 ATOM 5166 CD GLU 670 49.422 13.332 30.079 1.00 42.72 ATOM 5167 OE1 GLU 670 50.332 12.481 30.066 1.00 41..43 ATOM 5168 0E2 GLU 670 48.212 13.036 30.015 1.00 44.44 ATOM 5169 C GLU 670 48.993 16.772 28.195 1.00 44.88 ATOM 5170 0 GLU 670 49.248 17.968 28.194 1.00 45.08 ATOM 5171 N ALA 671 49.565 -15.908 27.358 1.00 44.75 ATOM 5173 CA ALA 671 50.573 16.323 26.392 1.00 45.92 ATOM 5174 CB ALA 671 51.256 15.095 25.766 1.00 44.10 ATOM 5175 C ALA 671 49.944 17.193 25.314 1.00 47.96 ATOM 5176 0 ALA 671 50.526 18.192 24.894 1.00 49.16 ATOM 5177 N LEU 672 48.729 16.836 24.917 1.00 49.84 ATOM 5179 CA LEU 672 47.989 17.554 23.881 1.00 50.74 ATOM 5180 CB LEU 672 46.926 16.619 23.289 1.00 53.20 ATOM 5181 CG LEU 672 46.184 16.989 22.004 1.00 55.26 ATOM 5182 CD1 LEU 672 47.153 17.155 20.856 1.00 57.12 ATOM 5183 CD2 LEU 672 45.203 15.895 21.680 1.00 52.86 ATOM 5184 C LEU 672 47.327 18.826 24.408 1.00 50.79 ATOM 5185 0 LEU 672 47.302 19.855 23.736 1.00 50.95 ATOM 5186 N PRE 673 46.792 18.751 25.618 1.00 52.07 ATOM 5188 CA PHE 673 46.111 19.884 26.226 1.00 54.39 ATOM 5189 CB PHE 673 44.892 19.396 27.019 1.00 51.21 ATOM 5190 CG PHE 673 43.871 18.656 26.186 1.00 48.49 ATOM 5191 CD1 PHE 673 43.304 17.473 26.646 1.00 47.79 ATOM 5192 CD2 PRE 673 43.470 19.149 24.949 1.00 49.04 ATOM 5193 CEl PRE 673 42.349 16.789 25.888 1.00 47.90 ATOM 5194 CE2 PRE 673 42.511 18.473 24.182 1.00 49.71 ATOM 5195 CZ PEE 673 41.952 17.288 24.655 1.00 46.86 ATOM 5196 C PHE 673 47.007 20.741 27.123 1.00 58.25 ATOM 5197 0 PRE 673 47.000 21.971 27.034 1.00 60.52 ATOM 5198 N -ASP 674 47.784 20.094 27.983 1.00 59.63 ATOM 5200 CA ASP 674 48.652 20.815 28.905 1.00 62.11 ATOM 5201 CB ASP 674 48.568 20.196 30.307 1.00 63.81 ATOM 5202 CG ASP 674 47.143 20.015 30.791 1.00 66.46 ATOM 5203 ODi ASP 674 46.815 18.901 31.247 1.00 66.70 ATOM 5204 0D2 ASP 674 46.354 20.981 30.722 1.00 68.77 ATOM 5205 C ASP 674 50.119 20.852 28.482 1.00 63.36 ATOM 5206 0 ASP 674 50.979 21.175 29.310 1.00 64.11 ATOM 5207 N ARG 675 50.410 20.486 27.228 1.00 62.94 ATOM 5209 CA ARG 675 51.789 20.456 26.706 1.00 60.75 145. vOl WO 98107835 PCTIUS97/14885 184

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

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ATOM

ATOM

ATOM

-ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5210 5211 5212 5213 5215 5216 5219 5222 5223 5224 5226 5227 5228 5229 5230 5231 5232 5233 5235 5236 5237 5238 5239 5240 5241 5242 5243 5245 5246 5247 5249 5250 5251 5253 5254 5255 5256 5258 5259 5260 5261 5262 5264 5265 5267 5268 5269 5271 5272 5273 5274 5275 5276 5279

CB

CG

CD

NE

cz NHl NH2

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2 cz

OH

C

0

N

CA

CB

001 CG2

C

0

N

CA

CB

CG

CD2 ND1 CEl NE2

C

0

N

CA

CB

CG

CD

OE1 NE2

C

ARG 675 ARG 675 ARG 675 ARG 675 ARG 675 ARG 675 ARG 675 ARO 675 ARG 675 ILE 676 ILE 676 ILE 676 ILE 676 ILE 676 ILE 676 ILE 676 ILE 676 TYR 677 TYR 677 TYR 677 TYR 677 TYR 677 TYR 677 TYR 677 TYR 677 TYR 677 TYR 677 TYR 677 TYR 677 THR 678 TER 678 THR 678 THR 678 THR 678 THR 678 THR 678 HIS 679 HIS 679 HIS 679 HIS 679 HIS 679 HIS 679 HIS 679 HIS 679 HIS 679 HIS 679 GLN 680 GLN 680 GLN 680 GLN 680 GLN 680 GLN 680 OLN 680 GLN 680 52.277 51.474 51 .986 53.308 54. 063 53.637 55.254 52 .750 53 .933 52 .221 52. 992 52 .154 52 .749 52.049 51.306 53 .468 54. 773 55.343 56.232 55.466 55.158 54.491 55. 078 54 .411 54. 125 53.504 56.136 56. 983 55. 818 56.498 55.680 54.462 55.342 56 .661 56.258 57.264 57.423 58.348 59. 761 60.453 60.632 61. 803 61. 721 56.032 55.771 55.126 53 .754 53. 069 53.645 53.676 52.669 54.846 52. 927 21.874 22.560 23 .970 23 .980 25.068 26.254 24 .965 19.793 20.130 18 .859 18 .141 17.921 16 .811 19.230 19.103 16.796 15.891 16.671 15.436 15 .722 16.181 17.529 17.960 15.269 15.689 17 .035 17.457 14 .730 15.335 13 .464 12 .664 12.593 11.867 13 .988 11.242 10.917 10.388 9.003 8 .294 8 .798 9.569 8 .507 9.071 9 .722 8 .376 7.458 8 .908 8.407 8 .815 8 .128 6.595 5 .925 6 .043 8 .842 26.360 25.261 24.964 24.337 24.173 24.590 23.593 27.700 27.766 28.483 29.489 30.765 31.629 31.540 32.845 28.953 28.730 28 .745 28.236 27.031 25.809 25.619 24.479 24.823 23.679 23.512 22.360 29.316 29.970 29.537 30.535 31.861 31.642 32.383 30.011 28.897 30.825 30.457 31.439 31. 404 32.278 30.380 30.621 31.766 30.441 29.660 31. 264 31.332 32.640 33.884 33.780 33.996 33.464 30. 121 1.00 1.00 1.00 1. 00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1. 00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 60.56 63 .67 66 .99 69 .34 68.48 65.81 68 .76 58.06 59.30 55.62 54 .09 52 .69 49.38 53 57. 79 5-3 .83 54 .87 51 .76 49.42 51.33 56 .22 56.12 56 .18 58 .13 57.65 58.23 61 .71 46 .46 48 41. 73 39. 83 41.78 45.77 41.84 37.46 37.51 36 .36 35. 91 35.05 37.68 37.89 37.49 39.58 39.81 36 .76 37.16 36.27 37 .71 40.95 45.23 44.44 42 .76 40.57 37.54 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 185 ATOM 5280 0 GLN 680 51.950 8.185 29.765 1.00 37.93 ATOM 5281 N SER 681 53.282 9.961 29.504 1.00 36.38 ATOM 5283 CA SER 681 52.563 10.367 28.306 1.00 38.05 'ATOM 5284 CB SER 681 52.857 11.819 27.940 1.00 41.41 ATOM 5285 OG SER 681 54.239 12.069 27.938 1.00 42.92 ATOM 5287 C SER 681 52.991 9.421 27.178 1.00 37.92 ATOM 5288 0 SER 681 52.205 9.148 26.263 1.00 37.21 ATOM 5289 N ASP 682 54.237 8.932 27.248 1.00 34.77 ATOM 5291 CA ASP 682 54.750 7.972 26.267 1.00 31.99 ATOM 5292 CB ASP 682 56.243 7.683 26.481 1.00 31.08 ATOM 5293 CG ASP 682 57.165 8.638 25.721 1.00 33.63 ATOM 5294 ODi ASP 682 58.386 8.503 25.920 1.00 32.35 ATOM 5295 0D2 ASP 682 56.707 9.500 24.930 1.00 29.46 ATOM 5296 C ASP 682 53.969 6.672 26.457 1.00 31.54 ATOM 5297 0 ASP 682 53.675 5.971 25.493 1.00 29.94 ATOM 5298 N VAL 683 53.677 6.334 27.712 1.00 30.48 ATOM 5300 CA VAL 683 52.913 5.126 28.023 1.00 32.94 ATOM 5301 CB VAL 683 52.731 4.939 29.572 1.00 33.94 ATOM 5302 CG1 VAL 683 51.635 3.905 29.872 1.00 32.71 ATOM 5303 CG2 VAL 683 54.042 4.474 30.209 1.00 27.41 ATOM 5304 C VAL 683 51.545 5.164 27.299 1.00 32.27 ATOM 5305 0 VAL 683 51.106 4.158 26.733 1.00 30.54 ATOM 5306 N TRP 684 50.902 6.332 27.282 1.00 32.57 ATOM 5308 CA TRP 684 49.616 6.477 26.600 1.00 32.76 ATOM 5309 CB TRP 684 49.06.0 7.895 26.765 1.00 33.67 ATOM 5310 CG TRP 684 47.855 8.210 25.891 1.00 38.22 ATOM 5311 CD2 TRP 684 46.503 8.435 26.328 1.00 39.96 ATOM 5312 CE2 TRP 684 45.734 8.735 25.177 1.00 39.59 ATOM 5313 CE3 TRP 684 45.869 8.416 27.578 1.00 39.26 ATOM 5314 CD1 TRP 684 47.842 8.373 *24.528 1.00 39.02 ATOM 5315 NEl TRP 684 46.576 8.687 24.096 1.00 38.42 ATOM 5317 CZ2 TRP 684 44.362 9.011 25.240 1.00 36.62 ATOM 5318 CZ3 TRP 684 44.502 8.691 27.641 1.00 40.70 ATOM 5319 CH2 TRP *684 43.766 8.982 26.475 1.00 40.57 ATOM 5320 C TRP 684 49.819 6.158 25.125 1.00 31.98 ATOM 5321 0 TRP 684 49.066 5.367 24.557 1.00 32.43 ATOM 5322 N SER 685 50.859 6.748 24.529 1.00 29.63 ATOM 5324 CA SER 685 51.195 6.531 23.119 1.00 28.62 ATOM 5325 CB SER 685 .52.457 7.296 22.751 1.00O 24.72 ATOM 5326 OG SER 685 52.323 8.664 23.072 1.00 30.04 ATOM 5328 C SER 685 51.414 5.055 22.825 1.00 27.91 ATOM 5329 0 SER 685 51.022 4.555 21.767 1.00 28.60 ATOM 5330 N PEE 686 52.063 4.372 23.763 1.00 27.96 ATOM 5332 CA PEE 686 52.333 2.947 23.662 1.00 27.03 ATOM 5333 CB PHE 686 .53.163 2.499 24.868 1.00 25.79 ATOM 5334 CG PEE 686 53.440 1.029 24.890 1.00 26.25 ATOM 5335 CD1 PEE 686 54.252 0.451 23.923 1.00 27.32 ATOM 5336 CD2 PEE 68.6 52.839 0.208 25.841 1.00 26.22 ATOM 5337 CEl PHE 686 54.464 -0.930 23.900 1.00 25.87 ATOM 5338 CE2 PHE 686 53.046 -1.170 25.828 1.00 24.37 ATOM 5339 CZ PEE 686 53.856 -1.740 24.854 1.00 26.42 ATOM 5340 C PEE 686 51.003 2.160 23.596 1.00 28.82 ATOM 5341 0 PEE 686 50.912 1.129 22.914 1.00 26.74 ATOM 5342 N GLY 687 49.991 2.636 24.324 1.00 29.52 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 186 ATOM 5344 CA GLY 687 48.688 1.982 24.302 1.00 31.57 ATOM 5345 C GLY 687 48.095 2.036 22.896 1.00 30.73 ATOM 5346 0 GLY 687 47.490 1.069 22.414 1.00 29.83 ATOM 5347 N VAL 688 48.269 3.179 22.238 1.00 29.06 ATOM 5349 CA VAL 688 47.777 3.350 20.879 1.00 28.93 ATOM 5350 CB VAL 688 47.800 4.831 20.424 1.00 27.24 ATOM 5351 CGI VAL 688 47.211 4.963 19.020 1.00 28.29 ATOM 5352 CG2 VAL 688 46.990 5.691 21.404 1.00 26.96 ATOM 5353 C VAL 688 48.612 2.475 19.951 1.00 28.49 ATOM 5354 0 VAL 688 48.080 1.866 19.024 1.00 28.84 ATOM 5355 N LEU 689 49.905 2.350 20.252 1.00 27.99 ATOM 5357 CA LEU 689 50.804 1.512 19.461 1.00 26.14 ATOM 5358 CB LEU 689 52.268 1.688 19.911 1.00 27.31 ATOM 5359 CG LEU 689 53.368 1.014 19.065 1.00 26.60 ATOM 5360 CD1 LEU 689 54.688 1.767 19.175 1.00 28.19 ATOM 5361 CD2 LEU 689 53.567 -0.401 19.475 1.00 25.55 ATOM 5362 C LEU 689 50.362 0.053 19.605 1.00 26.48 ATOM 5363 0 LEU 689 50.377 -0.686 18.626 1.00 27.06 ATOM 5364 N LEU 690 49.953 -0.344 20.816 1.00 28.55 ATOM 5366 CA LEU 690 49.465 -1.708 21.085 1.00 29.16 ATOM 5367 CB LEU 690 49.070 -1.888 22.560 1.00 31.40 ATOM 5368 CG LEU 690 50.114 -2.085 23.667 1.00 31.49 ATOM 5369 CDI LEU 690 49.427 -2.028 25.026 1.00 34.09 ATOM 5370 CD2 LEU 690 50.821 -3.410 23.491 1.00 30.84 ATOM 5371 C LEU 690 48.240 -1.958 20.220 1.00 26.51 ATOM 5372 0 LEU 690 48.088 -3.023 19 .631 1.00 25.15 ATOM 5373 N TRP 691 47.376 -0.954 20.139 1.00 28.51 ATOM 5375 CA TRP 691 46.169 -1.049 19.319 1.00 29.56 ATOM 5376 CB TRP 691 45.332 0.227 19.465 1.00 28.91 ATOM 5377 CG TRP 691 43.992 0.169 18.759 1.00 30.95 ATOM 5378 CD2 TRP 691 43.718 0.556 17.406 1.00 29.87 ATOM 5379 CE2 TRP 691 42.337 0.367 17.189 1.00 31.97 ATOM 5380 CE3 TRP 691 44.505 1.049 16.358 1.00 27.72 ATOM 5381 CD1 TRP 691 42.796 -0.231 19.292 1.00 30.68 ATOM 5382 NEl TRP 691 41.797 -0.111 18.355 1.00 33.68 ATOM 5384 CZ2 TRP 691 41.729 0.652 15.967 1.00 29.42 ATOM 5385 CZ3 TRP 691 43.906 1.327 15.154 1.00 27.13 ATOM 5386 CH2 TRP 691 42.523 1.129 14.965 1.00 29.18 'ATOM 5387 C TRP 691 46.564 -1.289 17.856 1.00 28.78 ATOM 5388 0 TRP 691 45.996 -2.156 17.194 1.00 27.64 ATOM 5389 N GLU 692 47.564 -0.543 17.380 1.00 29.83 ATOM 5391 CA GLU 692 48.078 -0.669 16.018 1.00 28.08 ATOM 5392 CB GLU 692 49.267 0.262 15.790 1.00 26.40 ATOM 5393 CG GLU 692 48.945 1.735 15.680 1.00 26.45 ATOM 5394 CD -GLU 692 50.183 2.561 15.369 1.00 29.47 ATOM 5395 OE1 GLU 692 50.938 2.886 16.320 1.00 29.66 ATOM 5396 OE2 GLU 692 50.413 2.875 14.182 1.00 29.44 ATOM 5397 C GLU 692 48.563 -2.082 15.761 1.00 30.07 ATOM 5398 0 GLU 692 48.385 -2.612 14.665 1.00 30.18 ATOM 5399 N ILE 693 49.244 -2.663 16.746 1.00 29.87 ATOM 5401 CA ILE 693 49.754 -4.024 16.608 1.00 29.51 ATOM 5402 CB ILE 693 50.632 -4.443 17.828 1.00 28.18 ATOM 5403 CG2 ILE 693 51.037 -5.907 17.706 1.00 27.45 ATOM 5404 CG1 ILE 693 51.907 -3.594 17.890 1.00 26.99 SSSD/55145. vOl WO 98/07835 WO 9807835PCT/US97/14885 187

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5405 5406 5407 5408 5410 5411 5412 5413 5414 5415 5416 5417 5418 5419 5420 5422 5423 5424 5426 5427 5428 5429 5431 5432 5433 5434 5435 5436 5437 5438 5440 5441 5442 5443 5445 5446 5447 5448 5450 5451 5452 5454 5455 5456 5457 5458 5459 5460 5461 5462 5463 5465 5466 5467 CD1

C

0

N

CA

CB

CG

CD1 CD2 CE 1 CE2

CZ

C

0

N

CA

CB

OG1 CG2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

C

0

N

CA

C

0

N

CA

CB

OG

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

ILE

ILE

ILE

PHE

PHE

PHE

PHE

PE

PHE

PE

PE

PE

PHE

PHE

THR

THR

THR

THR

THR

THR

THR

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

GLY

GLY

GLY

GLY

GLY

GLY

GLY

GLY

SER

SER

SER

SER

SER

SER

PRO

PRO

PRO

PRO

PRO

PRO

PRO

TYR

TYR

TYR

TYR

693 693 693 694 694 694 694 694 694 694 694 694 694 694 695 695 695 695 695 695 695 696 696 696 696 696 696 696 696 697 697 697 697 698 698 698 698 699' 699 699 699 699 699 700 700 700 700 700 700 700 701 701 701 701 52.663 48.603 48.568 46 .523 45 .958 46 .978 47.606 47.424 48 .669 48 .484 49.110 45.481 44.623 45.617 44 .742 44 .113 45.142 43.254 45.596 45.153 46 .832 47.799 47.421 47.270 47.010 48.515 48. 066 48.135 48 .302 48.591 47.375 47.322 46.392 45.187 45.408 46.336 44 .517 44.552 44.062 44.019 43 .644 42.431 44.228 45.645 43 .353 44.345 45.552 42.484 42.899 41.235 40.291 40.650 -3.747 5.023 -5.807 -4.942 -5.888 -6.114 -6.717 -5.942 -8.024 -6.460 -8.546 -7.762 -5.715 -6.579 -4.637 -4.379 -2.957 -1.961 -2.759 -4.533 -4.241 -4.987 -5.199 -6.418 -7.741 -8.838 -8.061 -3.976 -4.067 -2.839 -1.632 -0.765 0.042 -0.921 -0.122 1.368 1.803 2.148 3 .595 4.202 5.616 4.014 3.759 4.597 4.842 4.992 5.341 5.800 6.170 7.021 6 .144 7.223 8.416 19.194 16.452 15.512 17.336 17.279 18.687 19.621 20.586 19.426 21.333 20.170 21. 118 16 .176 15.982 15.404 14 .263 14.278 14.218 15.524 13 .011 11.906 13.209 12 .134 11.291 12 .042 11.052 12.830 11.249 10.024 11.890 11.141 10.924 9 .994 11.797 11.681 11.877 12 .553 11. 285 11.376 10.058 10.123 12.538 12.525 13.594 13.919 14.697 15.809 15.061 14.295 13.510 14 .736 14.445 15.323 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 25.37 29.21 27.89 31.33 34.41 35.37 35.60 37.23 35.59 36.39 35 .34 35.71 34.41 34.48 33.03 31.81 29.75 30.72 29.40 31.44 33 .00 31.24 31.36 33 .53 33 .00 35.50 36 .09 30 .84 28 .23 31. 54 33 .87 32 .77 33 33.29 32.66 30.57 27.36 30.92 32.19 34.24 38.67 31.81 31.39 31.82 -28 .82 31.31 31.31 30.41 31.19 29.93 32.69 32.54 34.47 40.512 8.141 16.794 1.00 39.16 45. vOl WO 98/07835 WO 9807835PCT1US97/14885' 188 ATOM 5468 CD1 TYR 701 41.542 8.433 17.683 1.00 44.31 ATOM 5469 CEl TYR 701 41.372 8.241 19.060 1.00 46.65 ATOM 5470 CD2 TYR 701 39.321 7.642 17.307 1.00 41.21 ATOM 5471 CE2 TYR 701 39.147 7.447 18.657 1.00 45.05 ATOM 5472 CZ TYR 701 40.164 7.750 19.535 1.00 47.24 ATOM 5473 OH TYR 701 39.949 7.590 20.886 1.00 52.18 ATOM 5475 C TYR 701 40.215 7.655 12.972 1.00 30.56 ATOM 5476 0 TYR 701 40.379 8.836 12.647 1.00 29.73 ATOM 5477 N PRO 702 39.928 6.712 12.058 1.00 30.38 ATOM 5478 CD PRO 702 39.659 5.278 12.261 1.00 30.22 ATOM 5479 CA PRO 702 39.847 7.071 10.642 1.00 28.87 ATOM 5480 CB PRO 702 39.693 5.722 9.948 1.00 29.63 ATOM 5481 CG PRO 702 39.007 4.889 10.959 1.00 30.99 ATOM 5482 C PRO 702 38.722 8.048 10.283 1.00 30.88 ATOM 5483 0 PRO 702 37.557 7.843 10.636 1.00 33.98 ATOM 5484 N GLY 703 39.100 9.116 9.584 1.00 29.03 ATOM 5486 CA GLY 703 38.154 10.134 9.169 1.00 28.98 ATOM 5487 C GLY 703 37.893 11.169 10.244 1.00 29.69 ATOM 5488 0 GLY 703 37.074 12.068 10.048 1.00 31.71 ATOM 5489 N VAL 704 38.579 11.040 11.378 1.00 30.74 ATOM 5491 CA VAL 704 38.416 11.951 12.509 1.00 32.06 ATOM 5492 CB VAL 704 38.582 11.208 13.860 1.00 31.70 ATOM 5493 CG1 VAL 704 38.522 12.197 15.044 1.00 30.29 ATOM 5494 CG2 VAL 704 37.506 10.144 14.005 1.00 31.56 ATOM 5495 C VAL 704 39.430 13.087 12.449 1.00 33.72 ATOM 5496 0 VAL 704 40.634 12.867 12.548 1.00 35.31 ATOM 5497 N PRO 705 38.957 14.309 12.200 1.00 34.23 ATOM 5498 CD PRO 705 37.594 14.692 11.787 1.00 33.20 ATOM 5499 CA PRO 705 39.875 15.443 12.135 1.00 33.73 ATOM 5500 CB PRO 705 39.053 16.495 11.394 1.00 34.93 ATOM 5501 CG PRO 705 37.647 16.187 11.831 1.00 36.93 ATOM 5502 C PRO 705 40.280 15.879 13.543 1.00 33.25 ATOM 5503 0 PRO 705 39.651 .15.490 14.532 1.00 31.71 ATOM 5504 N VAL 706 41.322 16.697 13.623 1.00 34.46 ATOM 5506 CA VAL 706 41.852 17.176 14.900 1.00 36.99 ATOM 5507 CB VAL 706 42.923 18.261 14.687 1.00 39.01 ATOM :5508 CG1 VAL 706 43.577 18.618 16.017 1.00 40.33 ATOM '5509 CG2 VAL 706 43.961 17.786 13.673 1.00 38.61 ATOM 5510 C VAL 706 40.826 17.716 15.895 1.00 35.65 ATOM 5511 0 VAL 706 40.823 17.319 17.065 1.00 33.55 ATOM 5512 N GLU 707 39.955 18.605 15.426 1.00 36.74 ATOM 5514 CA GLU 707 38.941 19.220 16.278 1.00 37.20 ATOM 5515 CB GLU 707 38.129 20.242 15.482 1.00 38.98 ATOM 5516 C GLU 707 38.014 18.188 16.900 1.00 38.46 ATOM 5517 0 GLU 707 37.634 18.295 -18.074 1.00 39.04 ATOM 5518 N GLU 708 37.681 17.170 16.115 1.00 37.81 ATOM 5520 CA GLU 708 36.802 16.105 16.571 1.00 37.70 ATOM 5521 CB GLtJ 708 36.316 15.289 15.378 1.00 40.73 ATOM 5522 CG GLU 708 35.459 16.091 14.413 1.00 43.44 ATOM 5523 CD GLU 708 34.235 16.677 15.084 1.00 51.52 ATOM 5524 OE1 GLU 708 33.629 16.007 15.961 1.00 50.14 ATOM 5525 0E2 GLU 708 33.882 17.824 14.732 1.00 59.46 ATOM 5526 C GLU 708 37.506 15.223 17.588 1.00 36.53 ATOM 5527 0 GLU 708 36.897 14.782 18.567 1.00 36.80 145. vOl WO 98/07835 PCTIUS97/14885 189 ATOM 5528 N LEU 709 38.799 14.993 17.376 1.00 35.69 ATOM 5530 CA LEU 709 39.584 14.179 18.301 1.00 35.48 ATOM 5531 CB LEU 709 41.039 14.044 17.830 1.00 34.84 ATOM 5532 CG LEU 709 41.921 13.250 18.802 1.00 32.41 ATOM 5533 CD1 LEU 709 41.608 11.787 18.674 1.00 30.10 ATOM 5534 CD2 LEU 709 43.378 13.514 18.560 1.00 29.93 ATOM 5535 C LEIY 709 39.568 14.842 19.673 1.00 35.58 ATOM 5536 0 LEU 709 39.377 14.177 20.694 1.00 35.43 ATOM 5537 N PHE 710 39.792 16.150 19.686 1.00 36.79 ATOM 5539 CA PHE 710 39.800 16.918 20.927 1.00 40.58 ATOM 5540 CB PHE 710 39.944 18.413 20.637 1.00 42.55 ATOM 5541 CG PHE 710 41.308 18.808 20.162 1.00 46.38 ATOM 5542 CD1 PHE 710 42.392 17.942 20.313 1.00 47.29 ATOM 5543 CD2 PHE 710 41.515 20.050 19.580 1.00 47.93 ATOM 5544 CEl PHE 710 43.659 18.312 19.8.92 1.00 51.21 ATOM 5545 CE2 PHE 710 42.781 20.435 19.155 1.00 -50.89 ATOM 5546 CZ PHE 710 43.859 19.562 19.312 1.00 53.31 ATOM 5547 C PHE 710 38.517 16.676 21.694 1.00 40.14 ATOM 5548 0 PHE 710 38.543 16.446 22.898 1.00 39.86 ATOM 5549 N LYS 711 37.399 16.705 20.977 1.00 41.02 ATOM 5551 CA LYS 711 36.101 16.479 21.584 1.00 38.66 ATOM 5552 CB LYS 711 34.985 16.803 20.580 1.00 40.75 ATOM 5553 CG LYS 711 33.601 16.727 21.181 1.00 46.99 ATOM 5554 CD LYS 711 32.522 17.174 20.218 1.00 50.71 ATOM 5555 CE LYS 711 31.163 16.733 20.739 1.00 52.53 ATOM 5556 NZ LYS 711 30.041 17.194 19.884 1.00 57.76 ATOM 5560 C LYS 711 35.990 15.046 22.120 1.00 38.06 ATOM 5561 0 LYS 711 35.535 14.831 23.250. 1.00 Y6 .29 ATOM 5562 N LEU 712 36.431 14.066 21.330 1.00 38.10 ATOM 5564 CA LEU 712 36.392 12.662 21.764 1.00 38.69 ATOM 5565 CB LEU 712 36.914 11.714 20.672 1.00 37.19 ATOM 5566 CG LEU 712 36.070 11.436 19.424 1.00 34.73 ATOM 5567 CD1 LEU 712 36.814 10.453 18.524 1.00 35.54 ATOM 5568 CD2 LEU 712 34.709 10.872 19.818 1.00 30.90 ATOM 5569 C LEU 712 37.230 12.472 23.021 1.00 39.62 ATOM 5570 0 LEU 712 36.843 11.745 23.940 1.00 39.44 ATOM 5571 N LEU 713 38.398 13.101 23.044 1.00 4.0.10 ATOM 5573 CA LEU 713 39.279 12.999 24.199 1.00 42.81 ATOM 5574 CB LEU 713 40.606 13.716 23.924 1.00 41.70 ATOM 5575 CG LEU 713 41.495 13.040 22.868 1.00 41.86 ATOM 5576 CD1 LEU 713 42.742 13.862 22.607 1.00 37.19 ATOM 5577 CD2 LEU 713 41.873 11.647 23.340 1.00 41.17 ATOM 5578 C LEU 713 38.577 13.566 25.437 1.00 43.18 ATOM 5579 0 LEU 713 38.479 12.889 26.457 1.00 44.79 ATOM 5580 N LYS 714 38.004 14.760 25.312 1.00 42.75 ATOM 5582 CA LYS 714 37.301 15.389 26.425 1.00 43.70 ATOM 5583 CB LYS 714 36.842 16.796 26.043 1.00 44.69 ATOM 5584 CG LYS 714 38.001 17.746 25.836 1.00 47.92 ATOM 5585 CD LYS 714 37.543 19.171 25.583 1.00 55.01 ATOM 5586 CE LYS 714 38.733 20.077 25.238 1.00 59.44 ATOM 5587 N Z LYS 714 39.773 20.132 26.320 1.00 60.10 ATOM 5591 C LYS, 714 36.127 14.557 26.940 1.00 43.94 ATOM 5592 0 LYS 714 35.843 14.551 28.140 1.00 44.20 ATOM 5593 N GLU 715 35.477 13.819 26A046 1.00 43.29 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 190

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOMV

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM_

ATOM

ATOM

5595 5596 5597 5598 5599 5600 5601 5602 5603 5605 5606 5607 5608 5610 5611 5612 5613 5614 5616 5617 5619 5620 5621 5623 5624 5625 5626 5627 5629 5630 5633 5636 5637 5638 5640 5641 5642 5643 5644 5645 5646 5647 5649 5650 5651 5652 5653 5654 5655 5656 5658 5659 5660 5661

CA

CB

CG

CD

OE 1 0E2

C

0

N

CA

C

0

N

CA

CB

CG

CD2 NDl CEl NE2

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD

GLU

GLU

GLtJ

GLU

GLU

GLU

GLU

GLU

GLY

GLY

GLY

GLY

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

MET

MET

MET

MET

MET

MET

MET

MET

ASP

ASP

ASP

ASP

AS P

ASP

ASP

ASP

LYS

LYS

LYS

LYS

LYS

715 715 715 715 715 715 715 715 716 716 716 716 717 717 717 717 717 717 717 717 717 717 718 718 718 718 718 718 718 718 718 718 718 719 719 719 719 719 719 719 719 720 720 720 720 720 720 720 720 721 721 721 721 721 34.350 33.464 32.913 32 .020 32 .343 30.992 34.806 33.982 36.118 36.642 36 .510 36 .562 36 .359 36.215 35.859 35.813 34 .802 36 .912 36 .584 35.307 37.485 38.581 37 .304 38.387 38.500 38.844 40.214 40.658 40.521 39.940 41.024 38.080 36.911 39. 113 38.928 40.219 40.595 42 093 43.323 38.460 38.822 37.1635 37.090 36 .077 34.811 34.678 33.943 38 .177 39.235 37.876 38 .784 38.278 39.000 38.445 12 .979 12.682 13 .916 13. 566 12.605 14.251 11.665 10. 825 11.476 10.252 9. 054 7. 904 9.335 8.300 8. 918 7. 926 7. 152 7.625 6.708 6.404 7.481 8 .031 6.169 5.207 4.361 5.165 5.825 6. 549 7.861 8 .608 8.443 4.308 4.007 3.933 3. 079 2. 964 4.221 4. 079 3. 949 1. 694 1.216 1.075 -0.265 -0.660 0.181 1. 082 -0.067 -1.329 -1.172 -2.436 -3 .565 -4.565 -5.888 -6.805 26.435 25.225 24 .522 23 .332 22.596 23.136 27.064 27.421 27.182 27.770 26.847 27.290 25.554 24.541 23.183 22 .060 21.596 21.285 20.392 20.561 24.403 24.327 24.289 24.139 25.412 26 .658 26.495 27.685 27 .862 26.931 28.946 22 .927 22.650 22.174 21.004 20.181 19.413 18.400 19.613 21.432 22.516 20.582 20.824 19.733 19.749 20.612 18.880 20.823 20.199 21.487 21.555 22.587 22.570 23.628 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 42.29 44 .91 51.62 55.~01 58.09 55.83 41.07 38 .01 41.11 39.69 39.64 36.71 41.95 43 .32 43.38 44 .79 44 .64 46.21 46.21 45.55 43 45.45 43 .44 42 .68 41.00 40.09 41.06 39.51 39.90 36 .48 42 .06 43 .91 44.40 42 .56 42 .82 42.59 41.15 44 .11 41.33 44 .74 41.56 45.50 45.51 48 53.03 59.61 50 .58 43.64 43 .66 42 42 .96 42 .51 47.68 51.61 145. vOl WO 98/07835 WO 9807835PCT/tUS97/14885 191

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5662 5663 5667 5668 5669 5670 5671 5672 5673 5674 5675 5676 5678 5679 5680 5682 5683 5684 5686 5687 5688 5689 5690 5693 5694 5695 5697 5698 5699 5700 5701 5702 5704 5705 5706 5708 *5709 -5710 5711 5713 5714 5715 .5716 5717 5720 5721 5722 5724 5725 5726 5727 5728 5729 5730

CE

NZ

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

OD1 Nfl2

C

0

N

CA

CB

SG

C

0

N

CA

CB

OG1 CG2

C

0

N

CA

CB

CG

OD1 ND2

C

0

N

CA

CB

CG

CD

OE1 0E2

C

LYS 721 LYS 721 LYS 721 LYS 721 PRO 722 PRO 722 PRO 722 PRO 722 PRO 722 PRO 722 PRO 722 SER 723 SER 723 SER 723 SER 723 SER 723 SER 723 ASN 724 ASN 724 ASN 724 ASN 724 ASN 724 ASN 724 ASN 724 ASN 724 CYS .725 CYS 725 CYS 725 CYS 725 CYS 725 CYS 725 THR 726 THR 726 THR 726 THR 726 THR 726 THR 726 THR 726 ASN 727 ASN 727 ASN 727 ASN 727 ASN 727 ASN 727 ASN 727 ASN 727 GLU 728 GLU 728 GLU 728 GLU 728 GLU 728 GLU 728 GLU 728 GLU 728 38.450 38.165 38.825 37.779 40.025 41.337 40.139 41.631 42.074 39.726 39.730 39.311 38.947 38.205 39.049 40.294 41.284 40.338 41.598 42.256 41.682 41.637 41.218 42 .509 43.648 41.960 42 .686 42 .569 43.459 42.017 40.803 42 .810, 42.289 43.351 44 .307 44 .061 41.858 42.368 40.914 40.448 39.300 39.629 40.737 38.681 41.591 41.594 42 .572 43 .725 44 .573 45.806 46.643 46.867 47.085 44.551 -8.246 -9.190 -4 .215 -4 .577 -4.348 -3.872 -4.968 -4.856 -3.682 -6 .427 -7.023 -6 .982 -8.389 -8.707 -8.520 -9.102 -8 .575 -10 .300 -11.019 -11.202 -12 .374 -13 .492 -12 .125 -10 .255 -9.918 -9.935 -9.238 -7.717 -6.813 -9.697 -9.642 -10 .224 -10.711 -11.545 -10 .651 -12 .495 -9.545 8 .445 -9.789 -8.736 -9.237 -10 .544 -10. 734 -11.472 -8.212 -7.047 -9.073 -8.713 -9.952 -9.654 -10.889 -11.732 -11.010 -7.652 23 .163 24.282 20.182 19.625 19.601 20.067 18.275 17. 965 18.764 18.346 19.425 17.212 17.158 15.865 14.749 17.191 16.703 17.750 17.853 16 .476 15.715 16 .225 14.500 18 .811 18.495 19.973 21. 010 20.862 22.159 22.294 22.423 23 .212 24.482 25.217 25.786 24.233 25.359 25.216 26.257 27.141 28.022 28.731 29.229 28.735 27.999 28.390 28.260 29.071 29.379 30.245 30.568 29.668 31.733 28.356 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.0OQ 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 54 .96 59.67 43 46.08 43 .22 43.52 41.04 40.87 42.22 39.64 37.12 40.36 41.41 38.26 43.87 41.54 40. 44.89 48.14 52.43 57.29 61. 96 60.91 48.17 49.88 47.12 46.17 44.83 42 .51 45.78 44.83 45.63 45.47 45.93 45.04 42.99 45.73 46.91 45.93 47.85 54.88 65.11 70.58 69.68 44.18 41.35 42.82 42.37 43 .09 48.30 50.11 47. 98 51.69 39.57 145. vOl WO 98/07835 PCT/UJS97/1 4885* 192 ATOM 5731 0 GLU 728 44.852 -6.605 28.933 1.00 39.30 ATOM 5732 N LEU 729 44.872 -7.907 27.089 1.00 37.38 ATOM 5734 CA LEU 729 45.655 -6.977 26.274 1.00 36.74 ATOM 5735 CB LEU 729 46.027 -7.623 24.935 1.00 35.39 ATOM 5736 CG LEU 729 47.137 -8.679 25.001 1.00 35.41 ATOM 5737 CD1 LEU 729 47.107 -9.553 23.766 1.00 35.69 ATOM 5738 CD2 LEU 729 48.505 -8.017 25.174 1.00 37.72 ATOM 5739 C LEU 729 44.885 -5.679 26.050 1.00 35.52 ATOM 5740 0 LEU 729 45.467 -4.597 25.941 1.00 33.96 ATOM 5741 N TYR 730 43.565 -5.779 26.000 1.00 32.9 0 ATOM 5743 CA TYR 730 42.760 -4.598 25.812 1.00 32.41 ATOM 5744 CB TYR 730 41.335 -4.981 25.398 1.00 32.16 ATOM 5745 CG TYR 730 40 -445 -3.787 25.172 1.00 34.93 ATOM 5746 CD1 TYR 730 40.769 -2.827 24.203 1.00 32.49 ATOM 5747 CEl TYR 730 39.962 -1.716 23.-994 1.00 32.80 ATOM 5748 CD2 TYR 730 39.282 -3.605 25.931 1.00 33.45 ATOM 5749 CE2 TYR 730 38.465 -2.496 25.728 1.00 34.81 ATOM 5750 CZ TYR 730 38.814 -1.557 24.756 1.00 34.06 ATOM 5751 OH TYR 730 38.009 -0.465 24.551 1.00 36.66 ATOM 5753 C TYR 730 42.767 -3.788 27.107 1.00 33.48 ATOM 5754 0 TYR 730 42.837 -2.558 27.083 1.00 34.94 ATOM 5755 N MET 731 42.698 -4.466 28.248 1.00 35.29 ATOM 5757 CA MET 731 42.724 -3.755 29.525 1.00 38.38 ATOM 5758 CB MET 731 42.465 -4.709 30.690 1.00 42.01 ATOM 5759 CG MET 731 41.048 -5.264 30.702 1.00 53.67 ATOM 5760 SD MET 731 39.785 -3.965 30.830 1.00 62.97 ATOM 5761 CE MET 731 39.828 -3.688 32.641 1.00 61.83 ATOM 5762 C MET 731 44.073 -3 .049 29.670 1.00 34.52 ATOM 5763 0 MET 731 44.160 -1.958 30.232 1.00 33.2.3 ATOM 5764 N MET 732 45.118 -3.669 29.134 1.00 33.93 ATOM 5766 CA MET 732 46.445 -3.065 29.168 1.00 36.26 ATOM 5767 CB MET 732 47.506 -3.995 28.565 1.00 35.56 ATOM 5768 CG MET 732 48.935 -3.418 28.643 1.00 35.26 ATOM 5769 SD MET 732 50.186 -4.522 28.001 1.00 30.46 ATOM 5770 CE MET 732 50.480 -5.562 29.415 1.00 26.88 ATOM 5771 C MET 732 46.369 -1.750 28.389 1.00 34.75 ATOM 5772 0 MET 732 46.827 -0.722 28.8a73 1.00 35.49 ATOM 5773 N MET 733 45.741 -1.774 27.213 1.00 34.63 ATOM. 5775 CA MET 733 45.571 -0.566 26.413 1.00 32.79 ATOM 5776 CB MET 733 44.787 -0.853 25.130 1.00 33.16 ATOM 5777 CG MET 733 45.544 -1.601 24.047 1.00 32.32 ATOM 5778 SD MET 733 44.421 -1.990 22.670 1.00 35.66 ATOM 5779 CE MET 733 45.155 -3.496 22.068 1.00 29.47 ATOM 5780 C MET 733 44.789 0.452 27.229 1.00 33.94 ATOM 5781 0 MET 733 45.176 1.619 27.318 1.00 35.72 ATOM 5782 N ARG 734 43.679 0.018 27.818 1.00 33.73 ATOM 5784 CA ARG 734 42.854 0.913 28.621 1.00 33.41 ATOM 5785 CB ARG 734 41. 58G 0.197 29.095 1.00 33.42 ATOM 5786 CG ARG 734 40.726 -0.335 27.950 1.00 34.26 ATOM 5787 CD ARG 734 40.256 0.783 27.043 1.00 37.70 ATOM 5788 NE ARG 734 39.416 1.745 27.750 1.00 43.98 ATOM 5790 CZ ARG 734 38.092 -1.661 27.844 1.00 46.43 ATOM 5791 NH1 ARG 734 37.439 0.660 27.268 1.00 48.63 ATOM 5794 NH2 ARG 734 37.420 2.571 28.530 1.00 44.65 SSSD/55145. vOl WO 98/07835 WO 9807835PCT[US97/14885, 193

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5797 5798 5799 5801 5802 5803 5804 5805 5806 5807 5808 5810 5811 5812 5813 5814 5815 5817 5818 5819 5820 5821 5822 5823 5824 5826 5827 5828 5829 5830 5831 5833 5834 5835 5836 5837 5839 5840 5842 5843 5844 5846 5847 5848 5849 5850 5852 5853 5854 5855 5856 5857 5858 5859

C

0

N

CA

CB

CG

ODI

0D2

C

0

N

CA

CB

SG

C

0

N

CA

CB

CG

CD2 CE2 CE3 CD1 NEl CZ2 CZ3

MH

C

0

N

CA

CE

CG

CD2 ND1 CEl NE2

C

0

N

CA

CB

C

0

N

CA

CB

CG1 CG2

C

0

N

CD

ARG

ARG

AS P AS P AS P

ASP

AS P

ASP

ASP

ASP

CYS

CYS

CYS

CYS

CYS

CYS

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ALA

ALA

ALA

ALA

ALA

VAL

VAL

VAL

VAL

VAL

VAL

VAL

PRO

PRO

734 734 735 735 735 735 735 735 735 735 736 736 736 736 736 736 737 737 737 737 737 737 737 737 737 737 737 737 737 737 738 738 738 738 738 738 738 738 738 738 739 739 739 739 739 740 740 740 740 740 740 740 741 741 43.660 43.492 44.566 45.438 46.379 45.722 46.124 44 .824 46 .291 46.376 46.927 47.780 48.413 49.504 46 .994 47.562 45.680 44.812 43.808 44.451 43 .914 44.852 42.730 45.659 45.907 44 .644 42.527 43.480 44.080 43.047 44.624 44 .006 44.675 43 .925 43 .618 43.338 42.693 42 .848 44.118 45.179 43 .025 43.004 41.629 44.081 44.653 44.262 45.278 44.867 45.919 43.515 46.601 46.754 47.588 47.536 1.458 2.610 0.646 1 .076 0.055 -1 .052 -2.241 -0.646 2.251 3.286 2 .064 3 .077 2.545 1.159 4.325 5 .416 4 .174 5.308 4.927 4.487 3.565 3.461 2.816 4.890 4.279 2.633 1.991 1.909 5.895 6.551 5.681 6..208 5.635 5.924 7.096 4.935 5.487 6.798 7.726 8.-268 8.405 9.873 10.361 10.467 11.510 9.852 10.273 9.893 10.372 10.495 9.573 8.362 10.335 11. 794 29. 793 30.180 30.327 31.433 31. 857 32 .774 32.720 33. 552 30. 972 31.648 29. 816 29.204 27.921 28.180 28.885 28 .823 28 .711 28.395 27 .297 26 .010 25. 052 23. 999 24 .980 25.514 24 .309 22 .886 23 .876 22 .844 29.609 29 .474 30.798 32. 008 33.258 34 .522 35.126 35.279 36 .294 36 .223 32 .015 31.731 32.352 32 .398 32 .825 33 .317 33 .020 34.481 35.453 36.888 37 .890 '37 .211 35 .121 35 .347 34.637 34.437 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 .1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 32.12 35.37 33.75 36.72 42.71 47.31 50.99 48.45 34 34.31 31.85 29.93 24.97 31.35 31.62 30.73 35.03 36.35 36.43 34.34 34.81 33.92 33 .06 35.19 35. 00 33.45 32. 92 30.45 37.23 37.44 41.45 41.52 41.23 43 .31 41.58 44.22 46 .62 43 .99 41.-75 40.84 42.47 44.58 48 .19 45.12 45.66 46.64 46.78 47.74 49.35 47.89 45.24 45.01 43.46 43.51 145. vOl WO 98/07835 PTU9/48 PCTIUS97/14885 194

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5860 5861 5862 5863 5864 5865 5867 5868 5869 5871 5872 5873 5875 5876 5877 5878 5879 5880 5883 5884 5885 5887 5888 5889 5890 5891 5893 5894 5897 5900 5901 5902 5903 5904 5905 5906 5907 5908 5909 5911 5912 5913 5915 5916 5917 5918 5920 5921 5922 5923 5924 5925 5926 5927

CA

CB

CG

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

CD

OE 1 NE2

C

0

N

CA

CB

CG

CD

NE

CZ

NHl NH2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

OGi CG2

C

0

N

CA

CB

CG

CD1 CD2 CEl CE2

CZ

PRO

PRO

PRO

PRO

PRO

SER

SER

SER

SER

SER

SER

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

PRO

PRO

PRO

PRO

PRO

PRO

PRO

THR

THR

THR

THR

THR

PHE

PE

PE

PE

PHE

PE

PHE

PE

741 741 741 741 741 742 742 742 742 742 742 743 743 743 743 743 743 743 743 743 744 744 744 744 744 744 744 744 744 744 744 745 745 745 745 745 745 745 746 746 746 746 746 746 746 747 747 747 747 747 747 747 747 747 48. 905 49. 701.

48.632 49.588 50.245 49.394 49.994 49.845 48 .482 49.376 49.932 48 .199 47.511 46. 004 45.438 46.239 46. 898 46.202 47.816 47.365 48. 515 48 .902 49.350 48 .316 48 .854 47. 921 48.271 49.553 47.330 50.068 50.813 50 .203 49.345 51.332 51.019 50.250 52.640 52.634 53 .753 55. 050 56.085 56 .296 55.605 55.544 55.026 56. 538 57.093 58.121 57.504 56.772 57.609 56 .170 57.001 56.276 9.804 11.070 12 .010 8.936 7.950 9.280 8.532 9.317 9.488 7.150 6 .283 6 .962 5.689 5 .918 5.447 5.964 5.19G 7.277 4 .774 3.627 5.305 4 .506 5.397 6 .380 7.207 8.276 9.492 9 .813 10.404 3 .616 3 .945 2.441 1.739 1.607 0.261 0.645 2.202 3.027 1.843 2 .328 2 .380 1.059 3 .302 1.327 0 .213 1.708 0.782 1.472 2.287 1.666 3.667 2 .407 4.413 3 .776 34.266 33. 942 33 .426 35.328 34 .994 36.601 37.703 39.012 39.373 37.867 38.539 37.284 37 .384 37.531 38.871 40.051 40.749 40 .268 36 .212 36.182 35 .212 34 .046 32 .883 32.412 31.270 30 .946 30.543 30.399 30.322 34.471 35.405 33 .849 32 .876 34.266 33 .605 32 .377 33 .750 32.835 34.373 33 .913 3-5. 075 35.602 36.177 32.870 32.795 32 .066 31.083 30.193 29.096 28 .092 29.091 27.100 28.091 27.103 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 46.22 45.32 42.81 47.45 45 .12 48 .78 48 .76 51.11 53.50 47.77 47.31 47.57 47.14 50.16 54 .69 57.62 59.09 59.45 44.41 44.39 42.87 41.45 37.34 32.30 31.37 36 .76 39.88 39.94 39.12 41.40 42.84 40 .11 39.91 38.58 37.46 37.41 37.73 37.71 35. 34 .77 33.85 33 .92 32.17 32.69 31. 56 34.04 31.74 30.55 29.40 28.24 27.50 24.35 29.27 25.73 145. vOl WO 98/07835 WO 9807835PCT/US97/14885 195 ATOM 5928 C PHE 747 57.714 -0.413 31.782 1.00 31.92 ATOM 5929 0 PHE 747 57.727 -1.514 31.243 1.00 32.46 ATOM 5930 N LYS 748 58.233 -0.199 32.986 1.00 33.47 ATOM 5932 CA LYS 748 58.816 -1.302 33.733 1.00 35.57 ATOM 5933 CB LYS 748 59.468 -0.800 35.026 1.00 39.42 ATOM 5934 CG LYS 748 60.083 -1.923 35.861 1.00 46.49 ATOM 5935 CD LYS 748 60.817 -1.407 37.103 1.00 50.69 ATOM 5936 CE LYS 748 61.253 -2.574 37.999 1.00 52.57 ATOM 5937 NZ LYS 748 62.072 -2.129 39.155 .1.00 56.45 ATOM 5941 C LYS 748 57.700 -2.318 34.028 1.00 35.58 ATOM 5942 0 LYS 748 57.898 -3.526 33.871 1.00 34.72 ATOM 5943 N GLN 749 56.522 -1.818 34.411 1.00 35.59 ATOM 5945 CA GLN 749 55.369 -2.684 34.692 1.00 38.20 ATOM' 5946 CB GLN 749 54.154 -1.872 35.162 1.00 42.73 ATOM 5947 CG GLN 749 54.264 -1.171 36.499 1.00 49.30 ATOM 5948 CD GLN 749 53.060 -0.282 36.761 1.00 53.13 ATOM 5949 OE1 GLN 749 53.194 0.915 37.023 1.00 52.71 ATOM 5950 NE2 GLN 749 51.873 -0.856 36.644 1.00 58.54 ATOM 5953 C GLN 749 54.954 -3.392 33.409 1.00 36.16 ATOM 5954 0 GLN 749 54.745 -4.605 33.393 1.00 36.67 ATOM 5955 N LEU 750 54.801 -2.609 32.342 1.00 35.83 ATOM 5957 CA LEU 750 54.381 -3.117 31.037 1.00 34.49 ATOM 5958 CB LEtJ 750 54.324 -1.988 30.004 1.00 32.49 ATOM 5959 CG LEU 750 53.206 -0.958 30.188 1.00 31.94 ATOM 5960 CD1 LEU 750 53.411 0.230 29.267 1.00 30.45 ATOM 5961 CD2 LEU 750 51.859 -1.610 29.933 1.00 29.30 ATOM 5962 C LETJ 750 55.294 -4.214 30.559 1.00 33.87 ATOM 5963 0 LEU 750 54.828 208 30.027 1.00 34.72 ATOM 5964 N VAL 751 56.598 -4.038 30.759 1.00 36.12 ATOM 5966 CA VAL 751 57.585 -5.045 30.363 1.00 34.50 ATOM 5967 CB VAL 751 59.054 -4.532 30.559 1.00 31.96 ATOM 5968 CG1 VAL 751 60.052 -5.646 30.308 1.00 30.24 ATOM 5969 CG2 VAL 751 59.342 -3.386 29.604 1.00. 28.02 ATOM 5970 C VAL 751 57.349 -6.321 31.182 1.00 36.11 ATOM 5971 0 VAL 751 57.333 -7.422 30.638 1.00 36.45 ATOM 5972 N GLU 752 57.107 -6.165 32.479 1.00 37.83 ATOM 5974 CA GLU 752 56.869 -7.326 33.331 1.00 41.47 ATOM -5975 CB GLU 752 56.800 -6.910 34.804 1.00 43.03 ATOM 5976 CG GLU 752 58.122 -6.305 35.263 1.00 52.52 ATOM 5977 CD GLU 752 58.251 -6.176 36.761 1.00 57.18 ATOM 5978 OE1 GLU 752 58.600 -5.068 37.233 1.00 58.11 ATOM 5979 0E2 GLU 752 58.032 -7.191 37.461 1.00 61.59 ATOM 5980 C GLU 752 55.623 -8.097 32.890 1.00 40.16 ATOM 5981 0 GLU 752 55.689 -9.308 32.642 1.00 39.75 ATOM 5982 N ASP 753 54.524 -7.376 32.696 1.00 40.06 ATOM 5984 CA ASP 753 53.275 -7.982 32.264 1.00 39.73 ATOM 5985 CE ASP 753 52.157 -6.947 32.247 1.00 41.00 ATOM 5986 CG ASP 753 51.668 -6.591 33.640 1.00 45.17 ATOM 5987 ODi ASP 753 51.753 -7.468 34.543 1.00 49.78 ATOM 5988 0D2 ASP 753 51.210 -5.439 33.829 1.00 45:51 ATOM 5989 C ASP 753 53.396 -8.595 30.890 1.00 39.64 ATOM 5990 0 ASP 753 52.955 -9.720 30.674 1.00 41.84 ATOM 5991 N LEU 754 53.998 -7.861 29.960 1.00 37.75 ATOM 5993 CA LEU 754 54.161 -8.358 28.603 1.00 38.16 SSSD/55145. V01 WO 98/07835 PCT/US97/14885 196 ATOM 5994 CB LEU 754 54.664 -7.261 27.664 1.00 36.95 ATOM 5995 CG LEU 754 53.552 -6.270 27.307 1.00 36.64 ATOM 5996 CD1 LEU 754 54.141 -5.062 26.590 1.00 34.02 ATOM 5997 CD2 LEU 754 52.459 -6.968 26.465 1.00 34.13 ATOM 5998- C LEU 754 55.070 -9.561 28.571 1.00 38.46 ATOM 5999 0 LEU 754 54.905 -10.451 27.740 1.00 39.95 ATOM 6000 N ASP 755 56.014 -9.602 29.502 1.00 39.19- ATOM 6002 CA ASP 755 56.930 -10.728 29.594 1.00 40.87 ATOM 6003 CB ASP 755 57.956 -10.462 30.696 1.00 45.11 ATOM 6004 CG ASP 755 59.128 -11.415 30.652 1.00 48.64 ATOM 6005 0D1 ASP 755 59.759 -11.612 31.711 1.00 54.27 ATOM 6006 0D2 ASP 755 59.432 -11.954 29.565 1.00 51.46 ATOM 6007 C ASP 755 56.082 -11.952 *29.947 1.00 40.67 ATOM 6008 0 ASP 755 56.152 -12.996 29.289 1.00 38.49 ATOM 6009 N ARG 756 55.232 -11.771 30.955 1.00 40.06 ATOM 6011 CA ARG 756 54.340 -12.817 31.437 1.00 40.07 ATOM 6012 CB ARG 756 53.573 -12.316 32.661 1.00 40.24 ATOM 6013 CG ARG 756 52.435 -13.217 33.138 1.00 42.12 ATOM 6014 CD ARG 756 51.791 -12.631 34.389 1.00 42.33 ATOM 6015 NE ARG 756 51.353 -11.247 34.186 1.00 46.68 ATOM 6017 CZ ARG 756 50.295 -10.891 33.460 1.00 48.17 ATOM 6018 NH1 ARG 756 49.549 -11.818 32.866 1.00 46.64 ATOM 6021 NH2 ARG 756 49.998 -9.605 33.305 1.00 48.92 ATOM 6024 C ARG 756 53.362 -13.275 30.364 1.00 40.19 ATOM 6025 0 ARG 756 53.247 -14.469 30.110 1.00 42.24 ATOM 6026 N ILE 757 52.688 -12.327 29.717 1.00 38.18 ATOM 6028 CA ILE 757 51.706 -12.6G49 28.683 1.00 38.40 ATOM 6029* CB ILE 757 '50. 952 -11.382 28.187 1.00 36.55 ATOM 6030 CG2 ILE 757 49.952 -11.758 27.105 1.00 34.67 ATOM 6031 CG1 ILE 757 50.216 -10.726 29.364 1.00 34.65 ATOM 6032 CD1 ILE 757 49.554 -9.423 29.048 1.00 36.49 ATOM 6033 C ILE 757 52.301 -13.400 27.500 1.00 39.19 ATOM 6034 0 ILE 757 51.709 -14.360 27.025 1.00 39.66 ATOM 6035 N VAL 758 53.492 -12.996 27.061 1.00 42.36 ATOM 6037 CA VAL 758 54.161 -13.645 25.937 1.00 43.15 ATOM 6038 CB VAL 758 55.582 -13.052 25.682 1.00 41.72 ATOM 6039 CG1 VAL 758 56.308 -13.855 24.621 1.00 41.57 ATOM 6040 CG2 VAL 758 55.491 -11.619 *25.229 1.00 40.06 ATOM 6041 C VAL 758 54.299 -15.133 26.231 1.00 47.11 ATOM 6042 0 VAL 758 54.045 -15.971 25.369 1.00 48.62 ATOM 6043 N ALA 759 54.695 -15.446 27.464 1.00 49.64 ATOM 6045 CA ALA 759 54.879 -16.820 27.908 1.00 51.35 ATOM 6046 CB ALA 759 55.423 -16.830 29.317 1.00 50.11 ATOM 6047 C ALA 759 53.568 -17.598 27.850 1.00 54.72 ATOM 6048 0 ALA 759 53.520 -18.77-17 27.348 1.00 58.64 ATOM 6049 N LEU 760 52.496 -16.5983 -28.329 1.00 54.84 ATOM 6051 CA LEU 760 51.194 -17.628 28.343 1.00 55.87 ATOM 6052 CB LEU 760 50.330 -17.034 29.459 1.00 56.85 ATOM 6053 CG LEU 760 50.875 -17.165 30.885 1.00 56.80 ATOM 6054 CD1 LEU 760 49.991 -16.392 31.849 1.00 56.78 ATOM 6055 CD2 LEU 760 50.959 18.631 31.289 1.00 57.78 ATOM 6056 C LEU 760 50.454 -17.546 27.013 1.00 57.36 ATOM 6057 0 LEU 760 49.262 -17.859 26.944 1.00 57.65 ATOM 6058 N THR 761 51.151 -17.134 25.956 1.00 58.71 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 197

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

6060 6061 6062 6064 6065 6066 6067 6068 6069 6070 6071 2676 2679 2682 2685 2688 2691 2694 2697 2700 2703 2706 2709 2712 2715 2718 2721 2724 2727 2730 2733 2736 2739 2742 2745 2748 2751 2754 2757 2760 2763 2766 2769 2772 2775 2778 2781 2784 2787 2790 2793 2796 2799 2802

CA

CB

OG1 CG2

C

0

SG

CG

SD

CE

SG

OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 THR 761 THR 761 THR 761 THR 761 THR 761 THR 761 CYS 1603 MET 534 MET 534 MET 534 CYS 603 TIP3 1 TIP3 2 TIP3 3 TIP3 4 TIP3 5 TIP3 6 TIP3 7 TIP3 8 TIP3 9 TIP3 10 TIP3 11 TIP3 12 TIP3 13 TIP3 14 TIP3 15 TIP3 16 TIP3 17 TIP3 18 TIP3 19 TIP3 20 TIP3 21 TIP3 22 TIP3 23 TIP3 24 TIP3 25 TIP3 26 TIP3 27 TIP3 28 TIP3 29 TIP3 30 TIP3 31 TIP3 32 TIP3 33 TIP3 34 TIP3 35 TIP3 36 TIP3 37 TIP3 38 TIP3 39 TIP3 40 TIP3 41 TIP3 42 TIP3 43 50.541 50.839 50.287 50.213 51.049 52.255 18.474 69.311 69.286 70.539 56.046 71.794 39.750 83.809 83.630 75.073 86.549 51.913 55.093 57.161 52.169 41.110 45.145 64.465 76.944 79.062 83.066 13.957 38.359 5.442 27.008 34.242 20.167 50.794 17.261 27.516 31.574 27.119 28.439 88.706 -2.338 35.086 80.455 5.538 -10.685 29.210 6.195 31.898 19. 915 62.242 21.231 -15.809 40.120 19.583 -17.025 -15.657 -14.610 -15.584 -18.138 -18.295 -8.976 12.109 12.958 12.083 -7.949 25.061 3.992 19.717 20.056 16.616 19.594 11.060 9.421 4.614 4.735 5.543 8.857 -2.607 13.287 17.048 11.657 -9.951 -0.001 2.705 6.166 -1.725 2.428 -11.834 -5.993 7.803 0.146 -12.972 -17.074 14.393 -3.424 -4.130 17.922 3.619 5.290 -8.799 3.150 2.830 2.023 2.604 -7.063 8.838 2.154 11.128 24.630 23.971 24.775 22.590 23.721 23.530 20.202 23.281 24.867 25.804 16.446 2.660 15.898 10.596 7.685 6 .785 9 .502 24.263 22.524 32.443 13.281 22.764 21.555 28.883 23.954 18.200 15.958 0.095 .5.000 19.077 4.885 16.911 27.681 38.045 -1.757 15.070 6.684 27.844 13.203 7.969 11.295 18.836 9.507 10.835 11.288 20.241 13.803 0.154 -3.939 32.859 -3.900 22.610 8.433 -0.045 1.00 1.00 1.00 1.00 1.00 1.00 0.50 0.50 0.50 0 .50 0.50 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 59.04 56.72 56.53 53.81 60.44 61.40 37.82 PRT2 36.25 PRT2 42.66 PRT2 43.27 PRT2 36.47 PRT2 24.53 39.62 28.26 26.19 26.48 33.65 35.55 26.63 29.69 22.61 41.60 36.99 30.17 32.94 51.65 25.12 26.02 37.43 29.46 25.05 52.12 42.69 60.16 25.88 39.33 35.78 43.66 36.44 32.49 49.20 37.83 23.69 29.13 24.40 46.52 31.39 40.17 31.34 39.67 23.55 36.02 60.62 37.85 SSSD/55145. v01 WO 98/07835 PCT/US97/14885 198 ATOM 2805 OH2 TIP3 44 67.056 9.030 17.389 1.00 29.79 ATOM 2808 OH2 TIP3 45 87.772 18.919 18.595 1.00 48.44 ATOM 2811 OH2 TIP3 46 74.584 17.123 4.200 1.00 39.18 ATOM 2814 OH2 TIP3 47 29.365 16.707 10.560 1.00 34.11 ATOM 2817 OH2 TIP3 48 66'.486 6.826 15.051 1.00 32.28 ATOM 2820 OH2 TIP3 49 85.008 21.441 5.731 1.00 23.97 ATOM 2823 OH2 TIP3 50 -4.572 2.912 3.173 1.00 28.05 ATOM 2826 OH2 TIP3 51 19.496 5.141 4.881 1.00 28.88 ATOM 2829 OH2 TIP3 52 67.492 3.490 10.902 1.00 33.57 ATOM 2832 OH2 TIP3 53 34.791 5.413 24.797 1.00 40.16 ATOM 2835 OH2 TIP3 54 34.787 -16.910 13.756 1.00 39.46 ATOM 2838 OH2 TIP3 55 59.972 7.450 27.870 1.00 31.56 ATOM 2841 OH2 TIP3 56 -7.139 -1.696 6.345 1.00 42.00 ATOM 2844 OH2 TIP3 57 54.998 11.953 25.360 1.00 42.05 ATOM 2847 OH2 TIP3 58 68.697 6.686 16.740 1.00 46.12 ATOM 2850 0H2 TIP3 59 73.750 20.885 19.041 1.00 32.26 ATOM 2853 OH2 TIP3 60 3.431 -8.270 -8.218 1.00 31.22 ATOM 2856 OH2 TIP3 61 37.904 10.790 5.612 1.00 33.72 ATOM 2859 OH2 TIP3 62 29.982 -9.545 -1.303 1.00 39.11 ATOM 2862 OH2 TIP3 63 66.918 1.757 8.678 1.00 34.68 ATOM 2865 OH2 TIP3 64 49.117 1.310 12.227 1.00 34.31 ATOM 2868 OH2 TIP3 65 41.246 3.987 29.033 1.00 34 ATOM 2871 OH2 TIP3 66 10.755 -12.957 1.167 1.00 42 14 ATOM 2874 OH2 TIP3 67 -1.184 -4.327 21.439 1.00 37 ATOM 2877 OH2 TIP3 68 30.349 16.267 13.265 1.00 55 23 ATOM 2880 OH2 TIP3 69 8.111 4.362 3.445 1.00 23 88 ATOM 2883 OH2 TIP3 70 73.131 18.780 22.628 1.00 40 ATOM 2886 OH2 TIP3 71 -7.949 -3.409 24.953 1 00 35 49 ATOM 2889 OH2 TIP3 72 66.379 -4.621 28.423 1 00 45.46 ATOM 2892 OH2 TIP3 73 21.506 -20.711 4.815 1 00 52.46 ATOM 2895 OH2 TIP3 74 59.539 -6.865 4.928 1.00 48.87 ATOM 2898 OH2 TIP3 75 16.565 -13.297 -3.008 1 00 51.80 ATOM 2901 OH2 TIP3 76 -15.235 7.385 4.428 1.00 29.13 ATOM 2904 OH2 TIP3 77 32.926 2.785 13.213 1 00 37.62 ATOM 2907 OH2 TIP3 78 0.246 -2.768 10.996 1.00 28.25 ATOM 2910 OH2 TIP3 79 17.495 2.354 5.447 1.00 23.63 ATOM 2913 OH2 TIP3 80 6.336 2.434 21.950 1.00 29.56 ATOM 2916 OH2 TIP3 81 27.374 3.628 6.163 1.00 34.06 ATOM 2919 OH2 TIP3 82 -8.708 6.263 9.522 1.00 30.34 ATOM 2922 OH2 TIP3 83 1.500 -1.935 8.721 1.00 27.61 ATOM 2925 OH2 TIP3 84 -4.825 -3.133 6.984 1.00 33.50 ATOM 2928 OH2 TIP3 85 17.513 2.839 1.966 1.00 24.27 ATOM 2931 OH2 TIP3 86 20.298 3.414 2.920 1.00 26.15 ATOM 2934 OH2 TIP3 87 0.488 -2.158 22.213 1.00 25.95' ATOM 2937 OH2 TIP3 88 19.939 -6.185 -1.553 1.00 19.14 ATOM 2940 OH2 TIP3 89 10.670 -15.654 6.839 1.00 33.36 ATOM 2943 OH2 TIP3 90 4.107 -12.003 11.805 1.00 33 92 ATOM 2946 OH2 TIP3 91 6.238 0.927 -3.342 1.00 23 31 ATOM 2949 OH2 TIP3 92 -13.563 1.438 5.472 1.00 27 86 ATOM 2952 OH2 TIP3 93 15.707 -7.454 0.106 1.00 26 69 ATOM 2955 OH2 TIP3 94 -1.856 -5.393 3.795 1.00 39 91 ATOM 2958 OH2 TIP3 95 12.654 4.928 -4.474 1.00 31 32 ATOM 2961 OH2 TIP3 96 69.774 27.363 2.127 1.00 35 86 ATOM 2964 OH2 TIP3 97 24.636 -13.192 0.040 1.00 48 53 SSSD/55145. v01 WO 98/07835 PCT/US97/14885 199 ATOM 2967 OH2 TIP3 98 60.453 -4.625 33.829 1.00 31.97 ATOM 2970 OH2 TIP3 99 10.513 5.719 3.487 1.00 38.90 ATOM 2973 OH2 TIP3 ibo00 -9.499 -4.011 4.342 1.00 30.61 ATOM 2976 OH2 TIP3 101 73.056 -1.608 10.514 1.00 36.08 ATOM 2979 OH2 TIP3 102 -3.152 5.709 30.608 1.00 29.38 ATOM 2982 OH2 TIP3 103 36.630 0.702 11.792 1.00 47.80 ATOM 29785 OH2 TIP3 104 21.475 6.325 16.924 1.00 24.03 ATOM 2988 OH2 TIP3 105 31.272 0.656 19.432 1.00 53.74 ATOM 2991 OH2 TIP3 106 5.620 -8.417 22.266 1.00 51.90 ATOM 2994 OH2 TIP3 107 -13.144 8.294 17.464 1.00 35.23 ATOM 2997 OH2 TIP3 108 26.680 -10.556 -1.042 1.00 27.83 ATOM 3000 OH2 TIP3 109 24.149 1.846 18.172 1.00 30.90 ATOM 3003 OH2 TIP3 110 -1.943 12.643 3.558 1.00 33.82 ATOM 3006 OH2 TIP3 111 59.560 13.617 33.196 1.00 54.79 ATOM 3009 OH2 TIP3 112 4.351 -10.740 1.991 1.00 37.96 ATOM 3012 OH2 TIP3 113 8.396 2.913 0.958 1.00 29.64 ATOM 3015 OH2 TIP3 114 75.905 1.753 25.812 1.00 38.73 ATOM 3018 OH2 TIP3 115 48.783 15.535 14.189 1.00 35.24 ATOM 3021 OH2 TIP3 116 2.419 -11.312 9.146 1.00 32.85 ATOM 3024 OH2 TIP3 117 83.014 26.360 12.964 1.00 41.83 ATOM 3027 OH2 TIP3 118 8.761 -6.579 -3.252 1.00 42.78 ATOM 3030 OH2 TIP3 119 -8.417 4.493 4.305 1.00 28.32 ATOM 3033 OH2 TIP3 120 7.908 -13.690 8.639 1.00 33.73 ATOM 3036 OH2 TIP3 121 51.437 6.329 10.373 1.00 31.72 ATOM 3039 OH2 TIP3 122 20.660 3.686 15.591 1.00 32.37 ATOM 3042 OH2 TIP3 123 73.039 3.790 20.450 1.00 35.80 ATOM 3045 OH2 TIP3 124 5.155 -11.467 22.590 1.00 45.12 ATOM 3048 OH2 TIP3 125 34.172 2.412 16.-576 1.00 41.90 ATOM 3051 OH2 TIP3 126 9.597 -11.905 7.083 1.00 24.83 ATOM 3054 OH2 TIP3 127 8.276 3.860 -1.622 1.00 35.46 ATOM 3057 OH2 TIP3 128 66.282 5.755 12.352 1.00 35.43 ATOM 3060 OH2 TIP3 129 7.377 6.932 2.982 1.00 40.68 ATOM 3063 OH2 TIP3 130 35.832 -1.778 0.201 1.00 34.99 ATOM 3066 OH2 TIP3 131 44.781 10.362 11.064 1.00 42.31 ATOM 3069 OH2 TIP3 132 27.790 -12.638 18.958 1.00 58.71 ATOM 3072 OH2 TIP3 133 45.221 11.540 21.428 1.00 36.75 ATOM 3075 OH2 TIP3 134 57.560 -10.846 14.099 1.00 52.90 ATOM 3078 OH2 TIP3 135 -3.354 15.001 16.515 1.00 37.81 ATOM 3081 OH2 TIP3 136 85.717 11.251 9.062 1.00 35.18 ATOM 3084 OH2 TIP3 137 12.951 -2.469 2.075 1.00 22.07 ATOM 3087 OH2 TIP3 138 75.645 3.486 20.527 1.00 38.01 ATOM 3090 OH2 TIP3 139 13.237 7.412 -2.649 1.00 33.50 ATOM 3093 OH2 TIP3 140 11.262 -9.970 0.974 1.00 26.14 ATOM 3096 OH2 TIP3 141 59.480 10.772 14.098 1.00 52.08 ATOM 3099 OH2 TIP3 142 13.869 -16.121 3.919 1.00 40.06 ATOM 3102 OH2 TIP3 143 -6.407 3.413 16.641 1.00 44.38 ATOM 3105 OH2 TIP3 144 25.667 -12.645 3.411 1.00 48.28 ATOM 3108 OH2 TIP3 145 -16.282 10.641 6.423 1.00 40.94 ATOM 3111 OH2 TIP3 146 86.637 12.861 7.008 1.00 39.45 ATOM 3114 OH2 TIP3 147 32.082 -4.569 1.892 1.00 27.35 ATOM 3117 OH2 TIP3 148 44.809 7.627 11.670 1.00 35.65 ATOM 3120 1OH2 TIP3 149 80.693 12.459 16.523 1.00 37.21 ATOM 3123 OH2 TIP3 150 2.941 -7.118 -1.805 1.00 38.43 ATOM 3126 OH2 TIP3 151 31.794 -6.086 20.704 1.00 42.80 SSSD/55145.vOl WO 98/07835 PCT/US97/14885 200 ATOM 3129 OH2 TIP3 152 74.770 -2.683 12.398 1.00 40.40 ATOM 3132 OH2 TIP3 153 7.731 6.640 -1.037 1.00 35.61 ATOM 3135 OH2 TIP3 154 71.617 5.599 21.838 1.00 40.14 ATOM 3138 OH2 TIP3 155 68.113 -4.968 8.886 1.00 34.38 ATOM 3141 OH2 TIP3 156 0.042 -9.364 7.055 1.00 33.08 ATOM 3144 OH2 TIP3 157 68.020 18.352 10.995 1.00 34.76 ATOM 3147 OH2 TIP3 158 3.795 8.550 4.533 1.00 34.69 ATOM 3150 OH2 TIP3 159 52.106 11.746 18.410 1.00 40.06 ATOM 3153 OH2 TIP3 160 6.414 3.927 16.889 1.00 37.07 ATOM 3156 OH2 TIP3 161 -10.282 6.603 4.715 1.00 38.48 ATOM 3159 OH2 TIP3 162 76.410 1.681 -0.781 1.00 42.87 ATOM 3162 OH2 TIP3 163 9.910 -12.046 17.157 1.00 32.79 ATOM 3165 OH2 TIP3 164 33.983 14.219 18.191 1.00 37.35 ATOM 3168 OH2 TIP3 165 2.330 -7.952 16.978 1.00 44.25 ATOM 3171 OH2 TIP3 166 29.701 1.780 5.987 1.00 39.86 ATOM 3174 OH2 TIP3 167 32.494 -17.319 11.798 1.00 38.46 ATOM 3177 OH2 TIP3 168 42.107 17.932 10.978 1.00 44.83 ATOM 3180 OH2 TIP3 169 87.822 10.537 5.568 1.00 54.30 ATOM 3183 OH2 TIP3 170 70.261 -4.143 25.064 1.00 44.75 ATOM 3186 OH2 TIP3 171 77.519 5.882 23.891 1.00 42.67 ATOM 3189 OH2 TIP3 172 -0.921 -8.166 4.521 1.00 45.91 ATOM 3192 OH2 TIP3 173 34.213 15.329 1.478 1.00 40.10 ATOM 3195 OH2 TIP3 174 -9.647 7.731 7.383 1.00 35.63 ATOM 3198 OH2 TIP3 175 11.619 5.799 7.440 1.00 36.36 ATOM 3201 OH2 TIP3 176 -8.709 13.964 13.507 1.00 51.97 ATOM 3204 OH2 TIP3 177 31.770 3.376 18.354 1.00 46.26 ATOM 3207 OH2 TIP3 178 -8.494 9.789 24.269 1.00 50.98 ATOM 3210 OH2 TIP3 179 -1.234 -6.253 15.622 1.00 38.47 ATOM 3213 OH2 TIP3 180 80.252 0.887 15.691 .1.00 39.48 ATOM 3216 OH2 TIP3 181 67.248 20.272 -1.555 1.00 48.22 ATOM 3219 OH2 TIP3 182 -0.566 4.367 1.362 1.00 39.84 ATOM 3222 OH2 TIP3 183 0.120 6.523 2.615 1.00 33.11 ATOM 3225 OH2 TIP3 184 -1.496 8.789 1.237 1.00 41.03 ATOM 3228 OH2 TIP3 185 -5.143 9.130 2.236 1.00 40.47 ATOM 3231 OH2 TIP3 186 -7.275 10.106 3.833 1.00 40.55 ATOM 3234 OH2 TIP3 187 2.717 7.275 0.769 1.00 44.67 ATOM 3237 OH2 TIP3 188 5.176 10.645 8.459 1.00 34.48 ATOM 3240 OH2 TIP3 189 63.822 12.690 22.883 1.00 41.88 ATOM 3243 OH2 TIP3 190 79.109 1.028 18.201 1.00 46.40 ATOM 3246 OH2 TIP3 191 59.332 -11.681 7.236 1.00 63.45 ATOM 3249 OH2 TIP3 192 13.967 -1.218 -4.268 1.00 34.79 ATOM 3252 OH2 TIP3 193 59.444 2.867 33.368 1.00 41.00 ATOM 3255 OH2 TIP3 194 32.024 13.487 19.852 1.00 53.61 ATOM 3258 OH2 TIP3 195 72.101 16.218 22.802 1.00 44.03 ATOM 3261 OH2 TIP3 196 0.987 -8.546 14.474 1.00 41.38 ATOM 3264 OH2 TIP3 197 -0.491 5.461 30.372 1.00 38.51 ATOM 3267 OH2 TIP3 198 61.179 6.795 11.905 1.00 41.77 ATOM 3270 OH2 TIP3 199 -1.365 -4.128 27.656 1.00 50.98 ATOM 3273 OH2 TIP3 200 81.440 15.558 17.262 1.00 44.47 ATOM 3276 OH2 TIP3 201 -17.491 4.116 23.873 1.00 50.58 ATOM 3279 OH2 TIP3 202 27.546 10.513 14.499 1.00 39.06 ATOM 3282 OH2 TIP3 203 34.992 4.513 27.719 1.00 49.89 ATOM 3285 OH2 TIP3 204 -3.486 -4.591 9.171 1.00 49.53 ATOM 3288 OH2 TIP3 205 42.799 7.848 22.320 1.00 43.50 SSSD/55145. v01 WO 98/07835 PCT/US97/14885 201 ATOM 3291 OH2 TIP3 206 52.728 11.884 21.811 1.00 39.98 ATOM 3294 OH2 TIP3 207 26.706 14.069 19.833 1.00 46.68 ATOM 3297 OH2 TIP3 208 -7.154 8.907 6.444 1.00 42.83 ATOM 3300 OH2 TIP3 209 86.648 5.606 16.034 1.00 51.15 ATOM 3303 OH2 TIP3 210 54.879 15.840 20.379 1.00 50.23 ATOM 3306 OH2 TIP3 211 51.417 19.473 22.691 1.00 48.35 ATOM 3309 OH2 TIP3 212 20.102 6.924 7.085 1.00 38.15 ATOM 3312 OH2 TIP3 213 28.991 1.941 -3.570 1.00 47.39 ATOM 3315 OH2 TIP3 214 26.505 2.386 -4.633 1.00 46.48 ATOM 3318 OH2 TIP3 215 36.482 2.810 18.521 1.00 46.26 ATOM 3321 OH2 TIP3 216 16.941 -20.504 14.128 1.00 49.74 ATOM 3324 OH2 TIP3 217 28.572 -14.448 6.157 1.00 49.13 ATOM 3327 OH2 TIP3 218 31.380 1.471 -1.998 1.00 43.02 ATOM 3330 OH2 TIP3 219 10.065 -16.338 15.455 1.00 42.75 ATOM 3333 OH2 TIP3 220 7.350 -11.974 5.652 1.00 55.35 ATOM 3336 OH2 TIP3 221 -12.328 14.547 10.986 1.00 51.29 ATOM 3339 OH2 TIP3 222 11.186 9.609 -1.388 1.00 37.68 ATOM 3342 OH2 TIP3 223 11.389 12.276 -1.400 1.00 46.93 ATOM 3345 OH2 TIP3 224 34.202 13.069 -1.161 1.00 41.79 ATOM 3348 OH2 TIP3 225 31.303 17.822 7.853 1.00 48.21 ATOM 3351 OH2 TIP3 226 36.875 11.804 -2.106 1.00 59.03 ATOM 3354 OH2 TIP3 227 35.134 3.048 11.020 1.00 50.41 ATOM 3357 OH2 TIP3 228 63.950 13.409 26.627 1.00 43.40 ATOM 3360 OH2 TIP3 229 36.367 6.116 15.221 1.00 57.79 ATOM 3363 OH2 TIP3 230 90.606 4.355 6.342 1.00 47.53 ATOM 3366 OH2 TIP3 231 50.038 -11.673 10.767 1.00 56.90 ATOM 3369 OH2 TIP3 232 60.196 -10.144 16.590 1.00 51.61 ATOM 3372 OH2 TIP3 233 18.021 -21.179 7.008 1.00 49.93 ATOM 3375 OH2 TIP3 234 66.236 -1.218 30.583 1.00 39.55 ATOM 3378 OH2 TIP3 235 74.959 18.928 20.659 1.00 38.04 ATOM 3381 OH2 TIP3 236 -2.816 10.082 3.187 1.00 49.31 ATOM 3384 OH2 TIP3 237 5.894 -3.410 25.289 1.00 35.55 ATOM 3387 OH2 TIP3 238 35.784 6.047 12.543 1.00 41.96 ATOM 3390 OH2 TIP3 239 -5.400 16.537 14.180 1.00 43.13 ATOM 3393 OH2 TIP3 240 46.589 -11.622 26.970 1.00 43.71 ATOM 3396 OH2 TIP3 241 6.199 6.592 13.797 1.00 46.51 ATOM 3399 OH2 TIP3 242 -3.777 -5.158 20.907 1.00 42.08 ATOM 3402 OH2 TIP3 243 1.969 -3.711 -0.282 1.00 37.38 ATOM 3405 OH2 TIP3 244 86.200 11.629 22.877 1.00 56.51 ATOM 3408 OH2 TIP3 245 10.557 7.565 5.514 1.00 47.58 ATOM 3411 OH2 TIP3 246 4.802 8.149 2.136 1.00 50.70 ATOM 3414 OH2 TIP3 247 64.590 -8.128 20.596 1.00 43.65 ATOM 3417 OH2 TIP3 248 11.346 -17.840 13.283 1.00 47.64 ATOM 3420 OH2 TIP3 249 42.116 -6.808 14.953 1.00 53.79 ATOM 3423 OH2 TIP3 250 2.745 054 22.128 1.00 60.88 ATOM 3426 OH2 TIP3 251 71.999 1.177 -2.124 1.00 47.90 ATOM 3429 OH2 TIP3 252 50.328 -3.210 33.068 1.00 57.01 ATOM 3435 OH2 TIP3 253 57.838 9.337 11.631 1.00 52.55 ATOM 3438 OH2 TIP3 254 43.373 20.489 30.490 1.00 51.97 ATOM 3441 OH2 TIP3 255 67.045 16.529 15.793 1.00 49.02 ATOM 3444 OH2 TIP3 256 87..509 21.566 5.114 1.00 54.21 ATOM 3447 OH2 TIP3 257- 21.060 10.052 -9.215 1.00 60.32 ATOM 3450 OH2 TIP3 258 11.827 2.450 27.951 1.00 54.26 ATOM 3453 OH2 TIP3 259 64.788 -0.418 3.563 1.00 50.94 SSSD/55145. v01 WO 98/07835 PTU9/48 PCT/US97/14885- 202 ATOM 3456 0H2 TIP3 260 ATOM 3459 0112 TIP3 261 ATOM 3462 0112 TIP3 262 ATOM 3465 0112 TIP3 263 ATOM 3468 OH2 TIP3 264 ATOM 3471 0112 TIP3 265 71.859 28.473 7.950 1.00 62.81 25.605 -8.106 27.287 1.00 52.81 -18.804 10.886 12.628 1.00 55.25 30.652 11.349 16.201 1.00 50.40 22.350 -16.098 -2.742 1.00 53.27 29.720 9.106 18.465 1.00 57.23 SSSD/55145. vOl WO 98107835 PCTIUS97/14885 203 TABLE 2 Atom No.

Atom A. A A.A Type Type No.

Z 0CC B

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

I

N

CA

CB

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

CD

0E1 0E2

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

GLU

GLU

GLU

GLU

GLU

LEtJ

LEU

LEU

LEU

LEU

LEU

LEU

LETJ

PRO

PRO

PRO

PRO

PRO

PRO

PRO

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ARG

ARG

ARG

ARG

1464 1464 1464 1464 1464 1465 1465 1465 1465 1465 1465 1465 1465 1466 1466 1466 1466 1466 1466 1466 1467 1467 1467 1467 1467 1467 1467 1467 1467 1468 1468 1468 1468 1468 1468 1468 1468 1469 1469 1469 1469 1469 1469 1469 1470 1470 1470 1470 -13.425 -12.536 11. 383 -11.998 -12.134 11. 406 -10.871 -10.102 -8.608 -8.338 -8.064 -12.000 -13.101 -11.760 -10.535 -12.740 -12.134 -10.658 -12.906 -11.929 -14.145 -14.428 -15.931 -16.565 -17.998 -18.474 -18.650 -13.972 -14.061 -13.473 -13.024 11. 507 -11.025 -11.689 -13.394 -12.618 -14.569 -15.482 -15.100 -16.352 -16.783 -14.146 -14.272 -13.198 -12.240 11. 386 -12.107 16.769 16.852 17.829 15.478 15. 076 14.749 13.424 12 .844 13 .123 14,~592 12.286 12 .475 12.577 11.580 11.534 10.591 10.111 10.213 9.441 8.936 9.044 7. 9-60 7.904 9.238 9.093 7.949 10.120 6 .628 6.426 5.731 4.404 4 358 3.002 1.958 2.974 3.441 3.209 2.819 2.963 1.863 1.331 2.496 0.731 0.135 0.442 -0.636 -0.860 -1.437 8 .973 7.821 8.085 7.427 6 .274 8.368 8 .062 9.249 9.384 9.663 10.512 7.700 8 .239 6 .732 5. 913 6.269 4.959 5.220 7.261 7.816 7.500 8 .427 8.712 9.105 9.606 9.741 9.879 7.837 6 .620 8.689 8.256 7.992 7.440 7.603 6.835 9.369 10.302 9.247 8.097 10.220 9.510 8 .656 10.590 11.654 9.704 9.917 8.660 7.448 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 61.21 59.70 60.05 57.11 59.75 52 .21 46.72 44 .98 46.11 51.13 4.99 44 .16 44.04 42 .53 41.30 41.16 41.48 41.30 41.31 41.05 41.02 42 .42 47. 98 52 .79 54.21 58 55.90 40.93 44 .32 35.10 31.82 30.65 29.93 29.63 33.63 31.81 31.91 29.68 28.33 31.80 32 .51 27.41 30.44 30.02 31.06 31.86 31.36 33 .08 SSSD/55145. vOl WO 98/07835 PCTIUS971485 204 ATOM 54 CD ARG 1470 -11.148 -1.588 6.248 1.00 31.08 ATOM 55 NE ARG 1470 -10.540 -0.310 5.891 1.00 34.36 ATOM 57 CZ ARG 1470 -9.656 -0.135 4.919 1.00 33.32 ATOM 58 NH1 ARG 1470 -9.260 -1.164 4.185 1.00 35.90 ATOM 61 NH2 ARG 1470 -9.155 1.074 4.687 1.00 32.79 ATOM 64 C ARG 1470 -11.290 -0.436 11.095 1.00 32.68 ATOM 65 0 ARG 1470 -10.820 -1.410 11.683 1.00 33.43 ATOM 66 N TRP 1471 -11.031 0.814 11.456 1.00 31.84 ATOM 68 CA TRP 1471 -10.063 1.090 12.505 1.00 31.17 ATOM 69 CB TRP 1471 -8.816 1.677 11.850 1.00 30.15 ATOM 70 CG TRP 1471 -8.173 0.725 10.941 1.00 29.54 ATOM 71 CD2 TRP 1471 -7.288 -0.329 11.315 1.00 31.07 ATOM 72 CE2 TRP 1471 -6.913 -0.992 10.132 1.00 34.41 ATOM 73 CE3 TRP 1471 -6.762 -0.768 12.536 1.00 29.46 ATOM 74 CD1 TRP 1471 -8.309 0.660 9.587 1.00 30.20 ATOM 75 NEl TRP 1471 -7.557 -0.371 9.089 1.00 33.09 ATOM 77 CZ2 TRP 1471 -6.042 -2.085 10.135 1.00 31.68 ATOM 78 CZ3 TRP 1471 -5.897 -1.853 12.540 1.00 29.65 ATOM 79 CH2 TRP 1471 -5.541 -2.494 11.347 1.00 30.18 ATOM 80 C TRP 1471 -10.477 2.019 13.620 1.00 29.94 ATOM 81 0 TRP 1471 -9.782 2. 108 14.631 1.00 30.00 ATOM 82 N GLU 1472 -11.573 2.737 13.416 1.00 29.06 ATOM 84 CA GLU 1472 -12.051 3.706 14.380 1.00 28.62 ATOM 85 CB GLU 1472 -13.312 4.386 13.849 1.00 29.16 ATOM 86 CG GLU 1472 -13.641 5.733 14.529 1.00 30.74 ATOM 87 CD GLU 1472 -12.676 6.848 14.156 1.00 30.05 ATOM 88 OE1 GLU 1472 -12.090 6.799 13.057 1.00 31.32 ATOM 89 OE2 GLU 1472 -12.511 7.784 14.961 1.00 30.26 ATOM 90 C GLU 1472 -12.327 3.159 15.767 1.00 28.70 ATOM 91 0 GLU 1472 -12.969 2.125 15.916 1.00 31.01 ATOM 92 N LEU 1473 -11.810 3.842 16.781 1.00 27.38 ATOM 94 CA LEU 1473 -12.054 3.451 18.161 1.00 29.61 ATOM 95 CB LEU 1473 -10.763 3.073 18.899 1.00 28.56 ATOM 96 CG LEU 1473 -10.923 2.756 20.403 1.00 30.06 ATOM 97 CD1 LEU 1473 -11.485 1.354 20.639 1.00 28.42 ATOM 98 CD2 LEU 1473 -9.595 2.876 21.115 1.00 28.15 ATOM 99 C LEU 1473 -12.617 4.714 18.764 1.00 31.81 ATOM 100 0 LEU 1473 -12.179 5.814 18.407 1.00 33.00 ATOM 101 N PRO 1474 -13.670 4.591 19.596 1.00 31.45 ATOM 102 CD PRO 1474 -14.488 3.400 19.859 1.00 31.72 ATOM 103 CA PRO 1474 -14.261 5.774 20.226 1.00 31.23 ATOM 104 CB PRO 1474 -15.400 5.176 21.048 1.00 29.01 ATOM 105 CG PRO 1474 -15.815 4.005 20.247 1.00 29.09 ATOM 106 C PRO 1474 -13.217 6.444 21.120 1.00 33.36 ATOM 107 0 PRO 1474 -12.447 5.765 21.808 1.00 36.40 ATOM 108 N ARG 1475 -13.188 7.770 21.112 1.00 33.67 ATOM 110 CA ARG 1475 -12.228 8.498 21.924 1.00 33.96 ATOM 111 CB ARG 1475 -12.433 9.991 21.735 1.00 35.31 ATOM 112 CG ARG 1475 -12.134 10.405 20.333 1.00 40.10 ATOM 113 CD ARG 1475 -12.060 11.906 20.145 1.00 42.98 ATOM 114 NE ARG 1475 -11.785 12.194 18.737 1.00 42.91 ATOM 116 CZ ARG 1475 -10.578 12.443 18.253 1.00 41.30 ATOM 117 NH1 ARG 1475 -9.529 12.467 19.064 1.00 41.88 ATOM 120 NH2 ARG 1475 -10.413 12.567 16.943 1.00 40.98 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 205 ATOM 123 C ARC 1475 -12.278 8.142 23.404 1.00 35.88 ATOM 124 0 ARC 1475 -11.240 8.046 24.061 1.00 37.10 ATOM 125 N ASP 1476 -13.479 7.920 23.928 1.00 36.47 ATOM 127 CA ASP 1476 -13.632 T. 581 25.335 1.00 37.24 ATOM 128 CB ASP 1476 -15.112 7.629 25.741 1.00 39.66 ATOM 129 CC ASP 1476 -15.930 6.480 25.163 1.00 42.38 ATOM 130 ODi ASP 1476 -15.438 5.706 24.322 1.00 47.52 ATOM 131 0D2 ASP 1476 -17.098 6.349 25.568 1.00 48.06 ATOM 132 C ASP 1476 -13.023 6.232 25.724 1.00 36.93 ATOM 133 0 ASP 1476 -13.034 5.856 26.898 1.00 40.09 ATOM 134 N ARG 1477 -12.564 5.475 24.732 1.00 34.34 ATOM 136 CA ARC 1477 -11.961 4.171 24.993 1.00 32.47 ATOM 137 CB ARC 1477 -12.269 3.212 23.852 1.00 31.59 ATOM 138 CG ARC 1477 -13.716 2.939 23.640 1.00 29.66 ATOM 139 CD ARC 1477 -14.314 2.342 24.875 1.00 30.65 ATOM 140 NE ARG- 1477 -14.498 3.342 25.918 1.00 31.37 ATOM 142 CZ ARG 1477 -14.822 3.055 27.174 1.00 32.81 ATOM 143 NH1 ARC 1477 -15.002 1.794 27.549 1.00 33.92 ATOM 146 NH2 ARC 1477 -14.950 4.025 28.062 1.00 31.74 ATOM 149 C ARG 1477 -10.452 4.266 25.153 1.00 33.13 ATOM 150 0 ARC 1477 -9.777 3.281 25.445 1.00 33.55 ATOM 151 N LEU 1478 -9.923 5.466 24.984 1.00 34.43 ATOM 153 CA LEU 1478 -8.493 5.663 25.076 1.00 35.68 ATOM 154 CB LEU 1478 -8.008 6.350 23.790 1.00 34.98 ATOM 155 CC LEU 1478 -6.581 6.137 23.284 1.00 31.11 ATOM 156 CD1 LEU 1478 -6.280 4.650 23.161 1.00 26.62 ATOM 157 CD2 LEU 1478 -6.428 6.839 21.940 1.00 28.80 ATOM 158 C LEU 1478 -8.158 6.505 26.295 1.00 36.21 ATOM 159 0 LEU 1478 -8.501 7.688 26.361 1.00 39.67 ATOM 160 N VAL 1479 -7.558 5.878 27.293 1.00 35.42 ATOM 162 CA VAL 1479 -7.156 6.599 28.491 1.00 35.80 ATOM 163 CB VAL 1479 -7.269 5.707 29.742 1.00 36.29 ATOM 164 CG1 VAL 1479 -7.017 6.527 30.983 1.00 37.23 ATOM 165 CG2 VAL 1479 -8.650 5.059 29.812 1.00 34.41 ATOM 166 C VAL 1479 -5.704 7.046 28.244 1.00 35.68 ATOM 167 0 VAL 1479 -4.764 6.246 28.319 1.00 33.45 ATOM 168 N LETI 1480 -5.538 8.315 27.885 1.00 38.15 ATOM 170 CA LEU 1480 -4.213 8.860 27.584 1.00 42.61 ATOM 171 CB LEU 1480 -4.332 10.205 26.857 1.00 39.14 ATOM 172 CG LEU 148.0 -4.969 10.179 25.460 1.00 38.44 ATOM 173 CDi LEU 1480 -4.901 11.579 24.879 1.00 39.39 ATOM 174 CD2 LEtJ 1480 -4.263 9.194 24.533 1.00 36.86 ATOM 175 C LEU 1480 -3.274 8.970 28.783 1.00 46.37 ATOM 176 0 LEU 1480 -3.659 9.445 29.850 1.00 48.86 ATOM 177 N GLY 1481 -2.033 8.537 28.594 1.00 47.13 ATOM 179 CA CLY 1481 -1.081 8.573 29.678 1.00 48.19 ATOM 180 C GLY 1481 0.163 9.388 29.425 1.00 50.27 ATOM 181 0 GLY 1481 0.152 10.367 28.675 1.00 51.19 ATOM 182 N LYS 1482 1.240 8.965 30.078 1.00 50.93 ATOM 184 CA LYS 1482 2.543 9.606 30.007 1.00 50.94 ATOM 185 CB LYS 1482 3.509 8.866 30.933 1.00 50.41 ATOM 186 CC LYS 1482 4.971 9.026 30.567 1.00 51.87 ATOM 187 CD LYS 1482 5.810 7.874 31.087 1.00 53.49 ATOM 188 CE LYS 1482 5.390 6.542 30.478 1.00 50.77 SSSD/551 45. vOl WO 98/07835 PCTIUS97/14885 206 ATOM 189 NZ LYS 1482 6.251 5.433 30.986 1.00 49.92 ATOM 193 C LYS 1482 3.145 9.676 28.609 1.00 52.31 ATOM 194 0 LYS 1482 3.115 8.700 27.851 1.00 52.30 ATOM 195 N PRO 1483 3.706 10.838 28.250 1.00 534 ATOM 196 CD PRO 1483 3.667 12.105 28.997 1.00 54.19 ATOM 197 CA PRO 1483 4.326 11.021 26.937 1.00 54.10 ATOM 198 -CB PRO 1483 4.772 12.480 26.976 1.00 54.25 ATOM 199 CG PRO 1483 3.772 13.118 27.895 1.00 55.30 ATOM 200 C PRO 1483 5.535 10.096 26.827 1.00 54.72 ATOM 201 0 PRO 1483 6.343 10.017 27.751 1.00 53.48 ATOM 202 N LEU 1484 5.619 9.351 25.731 1.00 57.05 ATOM 204 CA LEU 1484 6.739 8.447 25.503 1.00 59.26 ATOM 205 CB LEU 1484 6.307 7.241 24.669 1.00 59.35 ATOM 206 CG LEU 1484 5.391 6.216 25.343 1.00 60.87 ATOM 207 CD1 LEU 1484 4.975 5.161 24.329 1.00 57.14 ATOM 208 CD2 LEU 1484 6.081 5.571 26.55-1 1.00 59.79 ATOM 209 C LEU 1484 7.847 9.194 24.778 1.00 61.30 ATOM 210 0 LEU 1484 8.980 8.720 24.701 1.00 62.17 ATOM 211 N GLY 1485 7.494 10.351 24.220 1.00 63.75 ATOM 213 CA GLY 1485 8.456 11.173 23.507 1.00 66.33 ATOM 214 C GLY 1485 8.081 11.412 22.054 1.00 67.79 ATOM 215 0 GLY 1485 6.918 11.653 21.727 1.00 69.61 ATOM 216 N GLN 1491 4.615 13.762 18.385 1.00 58.26 ATOM 218 CA GLN 1491 4.353 13.353 19.762 1.00 57.98 ATOM 219 CB GLN 1491 3.476 14.379 20.468 1.00 61.80 ATOM 220 CG GLN 1491 3.134 14.034 21.920 1.00 70.31 ATOM 221 CD GLN 1491 2.019 14.911 22.482 1.00 75.91 ATOM 222 OE1 GLN 1491 1.355 15.636 21.748 1.00 77.85 ATOM 223 NE2 GLN 1491 1.820 14.832 23.788 1.00 78.30 ATOM 226 C GLN 1491 3.709 11.965 19.881 1.00 54.67 ATOM 227 0 GLN 1491 2.701 11.669 19.222 1.00 54.91 ATOM 228 N VAL 1492 4.305 11.125 20.729 1.00 50.04 ATOM 230 CA VAL 1492 3.825 9.763 20.988 1.00 44.93 ATOM 231 CB VAL 1492 4.861 8.705 20.583 1.00 42.65 ATOM 232 CG1 VAL 1492 4.378 7.325 20.958 1.00 39.71 ATOM 233 CG2 VAL 1492 5.119 8.766 19.099 1.00 40.98 ATOM 234 C VAL 1492 3.584 9.661 22.490 1.00 43.43 ATOM 235 0 VAL 1492 4.451 10.029 23.28§ 1.00 43.43 ATOM 236 N VAL 1493 2.400 9.212 22.888 1.00 41.13 ATOM 238 CA VAL 1493 2.107 9.080 24.304 1.00 38.77 ATOM 239 CB VAL 1493 1.052 10.133 24.782 1.00 36.35 ATOM 240 CG1 VAL 1493 1.410 11.508 24.287 1.00 36.06 ATOM 241 CG2 VAL 1493 -0.329 9.755 24.339 1.00 37.64 ATOM 242 C VAL 1493 1.589 7.693 24.619 1.00 37.77 ATOM 243 0 VAL 1493 0.948 7.058 23.783 1.00 38.88 ATOM 244 N LEU 1494 1.949 7.187 25.790 1.00 36.24 ATOM 246 CA LETJ 1494 1.468 5.880 26.205 1.00 35.92 ATOM 247 CB LEU 1494 2.252 5.383 27.429 1.00 35.41 ATOM 248 CG LEU 1494 1.886 4.009 28.004 1.00 36.21 ATOM 249 CD1 LEU 1494 1.927 2.931 *.26.924 1.00 33.60 ATOM 250 CD2 LEU 1494 2.835 670 .29.145 1.00 36.03 ATOM 251 C LEU 1494 -0.010 6.095 26.564 1.00 35.27 ATOM 252 0 LET) 1494 -0.425 7.215 26.887 1.00 34.35 ATOM 253 N ALA 1495 -0.807 5.043 26.468 1.00 34.93 145. vOl WO 98/07835 PCTIUS97/14885 207 ATOM 255 CA ALA 1495 -2.220 5.145 26.768 1.00 34.44 ATOM 256 CB ALA 1495 -2.955 5.794 25.616 1.00 35.29 ATOM 257 C ALA 1495 -2.781 3.770 27.018 1.00 34.59 ATOM 258 0 'ALA 1495 -2.128 2.766 26.748 1.00 35.52 ATOM 259 N GLU 1496 -3.996 3.723 27.536 1.00 36.64 ATOM 261 CA GLU 1496 -4.652 2.462 27.806 1.00 37.57 ATOM 262 CB GLU 1496 -5.000 2.354 29.287 1.00 38.97 ATOM 263 CG GLU 1496 -3.769 2.304 30.185 1.00 41.79 ATOM 264 CD GLU 1496 -4.110 2.475 31.645 1.00 43.65 ATOM 265 OE1 GLU 1496 -4.408 3.617 32.036 1.00 42.97 ATOM 266 0E2 GLU 1496 -4.086 1.475 32.398 1.00 46.65 ATOM 267 C GLU 1496 -5.896 2.404 26.943 1.00 38.50 ATOM 268 0 GLU 1496 -6.660 3.371 26.867 1.00 40.28 ATOM' 269 N ALA 1497 -6.051 1.301 26.223 1.00 37.34 ATOM 271 CA ALA 1497 -7.194 1.131 25.352 1.00 37.42 ATOM 272 CB ALA 1497 -6.743 0.625 23.985 1.00 35.92 ATOM 273 C ALA 1497 -8.146 0.148 26.000 1.00 36.77 ATOM 274 0 ALA 1497 -7.759 -0.977 26.323 1.00 35.74 ATOM 275 N ILE 1498 -9.354 0.616 26.291 1.00 37.03 ATOM 277 CA ILE 1498 -10.378 -0.224 26.896 1.00 36.80 ATOM 278 CB ILE 1498 -11.372 0.612 27.728 1.00 34.53 ATOM 279 CG2 ILE 1498 -12.373 -0.290 28.425 1.00 34.59 ATOM 280 CGl ILE 1498 -10.640 1.438 28.778 1.00 31.97 ATOM 281 CD1 ILE 1498 -11.552 2.344 29.541 1.00 31.12 ATOM 282 C ILE 1498 -11.126 -0.807 25.709 1.00 38.72 ATOM 283 0 ILE 1498 -11.647 -0.066 24.879 1.00 37.74 ATOM 284 N GLY 1499 -11.137 -2.126 25.590 1.00 40.98 ATOM 286 CA GLY 1499 -11.839 -2.728 24.482 1.00 44.64 ATOM 287 C GLY 1499 -10.931 -3.115 23.332 1.00 48.45 ATOM 288 0 GLY 1499 -10.260 -4.147 23.401 1.00 51.92 ATOM 289 N LEU 1500 -10.877 -2.269 22.303 1.00 47.,87 ATOM 291 CA LEU 1500 -10.076 -2.530 21.102 1.00 46.80 ATOM 292 CB LEU 1500 -8.594 -2.770 21.434 1.00 45.37 ATOM 293 CG LEU 1500 -7.543 -1.661 21.293 1.00 44.84 ATOM 294 CD1 LEU 1500 -6.174 -2.290 21.450 1.00 43.33 ATOM 295 CD2 LEU 1500 -7.623 -0.959 19.948 1.00 40.43 ATOM 296 C LEU 1500 -10.631 -3.737 20.349 1.00 45.63 ATOM 297 0 LEU 1500 -10.797 -4.823 20.915 1.00 44.42 ATOM 298 N PRO 1505 -13.569 -5.910 25.549 1.00 52.13 ATOM 299 CD PRO 1505 -14.316 -7.170 25.398 1.00 *54.09 ATOM 300 CA PRO 1505 -14.451 -4.828 25.999 1.00 50.46 ATOM 301 CB PRO 1505 -15.841 -5.455 25.891 1.00 49.86 ATOM 302 CG PRO 1505 -15.586 -6.898 26.193 1.00 52.17 ATOM 303 C PRO 1505 -14.136 -4.370 27.422 1.00 47.75 ATOM 304 0 PRO 1505 -14.148 -3.180 -27.710 1.00 47.93 ATOM 305 N ASN 1506 -13.778 -5.313 28.285 1.00 46.20 ATOM 307 CA ASN 1506 -13.458 -4.986 29.666 1.00 49.52 ATOM 308 CB ASN 1506 -14.310 -5.829 30.612 1.00 52.42 ATOM 309 CG ASN 1506 -15.788 -5.489 30.526 1.00 54.50 ATOM 310 ODi ASN 1506 -16.179 -4.331 30.680 1.00 57.16 ATOM 311 ND2 ASN 1506 -16.610 -6.489 30.244 1.00 56.82 ATOM 314 C ASN 1506 -11.973 -5.124 30.003 1.00 50.65 ATOM 315 0 ASN 1506 -11.583 -5.174 31.178 1.00 50.65 ATOM 316 N ARG 1507 -11.142 -5.145 28.968 1.00 50.90 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 208 ATOM 318 ATOM 319 ATOM 320 ATOM 321 ATOM 322 ATOM 324 ATOM 325 ATOM 328 ATOM 331 ATOM 332 ATOM 333 ATOM 335 ATOM 336 ATOM 337 ATOM 338 ATOM 339 ATOM 340 ATOM 341 ATOM 343 ATOM 344 ATOM 345 ATOM 347 ATOM 348 ATOM 349 ATOM 350 ATOM 352 ATOM 353 ATOM 354 ATOM 355 ATOM 356 ATOM 357 ATOM 361 ATOM 362 ATOM 363 ATOM 365 ATOM 366 ATOM 367 ATOM 368 ATOM 369 ATOM 370 ATOM 371 ATOM 373 ATOM 374 ATOM 375 ATOM 376 ATOM 377 ATOM 379 ATOM 380 ATOM 381 ATOM 382* ATOM 383 ATOM 384 ATOM 385 ATOM 387 145. vOl

CA

CB

CG

CD

NE

Cz NH1 NH2

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

0G1 CG2

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CE

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

ARG 1507 ARG 1507 ARG 1507 ARG 1507 ARG 1507 ARG 1507 ARG 1507 ARG 1507 ARG 1507 ARG 1507 VAL 1508 VAL 1508 VAL 1508 VAL 1508 VAL 1508 VAL 1508 VAL 1508 THR 1509 THR 1509 TIIR 1509 THR 1509 THR .1509 THR 1509 THR 1509 LYS 1510 LYS 1510 LYS 1510 LYS 1510 LYS 1510 LYS 1510 LYS 1510 LYS 1510 LYS 1510 VAL 1511 VAL 1511 VAL 1511 VAL 1511 VAL 1511 VAL 1511 VAL 1511 ALA 1512 ALA 1512 ALA 1512 ALA 1512 ALA 1512 VAL 1513 VAL 1513 VAL 1513 VAL 1533 VAL 1*513 VAL 1513 VAL 1513 LYS 1514 LYS 1514 -9.700 -9.192 -9.450 -8.408 -8.600 -8.024 -7.198 -8.335 -9.015 -9.452 -7.977 -7.2?16 -6.903 -8.184 -5.919 -5.929 -5.369 -5.517 -4.298 -4.571 -5.423 -3.267 -3.434 -3.927 -2.175 -1.291 -0.032 -0.277 1.023 0.947 -0.149 -0.929 -0.574 -1.092 -0.810 -2.129 -2.879 -3.026 -0.058 0.021 0.521 1.244 2.599 0.373 -0.151 0.204 -0.630 -1.731 -2.607 -2.567 0.203 0.924 0.105 0.818 -5.276 -6.483 -7.833 -8.149 -9.490 -9.944 -9.169 -11.151 -4.036 -3.464 -3.597 -2.443 -1.428 -1.015 -2.005 -2.970 -3.972 -2.345 -2.737 -3.187 -4.340 -3.540 -1.495 -0.408 -1.628 -0.479 -0.695 854 -0.658 -1.286 -0.728 0.355 -1.345 0.846 1.121 1.213 109 2 .354 2 .446 3.185 2.721 3 .969 3 .700 4.783 4.264 6.054 6 .914 7.591 8 .444 6.549 8 .008 8.750 8. 093 -9.104 29.127 1.00 49.77 28.339 1.00 55.81 28 .988 30.041 30.583 31.694 32 .392 32 .147 28.595 27.590 29.297 28.858 30.010 30.702 31 .012 28.248 *28. .708 27.157 26 .486 25.019 25.011 24.310 26 .473 26.174 26.880 26 .843 27 .680 29.162 29 948 31.342 32 .187 25.373 24 .734 24 .835 23.441 22 .621 22 .686 23 .148 23.353 24 .344 22 .186 21.954 21 .316 21.015 20 .040 21 .322 20.503 21.347 20.474 22 .087 19.837 20.510 18 .513 17.746 1.00 61.63 1.00 66.01 1.00 72.55 1.00 77.32 1.00 78.41 1.00 79.30 1.00 45.60 1.00 42.08 1.00 42.86 1.00 40.75 1.00 38.75 1.00 43.29 1.00 37.56 1.00 39.14 1.00 39.16 1.00 37.26 1.00 36.52 1.00 37.83 1.00 43.88 1.00 34.51 1.00 35.82 1.00 34.37 1.00 35.96 1.00 36.13 1.00 37.77 1.00 44.58 1.00 51.33 1.00 58.15 1.00 64.94 1.00 34.59 1.00 31.43 1.00 32.95 1.00 32.29 1.00 32.95 1.00 34.79 1.00 32.84 1.00 32.65 1.00 31.62 1.00 30.24 1.00 28.18 1.00 25.62 1.00 27.54 1.00 27.17 1.00 30.52 1.00 34.08 1.00 34.61 1.00 36.75 1.00 33.45 1.00 36.38 1.00 35.32 1.00 38.19 1.00 40.12 WO 98/07835 WO 9807835PCTIUS97/14895 209 ATOM 388 CB LYS 1514 1.339 8.513 16.439 1.00 40.93 ATOM 389 CG LYS 1514 2.452 7.488 16.632 1.00 42.52 ATOM 390 CD LYS 1514 2.861 6.803 15.338 1.00 46.25 ATOM 391 CE LYS 1514 3.268 7.796 14.261 1.00 49.76 ATOM 392 NZ LYS 1514 4.304 8.771 14.705 1.00 52.14 ATOM 396 C LYS 1514 -0.166 10.215 17.458 1.00 40.69 ATOM 397 0 LYS 1514 -1.313 9.953 17.110 1.00 41.69 ATOM 398 N MET 1515 0.277 11.45.4 17.613 1.00 43.28 ATOM 400 CA MET 1515 -0.569 12.610 17.379 1.00 46.21 ATOM 401 CB MET 1515 -1.363 12.936 18.644 1.00 46.96 ATOM 402 CG MET 1515 -0.488 13.293 19.837 1.00 47.61 ATOM 403 SD MET 1515 -1.413 13.464 21.358 1.00 49.77 ATOM 404 CE MET 1515 -1.593 11.761 21.814 1.00 47.84 ATOM 405 C MET 1515 0.299 13.805 17.000 1.00 49.90 ATOM 406 0 MET 1515 1.519 13.788 17.194 1.00 49.83 ATOM 407 N LEU 1516 -0.339 14.822 16.430 1.00 54.45 ATOM 409 CA LEU 1516 0.335 16.053 16.023 1.00 57.57 ATOM 410 CB LEU 1516 -0.483 16.762 14.944 1.00 54.-10 ATOM 411 CG LEU 1516 -0.800 16.007 13.664 1.00 50.71 ATOM 412 CD1 LEU 1516 -1.830 16.800 12.901 1.00 51.20 ATOM 413 CD2 LEU 1516 0.467 15.809 12.849 1.00 50.08 ATOM 414 C LEt) 1516 0.487 17.010 17.202 1.00 61.88 ATOM 415 0 LEU 1516 -0.170 16.852 18.235 1.00 63.30 ATOM 416 N LYS 1517 1.335 18.018 17.021 1.00 66.83 ATOM 418 CA LYS 1517 1.568 19.036 18.037 1.00 71.46 ATOM 419 CB LYS 1517 2.985 19.593 17.911 1.00 76.28 ATOM 420 CG LYS 1517 4.084 18.626 18.349 1.00 82.19 ATOM 421 CD LYS 1517 5.450 19.085 17.846 1.00 86.93 ATOM 422 CE LYS 1517 6.579 18.228 18.411 1.00 90.46 ATOM 423 NZ LYS 1517 7.896 18.513 17.763 1.00 92.51 ATOM 427 C LYS 1517 0.549 20.156 17.837 1.00 72.44 ATOM 428 0 LYS 1517. -0.142 20.198 16.819 1.00 72.12 ATOM 429 N SER 1518 0.474 21.075 18.793 1.00 73.90 ATOM 431 CA SER 151-8 0.470 22.185 18.697 1.00 74.96 ATOM 432 CB SER 1518 -0.498 22.980 20.002 1.00 74.72 ATOM .433 C SER 1518 -0.133 23.1-00 17.525 1.00 76.16 ATOM 434 0 SER 1518 -1.029 23.667 16.897 1.00 76.56 ATOM 435 N ASP 1519 1.158 23.245 17.232 1.00 77.24 ATOM 437 CA ASP 1519 1.601 24.094 16.125 1.00 78.51 ATOM 438 CB ASP 1519 2.849 *24.888 16.535 1.00 79.70 ATOM 439 C ASP 1519 1.887 23.264 .14.865 1.00 78.29 ATOM 440 0 ASP 1519 2.797 23.580 14.088 1.00 78.52 ATOM 441 N ALA 1520 1.121 22. 192 14.682 1.00 76.90 ATOM 443 CA ALA 1520 1.285 21.313 13.529 1.00 74.09 ATOM 444 CB ALA 1520 0.737 19.930 13.840 1.00 74.20 ATOM 445 C ALA 1520 0.580 21.895 12.318 1.00 71.82 ATOM 446 0 ALA 1520 -0.573 22.311 12.4.00 1.00 71.78 ATOM 447 N THR 1521 1.291 21.951 11.202 1.00 69.97 ATOM 449 CA THR 1521 0.734 22.480 9.970 1.00 68.86 ATOM 450 CB THR 1521 1.848 22.911 9.026 1.00 68.87 ATOM 451 OGi THR 1521 2.621 21.762 8.651 1.00 70.03 ATOM 453 CG2 THR 1521 2.756 23.912 9.715 1.00 71.55 ATOM 454 C THR 1521 -0.081 21.389 9.292 1.00 67.89 ATOM 455 0 THR 1521 0.111 20.204 9.563 1.00 69.03 145. vOl WO 98/07835 PCT/US97/14885 210 ATOM 456 ATOM 458 ATOM 459 ATOM 460 ATOM 461 ATOM 462 ATOM 464 ATOM 465 ATOM 466 ATOM 467 ATOM 468 ATOM 469 ATOM 473 ATOM' 474 ATOM 475 ATOM -477 ATOM 478 ATOM 479 ATOM 480 ATOM 481 ATOM 482 ATOM 483 ATOM 484 ATOM 486 ATOM 487 ATOM 488 ATOM 489 ATOM 490 ATOM 491 ATOM 492 ATOM 493 ATOM 495 ATOM 496 ATOM 497 ATOM 499 ATOM 500 ATOM 501 ATOM 503 ATOM 504 ATOM 505 ATOM 506 ATOM 507 ATOM 508 ATOM 509 ATOM 510 ATOM 512 ATOM 513 ATOM 514 ATOM 515 ATOM 516 ATOM 517 ATOM 518 ATOM 519 ATOM 521 145. vOl

N

CA

CB

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CE

OG

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

GLU 1522 GLU 1522 GLU 1522 GLU 1522 GLU 1522 LYS 1523 LYS 1523 LYS 1523 LYS 1523 LYS 1523 LYS 1523 LYS 1523 LYS 1523 LYS 1523 ASP 1524 ASP 1524 ASP 1524 ASP 1524 ASP 1524 ASP 1524 ASP 1524 ASP 1524 LEU .1525 LEU 1525 LEU 1525 LEU 1525 LEU 1525 LEU 1525 LEU 1525 LEU 1525 SER 1526 SER 1526 SER 1526 SER 1526 SER 1526 SER 1526 ASP 1527 ASP 1527 ASP 1527 ASP 1527 ASP 1527 ASP 1527 ASP 1527 ASP 1527 LEU 1528 LEU 1528 LEU 1528 LEU 1528 LEU 1528 LEU 1528 LEU 1528 LEU 1528 ILE 1529 ILE 1529 -0.964 -1.785 -2.737 886 -1.324 0.367 1. 314 2.629 3 .815 3 .510 4 .759 4.429 1.565 1.548 1. 786 2.036 2.297 3 .598 3.649 4.580 0.847 1.017 -0.354 -1.585 -2.801 193 -4.364 -5.215 -1.605 -1.921 -1.245 -1.211 -0.903 -2.012 192 -0.480 0. 994 2. 024 3.376 3-934 3.399 4.916 1.652 1.951 0.973 0.532 0.026 -0.505 0.499 -0.825 -0.568 -0.607 -1.450 -2.531 21.783 20.821 21.532 19.823 18.-729 20.205 19.326 20.064 19.162 18.288 17.596 16 .721 18 .173 17 .003 18 .523 17 .549 18 .271 19 .080 20.136 18 .658 16 .596 15.387 17 .155 16 .380 17.307 16 .665 15 .543 17 .740 15.372 14 .204 15 .822 14 .945 15.744 16 .546 13 .821 12 .669 14 .144 13 .128 13 .767 14 .555 14 .434 15.295 12 .053 10 .872 12 .460 11.513 12 .258 11.412 10.323 12 .315 10.611 9.400 11.210 10.472 8.382 1.00 66.59 7.657 1.00 65.71 6.692 1.00 65.61 6.909 1.00 64.32 6.549 1.00 66.29 6.677 1.00 59.93 6.016 1.00 57.38 5.747 1.00 60.47 5.370 1.00 62.75 4.160 1.00 63.95 3.652 1.00 65.88 2.494 1.00 70.37 6.974 1.00 54.80 6.581 1.00 54.44 8.239 1.00 51.67 9.295 1.00 49.43 10.622 1.00 51.06 10.613 1.00 54.03 11.283 1.00 56.32 9.956 1.00 56.02 9.413 1.00 47.73 9.580 1.00 45.85 9.300 1.00 47.62 9.354 1.00 45.95 9.271 1.00 43.61 9.234 1.00 44.56 10.268 1.00 46.02 9.468 1.00 43.80 8.210 1.00 45.67 8.416 1.00 46.78 7.014 1.00 45.44 5.851 1.00 46.33 4.584 1.00 48.48 4.218 1.00 57.28 5.995 1.00 43.84 5.674 1.00 45.24 6.489 1.00 40.88 6.646 1.00 39.70 6.960 1.00 37.62 5.786 1.00 37.01 4.657 1.00 35.78 5.992 1.00 40.23 7.659 1.00 38.51 7.461 1.00 37.68 8.725 1 .00F 38.16 9.744 1.00 38.29 10.985 1.00 37.12 12.153 1.00 39.03 12.539 1.00 35.39 13.334 1.00 35.29 9.155 1.00 38.10 9.413 1.00 37.21 8.355 -1.00 36.71 7,718 1.00 35.93 WO 98/07835 WO 9807835PCTIUS97/14885 211 ATOM 522 ATOM 523 ATOM 524 ATOM 525 ATOM 526 ATOM 527 ATOM 528 ATOM 530 ATOM 531.

ATOM 532 ATOM 534 ATOM 535 ATOM 536 ATOM 538 ATOM 539 ATOM 540 ATOM 541 ATOM 542 ATOM 543 ATOM 544 ATOM 545 ATOM 546 ATOM 548 ATOM 549 ATOM 550 ATOM 551 ATOM 552 ATOM 553 ATOM 554 ATOM 555 ATOM 557 ATOM 558 ATOM 559 ATOM 560 ATOM 561 ATOM 562 ATOM 563 ATOM 564 ATOM' 565 ATOM 567 ATOM 568 ATOM 569 ATOM 570 ATOM 571 -ATOM 572 ATOM 573 ATOM 574 ATOM 576 ATOM 577 ATOM 578 ATOM 579 ATOM 580 ATOM 581 ATOM 582 CB ILE 1529 CG2 ILE 1529 CG1 ILE 1529 CD1 ILE 1529 C ILE 1529 0 ILE 1529 N SER 1330 CA SER 1530 CB SER 1530 OG SER 1530 C SER 1530 SER 1530 N GLU 1531 CA GLU 1531 CB GLU 1531 CG GLU 1531 CD GLU 1531 OE1 GLU 1531 0E2 GLU 1531 o GLU 1531 0 GLU 1531 N MET 1532 CA MET 1532 CB MET 1532 CG MET 1532 SD MET 1532 CE MET 1532 C MET 1532 O MET 1532 N GLU 1533 CA GLU 1533 CB GLU 1533 CG GLU 1533 CD GLU 1533 OE1 GLU 1533 0E2 GLU 1533 C GLU 1533 0 GLU 1533 N MET 1534 CA- MET 1534 CB MET 1534 CG MET 1534 SD MET 1534 CE MET 1534 C MET 1534 0 MET 1534 N MET 1535 CA MET 1535 CB MET 1535 CG MET 1535 SD MET 1535 CE MET 1535 C MET 1535 O MET 1535 -3 .486 -4.492 -4 .259 -5.177 -1.912 -2.274 926 -0.217 0 .911 0 .424 0 .382 0 .234 1 .048 1.690 2 .506 3 .094 3.871 4 .473 3 .883 0.698 0 .991 -0.464 -1.521 -2.666 -3.880 173 -5 .462 -2.025 -2 .080 -2 .387 -2 .863 -3.090 -4.226 531 -6 .006 -6.086 -1.861 -2 .232 -0.590 0 .515 1. 826 3 .038 3.479 4 .349 0 .530 0 .689 0 .364 0.336 0.252 1 .509 1 .520 1. 183 -0.837 -0.704 11.419 10.619 12.295 13 .288 9.447 8.269 9. 893 9. 036 9. 822 10. 970 7 .808 6 .691 8. 028 6 .952 7.515 6.428 6 .962 6. 134 8. 193 5.911 4 .714 6.379 5 .496 6.336 5. 523 6. 510 7 .682 4 .638 3.401 5. 319 4 .674 5. 725 6 .677 5. 954 5.230 6 .104 3.638 2 .541 4 .014 3 .145 894 3 .047 3 .063 4.607 1.896 0. 776 2 .100 0.986 1.503 2.216 6.931 1.00 35.67 6.119 1.00 34.04 7.916 1.00 33.81 7.276 1.00 33.58 6.786 1.00 37.49 6.829 1.00 37.11 6.003 1.00 38.20 5.050 1.00 37.49 4.370 1.00 43.32 3.687 1.00 52.31 5.719 1.00 34.40 5.219 1.00 31.51 6.851 1.00 32.08 7.594 1.00 30.60 8.759 1.00 29.70 9.657 1.00 30.-53 10.839 1.00 33.17 11.552 1.00 33.38 11.062 1.00 37.52 8.094 1.00 30.17 8.100 1.00 29.76 8.530 1.00 31.34 9.015 1.00 30.72 9.591 1.00 29.99 10.020 1.00 30.10 10.727 1.00 29.46 9.455 1.00 23.76 7.843 1.00 30.47 7.925 1.00 27.05 6.756 1.00 30.56 5.542 1.00 30.56 4.458 1.00 28.60 4.761 1.00 29.08 5.014 1.00 31.28 4.117 1.00 33.09 6.121 1.00 34.97 5.064 1.00 29.86 4.677 1.00 32.28 5.107 1.00 32.54 4.719 1.00 33.39 4.885 1.00 34.70 4.654 1.00 44.51 2.943 1.00 52.81 2.874 1.00 47.34 5.607 1.00 32.98 5.115 1.00 34.00 6.910 1.00 31.92 7.848 1.00 30.80 9.294 1.00 33.77 9.810 1.00 32.26 2.433 11.617 1.00 34.75 4.173 11.723 1.00- 37.86 0.052 7.521 1.00 30.80 -1.175 7.589 1.00 32.03 145. vOl WO 98/07835 PCT/US97/14885 212

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

583 585 586 587 588 589 590 594 595 596 598 599 600 601 602 603 604 605 607 608 609 610 611 612 613 614 616 617 618 619 621 622 623 624 625 626 630 631 632 634 635 636 637 638 640 641 643 644 645 647 648 649 650 651

N

CA

CS

CG

CD

CE

NZ

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CS

CG2 CGl CD1

C

0

N

CA

C

0

N

CA

CS

CG

CD

CE

NZ

C

0

N

CA

CB

CG

CD2 ND1 CEl NE2

C

0

N

CA

CS

CG

CD

CE

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

MET

MET

MET

MET

MET

MET

MET

MET

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

GLY

GLY

GLY

GLY

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

LYS

LYS

LYS

LYS

LYS

LYS

1536 1536 1536 1536 1536 1536 1536 1536 1536 1537 1537.

1537 1537 1537 1537 1537 1537 1538 1538 1538 1538 1538 1538 1538 1538 1539 1539 1539 1539 1540 1540 1540 1540 1540 154.0 1540 1540 1540 1541 1541 1541 1541 1541 1541 1541 1541 1541 1541 1542 1542 1542 1542 1542 1542 -1.974 170 -4 .334 -4.864 -5.973 -6.434 -7.578 -2.887 -3.238 -2.309 -1.967 -1.370 -2.377 -3 .657 -3.069 -0.976 -1.218 0. 119 1.173 2 .359 3 .310 3 .126 4 .375 0 .717 1.178 -0.188 6.51 0.240 1 .308 -0.157 0. 539 -0.470 -1.438 -2 .496 -3 .548 -2.994 1.679 1.745 2 .565 3 .690 4.787 5.849 5.886 7. 052 7.775 7.097 4.245 4 .290 4.650 5.200 5.683 6.232 5.277 5.659 0 .638 123 0 .808 1.-625 2. 540 3 .401 4 .241 -1.003 -2 .175 -0.412 148 -0.200 0. 780 051 0. 266 -2 .276 -3.425 -1.950 -2 .923 -2.254 -3 .303 343 745 -4 .179 -5 .276 027 190 -5.533 -4 .937 -6 .561 976 520 -6 .483 103 069 996 962 794 856 -8 .761 -8 .506 -9.555 -10. 789 -9.413 -10 .509 -11. 355 -8.640 -7.549 -9.791 -9 .893 -11 .326 -11. 572 -11. 046 -11.475 7.142 6.767 6.415 7.552 7.103 8.248 7.868 5.561 5.560 4.523 3.307 2.267 1.654 0.685 -0.972 3 .572 3.210 4.259 4.563 5.313 5.865 4.350 4. 945 5.299 4. 996 6.258 6.997 8.179 8.368 8.916 10.120 11. 139 11.638 12.530 12.952 13.828 10.020 9.111 11.006 11.144 10.120 10. 125 9.555 10.791 10.633 9.889 12.565 13.132 13.108 14 .457 14.714 16.112 17.155 18. 551 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1-.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 31.04 31.15 31.21 27. 76 21.44 24.69 25. 84 30.71 34 .73 31.18 31.53 35.11 42.40 50. 50.20 30.86 30.07 30. 92 28 .12 28. 71 29.72 30.79 32.46 26.33 24.20 27.41 27.83 29.10 30.33 29.46 29.27 27.01 29.58 39.41 44 .14 46. 92 27.17 26.20 26. 96 27.30 22 21.32 23.29 19.41 23.61 21.81 28.64 30.64 29.47 28.78 30.16 32.63 42.90 48.13 145. vOl WO 98/07835 WO 9807835PCT1UJS97/14885 213 ATOM 652 NZ LYS 1542 4.726 -10.930 19.564 1.00 54.87 ATOM 656 C LYS 1542 6.351 -8.928 14.705 1.00 26.54 ATOM 657 0 LYS 1542 6.440 -8.321 15.773 1.00 26.19 ATOM 658 N ASN 1543 7.193 -8.733 13.697 1.00 24.36 ATOM 660 CA ASN 1543 8.357 -7.874 13.852 1.00 24.08 ATOM 661 CB ASN 1543 9.601 -8.596 13.359 1.00 22.69 ATOM 662 CG ASN 1543 9.781 -9.950 14.029 1.00 22.81 ATOM 663 ODI ASN 1543 9.664 -10.996 13.388 1.00 23.62 ATOM 664 ND2 ASN 1543 10.028 -9.938 15.324 1.00 24.94 ATOM 667 C ASN 1543 8.318 -6.429 13.377 1.00 23.48 ATOM 668 0 ASN 1543 9.351 -5.861 13.059 1.00 22.94 ATOM 669 N ILE, 1544 7.130 -5.821 13.380 1.00 24.15 ATOM 671 CA ILE 1544 6.976 -4.407 13.012 1.00 24.60 ATOM 672 CB ILE 1544 6.516 -4.191 11.531 1.00 24.90 ATOM 673 CG2 ILE 1544 7.495 -4.852 10.571 1.00 21.57 ATOM 674 CG1 ILE 1544 5.081 -4.-688 11.316 1.00 26.66 ATOM 675 CD1 ILE 1544 4.481 -4.321 9.945 1.00 23.98 ATOM 676 C ILE 1544 5.954 -3.785 13.955 1.00 24.78 ATOM 677 0 ILE 1544 5.160 -4.503 14.558 1.00 27.87 ATOM 678 N ILE 1545 6.035 -2.474 14.159 1.00 26.39 ATOM 680 CA ILE 1545 5.089 -1.779 15.025 1.00 26.79 ATOM 681 CB ILE 1545 5.588 -0.345 15.384 1.00 28.85 ATOM 682 CG2 ILE 1545 4.512 0.449 16.103 1.00 23.60 ATOM 683 CG1 ILE 1545 6.833 -0.423 16.269 1.00 27.20 ATOM 684 CD1 ILE 1545 6.565 0.990 17.639 1.00 27.12 ATOM 685 C ILE 1545 3.792 -1.708 14.224 1.00 26.99 ATOM 686 0 ILE 1545 3.720 -1.023 13.197 1.00 27.61 ATOM 687 N ASN 1546 2.809 -2.4-95 14.654 1.00 26.70 ATOM 689 CA ASN 1546 1.514 -2.565 13.983 1.00 26.53 ATOM 690 CB ASN 1546 0.871 -3.953 14.169 1.00 26.23 ATOM 691 CG ASN 1546 1.695 5.072 13.551 1.00 24.96 ATOM 692 ODi ASN 1546 1.773 -5.206 12.330 1.00 28.08 ATOM 693 ND2 ASN 1546 2.319 -5.872 14.387 1.00. 22.38 ATOM 696 C ASN 1546 0.521 -1.497 14.418 1.00 26.89 ATOM 697 0 ASN 1546 0.610 -0.952 15.523 1.00 27.40 ATOM 698 N LEU 1547 -0.349 -1.138 13.481 1.00 27.77 ATOM 700 CA LEU 1547 -1.416 -0.175 13.701 1.00 28.28 ATOM 701 CB LEU 1547 -1.958 0.313 12.361 1.00 27.04 ATOM 702 CG LEU 1547 -3.199 1.194 12.408 1.00 25.74 ATOM 703 CD1 LIEU 1547 -2.836 2.575 12.950 1.00 27.66 ATOM 704 CD2 LEU 1547 -3.799 1.289 11.014 1.00 23.38 ATOM 705 C LEU 1547 -2.498 -0.972 14.435 1.00 29.80 ATOM 706 0 LEU 1547 -2.766 -2.135 14.105 1.00 28.63 ATOM 707 N LIEU 1548 -3.088 -0.351 15.448 1.00 29.91 ATOM 709 CA LIEU 1548 -4.114 -0.997 16.256 1.00 28.46 ATOM 710 CB LEU .1548 -3.735 -0.956 17.749 1.00 26.76 ATOM 711 CG LEU 1548 -2.460 -1.701 18.162 1.00 22.44 ATOM 712 CD1 LIEU 1548 -2.277 -1.554 19.653 1.00 21.91 ATOM 713 CD2 LEU 1548 -2.551 -3.179 17.778 1.00 20.79 ATOM 714 C LEU 1548 -5.480 -0.365 16.058 1.00 27.31 ATOM 715 0 LEU 1548 -6.489 -1.043 16.193 1.00 28.25 ATOM 716 N GLY 1549 -5.506 0.925 15.732 1.00 24.02 ATOM 718 CA GLY 1549 -6.774 1.598 15.553 1.00 24.57 ATOM 719 C GLY 1549 -6.548 3.077 15.395 1.00 25.19 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 214

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

720 0 7221 N 723 CA 724 CB 725 C 726 0 727 N 729 CA 730 CB 731 SG 732 C 733 0 734 N 736 CA 737 CB 738 OGi 740 CG2 741 C 742 0 743 N 745 CA 746 CB 747 CG 748 CD 749 OE1 750 NE2 753 C 754 0 755 N 757 CA 758 CB 759 CG 760 OD1 761 0D2 762 C 763 0 764 N 766 CA 767 C 768 0 769 N 770 CD 771 CA 772 CB 773 -CG 774 C 775 0 776 N 778 CA 779 CB 780 CG 781 CD1 782 CD2 783 C

GLY

ALA

ALA

ALA

ALA

ALA

CYS

CYS

CYS

CYS

CYS

CYS

THR

THR

THR

THR

THR

THR

THR

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

GLY

GLY

GLY

GLY

PRO

PRO

PRO

PRO

PRO

PRO

PRO

LEU

LEU

LEU

LEU

LEU

LEU

LEU

1549 1550 1550 1550 1550 1550 1551 1551 1551 1551 1551.

1551 1552 1552 1552 1552 1552 1552 1552 1553 1553 1553 1553 1553 1553 1553 1553 1553 1554 155*4 1554 1554 1554 1554 1554 1554 1555 1555 1555 1555 1556 1556 1556 1556 1556 1556 1556 1557 1557 1557 1557 1557 1557 1557 -5.400 -7.617 -7-487 -7.206 -8.695 -9.810 -8.444 -9.482 -9.221 -9.378 -9.359 -8.482 -10.198 -10.135 -10.052 -11.276 -8.928 -11.282 -11. 171 -12.397 -13.585 -14.832 -14.915 -14.900 15.785 -13.876 -13.727 -13.358 -14.225 -14.479 -15.832 -17.003 -18.072 -16.860 -13.395 -13.611 -12.232 -11.131 -9.798 -9.737 -8.708 -8.672 -7.359 -6.484 -7.354 -7.164 -7.636 -6.451 -6.169 -5.496 -5.009 -6.169 -4.314 -5.244 3.488 3.875 5.319 5.68.0 6.103 5.590 7.336 8.270 8 .774 7.521 9.426 10.281 9.412 10.435 9.781 9.097 8.768 11. 419 12.525 11.014 11.846 10.968 10.238 11.200 12 .045 11.090 12.777 12.423 13.981 15.016 14.766 14.955 15.409 14.661 15.173 14.879 15.643 15.834 15.626 15.581 15.525 15.683 15.326 15.549 16.347 13.912 12.953 1:3.788 12.490 12.669 11. 404 10.436 11.775 11.732 15.231 15.427 15.282 13.824 15. 765 15.780 16.199 16 .639 18.055 19.317 15.656 15.800 14 .625 13.595 12.189 11.890 12 .144 13.591 13 .057 14 .179 14 .180 14 .020 12 .672 11.496 11.359 10.652 15.372 16 .489 15.090 16. 084 16.758 15.809 16.274 14.601 17.133 18.310 16.699 17 .617 16.935 15.716 17.702 19.164 17.177 18.411 19.345 16.665 17.287 15.547 14 .954 13.587 12.870 12.628 11.570 15.894 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 28. 77 24.66 24. 17 24.29 23 24 25. 03 28.21 26.76 34.39 29.98 32 .14 31.09 32. 91 32.60 32 .12 32. 74 35.26 35.10 39.01 41.97 41. 17 39.06 41.84 41.92 42 .33 45.35 47.02 48.60 50.64 54. 52 60.54 66.04 65.09 49.89 51.48 48.40 46.16 44 .64 45.22 44.68 45.39 42. 43 .74 47.32 42.34 42.75 39.83 36.64 34.49 31.29 27. 86 25.40 35.44 145. vOl WO 98/07835 WO 9807835PCT/US97/14885 215

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

-ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

784 785 787 788 789 790 791 792 793 794 795 797 798 799 801 802 803 804 805 806 807 809 810 811 812 813 814 815 816 818 8 19 820 821 822 823 824 826 827 828 829 830 831 832 833 834 836 837 838 839 840 841 842 843 844 0

N

CA

CB

CG

CD1 CE 1 CD2 CE2

CZ

OH

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG

CD

OE1.

0E2

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2

CZ

OH

LEU

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

VAL

VAL

VAL

VAL

VAL

VAL

VAL

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

VAL

VAL

VAL

VAL

VAL

VAL

VAL

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

1557 1558 1558 1558 1558 1558 1558 1558 1558 1558 1558 1558 1.558 1559 1559 1559 1559 1559 1559 1559 1560 1560 1560 1560 1560 1560 1560 1560 1561 1561 1561 1561 1561 1561 1561 1562 1562 1562 1562 1562 1562 1562 1562 1562 1563 1563 1563 1563 1563 1563 1563 1563 1563 1563 -4.210 -5.664 -4.861 -5.590 -5.695 -6 .566 -6.683 -4.945 -5.054 -5.921 -6.008 -4.600 -5.532 -3.331 -2 .947 -1.849 -1.516 -2.308 -2 .438 -1.393 -3.230 -2.915 -4.219 -3 .931 -5.172 -6.583 -2.073 -2.520 -0.858 0 .060 1.311 0. 8-q2 2 .074 0.509 0.221 1.166 1.658 2.278 1.251 1.864 1.272 2 .920 2.674 3.453 2.627 3 .534 2.782 3.632 4.366 5.140 3.683 4.452 5.173 5.920 12.264 10.539 9.697 9.348 10 .476 10 .394 11..456 11 .636 12.690 12 .598 13.668 8 .419 7 .750 8 .129 6.907 7 .160 5 .851 8.265 5 .979 6.223 4 .960 3 .998 3 .443 2.695 4.603 4 .190 2.857 2 .116 2 .714 1.667 2.269 3.019 3.201 0 .809 3.139 -0.311 -1.220 -2.465 -3.452 -4 .641 -5.739 -4.487 -0.538 0 .292 -0.871 -0.304 -0.088 0.376 1.552 1.992 -0.356 0 .072 1.245 1.677 16. 316- 16 .292 17.157 18.470 19.471 20.565 21.479 19.317 20.213 21.289 22.155 16.387 15.936 16.153 15.463 14.419 13.675 13.453 16.556 17.155 16.852 17.894 18.506 19.784 18.809 19.093 17.341 16.455 17.860 17.411 16.696 15.445 17.639 18.588 19.746 18 .286 19.318 18.693 18.208 17. 501 17.580 16.849 20.217 19.760 21.503 22.493 23.799 24.952 24 .873 25.947 26.136 27.211 27.113 28.184 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1. 00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 36. 12 32.49 31.87.

33 .93 35.34 37. 12 36 .44 37.*27 39.62 40.05 44.98 31.58 30.22 33.43 31.42 32.31 26.79 30.63 28.67 30.08 25.80 25.33 22.34 20.36 21.34 20.68 27. 16 29.67 27.69 28.27 27.34 21.76 26.00 28.70 30.52 28.64 27.77 24.57 24.76 27.27 28.27 29.25 28.79 29.38 30.84 31.43 32.10 33. 93 34.85 37.53 34.81 34.01 35.79 39.10 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 216 ATOM 846 C TYR 1563

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

847 848 850 851 852 853 854 856 857 858 860 861 862 864 865 866 867 868 869 873 874 875 877 878 879 880 882 883 884 885 886 889 890 891 893 894 895 896 897 898 899 900 902 903 904 905 906 908 909 912 915 916 917 0

N

CA

CB

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

C

0

N

CA

CB

CG

ODi ND2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

0

N

TYR

ALA

ALA

ALA

ALA

ALA

SER

SER

SER

SER

SER

SER

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

GLY

GLY

GLY

GLY

ASN

ASN

A.SN

ASN

ASN

ASN

ASN

ASN

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

GLU

1563 1564 1564 1564 1564 1564 1565 1565 1565 1565 1565 1565 1566 1566 1566 1566 1566 1566 1566 1566 1566 1567 1567 1567 1567 1568 1568 1568 1568 1568 1568 1568 1568 1569 1569 1569 1569 1569 1569 1569 1569 1570 1570 1570 1570 1570 1570 1570 1570 1570 1570 1570 1571 4.767 -1.166 4.672 -2.385 5.930 -0.525 7.198 -1.212 8.178 -0.866 7.711 -0.719 8.332 0.349 7.424 -1.482 7.801 -1.071 7.124 -1.945 7.606 -3.271 9.288 -0.968 9.674 -0.219 10.127 -1.673 11.557 -1.625 12.137 -3.033 11.555 -3.869 11.997 -5.308 11.632 -6.031 12.104 -7.436 12.380 -0.664 13.616 -0.691 11.686 0.223 12.345 1.224 13. 074 0.719 12.912 -0.430 13.883 1.589 14.632 1 230 15.066 2 .478 16.127 3.271 17.130 2 .733 15; 934 4.580 15.802 0.295 16.357 0.256 16.193 -0.428 17.269 -1.403 17.418 -2.083 18.415 -3.231 18.284 -4.261 18.184 -3 .863 18.609 -0.838 19.328 -1.499 18.954 0.370 20.218 0.983 20.348 2.394 21.586 3.129 21.672 4.538 20.428 5.278 19.975 5.721.

20.659 5.510 18.824 6.377 20.308 1.023 21.184 0.391 19.359 1.730 22.731 22 .905 22.725 22. 953 21.833 24.307 24.403 25.359 26 .700 27.750 27.696 26.996 27.886 26.243 26 .526 26 .530 27 .664 27.599 28.872 28.804 25.683 25.715 24 .973 24.156 22.928 22.530 22.331 21.139 20.365 21.074 21.508 21.144 21.393 22.483 20.354 20.417 19.054 18.893 20.024 17.523 20.878 21.618 20.432 20.834 20.256 20.758 20.221 20.412 21 .58-4 22 .712 21.622 22.371 22.970 22.981 1. 00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 31.38 30 .73 32.23 35.90 36 .44 36 .52 39.16 34 .62 34 .91 32 .11 32 .92 35.56 38.69 33 31.40 30. 56 32.32 36.47 36 .97 41.62 32 .18.

32 .57 33.39 32 .13 31.70 33 31. 08 31.00 31.30 30.47 32. 19 32 .13 30.62 32. 91 30.92 31.22 29.57 29.22 21.30 24. 99 32 .44 33.12 33 .24 33.01 32 .36 38 .28 41. 93 49.82 52.37 51.61 53 .28 33.90 33 .17 33 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 217 ATOM 919 ATOM 920 ATOM 921 ATOM 922 ATOM 923 ATOM 924 ATOM 925 ATOM 926 'ATOM 927 ATOM 929 ATOM 930 ATOM 931 ATOM 932 ATOM 933 ATOM 934 ATOM 935 ATOM 936 ATOM 937 ATOM 939 ATOM 940 ATOM 941 ATOM 943 ATOM 944 ATOM 945 ATOM 946 ATOM 947 ATOM 948 ATOM 949 ATOM 950 ATOM 952 ATOM 953 ATOM 954 ATOM 955 ATOM 956 ATOM 957 ATOM 960 ATOM 961 ATOM 962 ATOM 964 ATOM 965 ATOM 966 ATOM 967 ATOM 968 ATOM 970 ATOM 971 ATOM 972 ATOM 973 ATOM 974 ATOM 976 ATOM 977 ATOM 980 ATOM 983 ATOM 984 ATOM 985 SSSD/55145. vOl

CA

CB

CG

CD

0E1 0E2

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2 cz

OH

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD

OE1 NE2

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD

NE

CZ

NHl NH2

C

0

N

GLU 1571 GLU 1571 GLU 1571 GLU 1571 GLU 1571 GLU 1571 GLU 1571 GLU 1571 TYR 1572 TYR 1572 TYR 1572 TYR 1572 TYR 1572 TYR 1572 TYR 1572 TYR 1572 TYR 1572 TYR 1572 TYR 1572 TYR 1572 LEU 1573 LEU 1573 LEtJ 1573 LEU 1573 LEU 1573 LEU 1573 LEU 1573 LEU 1573 GLN 1574 GLN 1574 GLN 1574 GLN 1574 GIN 1574 GLN 1574 GL.N 1574 GLN 1574 GLN 1574 ALA 1575 ALA 1575 ALA 1575 ALA 1575 ALA 1575 ARG 1576 ARG 1576 ARG 1576 ARG 1576 ARG 1576 ARG 1576 ARG 1576 ARG 1576 ARG 1576 ARG 1576 ARG' 1576 ARG 1577 19.284 18 .052 18 .158 16 .814 15.759 16 .812 19.223 19. 968 18 .363 18 .204 17 .210 17.074 16 .105 15 .954 17 .899 17.760 16 .790 16 .651 19.549 19-.880 20 .334 21.625 22 .145 21.532 22 .097 21.807 22 .645 23 .354 22 .691 23.639 23 .601 24.033 23 .960 23 .592 24 .288 23.400 24 .343 22 .131 21.740 20 .261 22 .061 21.839 22 .563 22.897 21.994 20.555 19 .653 18 .279 17 .572 18 .114 16.298 24 .365 24 .735 25.200 1.861 2.688 4.145 4.870 4.199 6.120 0.487 0.202 -0.376 -1.728 -2.495 -3.971 -4.443 -5.804 -4.899 -6.260 -6.705 -8.052 -2.447 -3.126 -2.266 -2.923 -2.909 3.870 -3.563 -5.317 -2.308 -3.031 980 -0.293 1.206 1.559 3 .045 3.837 3.431 -0.588 -0.801 -0.667 -0.944 -0.678 -2.359 -2.692 -3.201 -4.568 544 -5.383 -6.282 -6.190 -5.066 -3.913 -5.102 -4.927 -6.113 -3.900 24.432 1.00 34.87 24.794 1.00 35.83 24.354 1.00 41.61 24.318 1.00 47.33 24.362 1.00 50.68 24.218 1.00 48.07 25.098 1.00 34.39 26.041 1.00 34.04 24.572 1.00 33.49 25.083 1.00 30.45 24.202 1.00 28.13 24.487 1.00 25.80 25.371 1.00 28.92 25.618 1.00 30.03 23.863 1.00 24.61 24.102 1.00 26.05 24.982 1.00 29.23 25.227 1.00 33.74 25.113 1.00 31.30 26.090 1.00 32.43 24.058 1.00 29.68 23.972 1.00 30.04 22.529 1.00 26.13 21.490 1.00 25.24 20.113 1.00 19.70 21.839 1.00 22.05 24.927 1.00 34.47 25.644 1.00 34.95 24.978 1.00 35.47 25.850 1.00 37.09 25.579 1.00 36.70 24.171 1.00 39.77 23.884 1.00 41.51 24.751 1.00 42.57 22.652 1.00 41.34 27.332 1.00 37.85 28.090 1.00 38.87 27.720 1.00 39.01 29.098 1.00 37.00 29.273 1.00 35.71 29.559 1.00 39.14 30.719 1.00 43.81 28.665 1.00 38.39 29.032 1.00 37.71 28.290 1.00 38.26 28.700 1.00 38.00 27.920 1.00 34.74 28.388 1.00 32.88 28.442 1.00 34.02 28.068 1.00 35.57 28.800 1.00 36.71 28.828 1.00 39.59 28.788 1.00 39.83 28.687 1.00 38.82 WO 98/07835 PCT/US97/14885 218 ATOM 987 CA ARG 1577 26.631 -4.101 28.520 1.00 39.07 ATOM 988 CB ARG 1577 27.310 -2.797 28.090 1.00 34.91 ATOM 989 CG ARG 1577 27.033 -2.323 26.681 1.00 33.87 ATOM 990 CD ARG 1577 27.730 -0.981 26.428 1.00 33.06 ATOM 991 NE ARO 1577 27.722 -0.612 25.015 1.00 38.87 ATOM 993 CZ ARG 1577 28.174 0.538 24.517 1.00 39.76 ATOM 994 NH1 ARG 1577 28.683 1.470 25.305 1.00 40.68 ATOM 997 NH2 ARG 1577 28.122 0.758 23.213 1.00 43.26 ATOM 1000 C ARG 1577 27.181 -4.501 29.885 1.00 41.58 ATOM 1001 0 ARG 1577 26.586 -4.181 30.917 1.00 42.48 ATOM 1002 N PRO 1578 28.294 -5.249 29.919 1.00 43.07 ATOM 1003 CD PRO 1578 29.110 -5 .812 28.823 1.00 43.36 ATOM 1004 CA PRO 1578 28.839 -5.626 31.223 1.00 42.69 ATOM 1005 CB PRO 1578 29.966 -6.595 30.857 1.00 42.22 ATOM 1006 CG PRO 1578 30.412 -6.103 29.516 1.00 43.64 ATOM 1007 C PRO 157.8 29.366 -4.350 31.882 1.00 43.37 'ATOM 1008 0 PRO 1578 29.530 -3.319 31.215 1.00 42.50 ATOM 1009 N PRO 1579 29.596 -4.380 33.198 1.00 45.24 ATOM 1010 CD PRO 1579 29.279 -5.435 34.174 1.00 44.69 ATOM 1011 CA PRO 1579 30.099 -3.187 33.882 1.00 46.27 ATOM 1012 CB PRO 1579 29.979 -3.567 35.353 1.00 45.78 ATOM 1013 CG PRO 1579 28.894 -4.615 35.361 1.00 46.15 ATOM 1014 C PRO 1579 31.548 -2.869 3.3.500 1.00 48.38 ATOM 1015 0 PRO 1579 32.410 -3.753 33.478 1.00 50.64 ATOM 1016 N GLU 1592 19.022 -5.398 32.495 1.00 65.98 ATOM 1018 'CA GLU 1592 20.442 -5.048 32.492 1.00 64.80 ATOM 1019 CB GLU J.592 20.796 -4.241 33.740 1.00 67.30 ATOM 1020 C GLU 1592 21.351 -6.275 32 .371 1 .00 63.80 ATOM 1021 0 GLU 1592 22.545 -6.149 .32.089 1.00 65.21 ATOM 1022 N GLU 1593 20.789 -7.458 32.607 1.00 61.44 ATOM 1024 CA GLU 1593 21.560 -8.691 32.495 1.00 60.82 ATOM 1025 CE GLU 1593 20.68.1 -9.899 32.807 1.00 61.47 ATOM 1026 C GLU 1593 22.144 -8.803 31.089 1.00 59.12 ATOM 1027 0 GLU 1593 21.468 -8.525 30.097 1.00 59.49 ATOM 1028 N GLN 1594 23.408 -9.201 31.017 1.00 57.33 ATOM 1030 CA GLN 1594 24.103 -9.334 29.744 1.00 55.30 ATOM 1031 CE GLN 1594 25.523 -9.880 29.957 1.00 54.87 ATOM 1032 CG GLN 1594 26.438 -8.959 30.757 1.00 53.34 ATOM 1033 CD GLN 1594 27.704 -9.660 31.248 1.00 55.27 ATOM 1034 OE1 GLN 1594 28.256 -10.536 30.572 1.00 56.47 ATOM 1035 NE2 GLN 1594 28.166 -9.275 32.434 1.00 51.46 ATOM 1038 C GLN 1594 23.336 -10.229 28.781 1.00 52.29 ATOM 1039 0 GLN 1594 22.648 -11.166 29.190 1.00 52.56 ATOM 1040 N LEU 1595 23.447 -9.913 27.499 1.00 49.40 ATOM 1042 CA LEU 1595 22.783 -10.676 26.455 1.00 46.00 ATOM 1043 CE LEU 1595 22.452 -9.760 25.274 1.00 42.94 ATOM 1044 CG LEU 1595 21.390 -8.711 25.626 1.00 43.90 ATOM 1045 CD1 LEU 1595 21.495 -7.484 24.743 1.00 39.46 ATOM 1046 CD2 LEU 1595 20.005 -9.347 25.569 1.00 41.86 ATOM 1047 C LEU 1595 23.741 -11.762 26.029 1.00 43.96 ATOM 1048 0 LEU 1595 24.950 -11.550 26.043 1.00 44.*24 ATOM 1049 N SER" 1596 23.217 -12.941 25.714 1.00 43.29 ATOM 1051 CA SER 1596 24.076 -14.027 25.275 1.00 42.40 ATOM 1052 CE SER 1596 23.388 -15.374 25.484 1.00 41.83 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 219

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1053 1055 1056 1057 1.059 1060 1061 1063 1064 1065 1067 1068 1069 1070 1071 1072 1076 1077 1078 1080 1081 1082 1083 1084 1085 1086 1087 1089 1090 1091 1092 1093 1094 1095 1096 1098 1099 1100 1101 1102 1103 1104 1106 1107 1108 1110 1111 1112 1114 1115 1116 1117 1118 1119

OG

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CD

CG1 CG2

C

0

N

CA

CD

OG

C

0

N

CA

CB

SG

C

0

N

SER 1596 22.218 SER 1596 24.392 SER 1596 23.857 SER 1597 25.277 SER 1597 25.629 SER 1597 26.739 SER 1597 27.812 SER 1597 24.380 SER 1597 24.113 LYS 1598 23.621 LYS 1598 .22.405 LYS 1598 21.848 LYS 1598 21.135 LYS 1598 20.*213 LYS 1598 19.766 LYS 1598 20.-930 LYS 1598' 21.348 LYS 1598 20.579 ASP 1599 21.321 ASP 1599 20.366 ASP 159.9 20.450 ASP 1599 19.822 ASP 1599 20.089 ASP 1599 19.060 ASP 1599 20.634 ASP 1599 19.704 LETI 1600 21.915' LEU 1600 22.355 LEU 1600 23.841 LEU 1600 24.238 LEU 1600 25.747 LEU 1600 23.529 LEU 1600 22.073 LEU 1600 21.578 VAL 1601 22.377 VAL 1601 22.111 VAL 1601 22.780 VAL 1601 22.615 VAL 1601 24.259 VAL 1601 20.591 VAL 1601 20.106 SER 1602 19.855 SER 1602 18.399 SER 1602 17.894 SER -1602 16.483 SER 1602 17.784 SER 1602 16.772 CYS 1603 18.385 CYS 1603 17.931 CYS 1603 18.791 CYS 1603 18.472 CYS 1603 18.057 CYS 1603 17.134 ALA 1604 19.192 -15.483 -13.817 -12 .900 -14.645 -14.553 -15.547 -15.436 -14 .909 -14.322 -15.881 -16.298 -17.575 -18.439 -19.434 -20.494 -21.290 -15. 194 -15. 053 -14 .408 -13.307 -12 .661 -13.505 -13.217 -14.444 -12 .243 -11.--701 -11.945 -10. 948 -10.654 -10 .057 -9 .869 -8.745 -11.393 -10.613 -12 .645 -13 .154 -14.513 -14. 922 -14 .422 -13 .247 -13 .040 -13 .493 -13.576 -14 .141 -14.158 -12.192 -12 .071 -11.157 -9.783 -8.790 -7.039 -9.468-.

-8.926 24.697 23.800 23.171 23 .255 21.850 21 .516 22.431 21.048 20.003 21 .544 20.867 21.483 20.468 21.118 20.122 19.623 20.895 19 .945 21 .969 22 .099 23.477 24 .562 25.742 24.240 21. 061 20.466 20.873 19 .902 20.097 21.449 21.522 21.626 18.458 17 .648 18 .134 16.793 16 .551 15.105 16 .873 16 .564 15.452 17.645 17.607 18.925 18.962 17.343 16 .641 17.925 17.717 18.516 18 .177 16.225 15.629 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 0.50 1. 00 1. 00 1. 00 44 42 .64 43 .14 42.59 42 .91 45.26 56.41 42.35 43 .71 40.61 38.61 36.33 40.09 43.39 48.25 50.46 38 .17 41 .27 35 34 .08 37 .83 39 .93 45. 41.06 32 .37 32 .58 30.45 29.59 28.59 24 .59 18 21.71 28.54 25.59 29.13 29.74 29.63 29.30 28.52 29.98 29 .73 30.97 29.64 30.45 39.63 29.30 28.74 27 .68 27.32 25.40 20.76 PRT1 28.34 29.70 29.36 9.83 7 -15.627 SSSD/55145. vOl WO 98/07835 PCT1US97/14885 220 ATOM 1121 CA ALA 1604 19.438 -9.601 14.195 1.00 28.78 ATOM 1122 CB ALA 1604 20.861 -10.066 13.808 1-00 22.61 ATOM 1123 C ALA 1604 18.386 -10.304 13.324 1.00 30.14 ATOM 1124 0 ALA 1604 17.792 -9.690 12.426 1.00 31.64 ATOM 1125 N TYR 1605 18.156 -11.587 13.605 1.00 29.84 ATOM 1127 CA TYR 1605 17.179 -12.392 12.874 1.00 28.26 ATOM 1128 CB TYR 1605 17.107 -13.789 13.488 1.00 28.74 ATOM 1129 CG TYR 1605 16.018 -14.673 12.912 1.00 31.12 ATOM 1130 CD1 TYR 1605 16.152 -15.256 11.650 1.00 32.53 ATOM 1131 CEl TYR 1605 15.144 -16.067 11.121 1.00 30.84 ATOM 1132 CD2 TYR 1605 14.853 -14.926 13.634 1.00 31.21 ATOM 1133 CE2 TYR 1605 13.850 -15.734 13.116 1.00 29.69 ATOM 1134 CZ TYR 1605 14.002 -16.296 11.864 1.00 30.82 ATOM 1135 OH TYR 1605 12.990 -17.069 11.359 1.00 33.77 ATOM 1137 C TYR 1605 15.788 -11.758 12.853 1.00 27.33 ATOM- 1138 0 TYR 1605 15.152 -11.691 11.805 1.00 27.94 ATOM 1139 N GLN 1606 15.323 -11.292 14.007 1.00 27.93 ATOM 1141 CA GLN 1606 14.008 -10.659 14.115 1.00 27.20 ATOM 1142 CB GLN 1606 13.686 -10.335 15.570 1.0.0 26.40 ATOM 1143 CG GLN 1606 13.301 -11.556 16.402 1.00 28.12 ATOM 1144 CD GLN 1606 13.114 -11.215 17.865 1.00 30.41 ATOM 1145 OE1 GIM 1606 12.188 -10.489 18.234 1.00 34.34 ATOM 1146 NE2 GLN 1606 14.008 -11.701 18.700 1.00 31.44 ATOM 1149 C GLN 1606 13.906 -9.397 13.2-/5 1.00 29.67 ATOM 1150 0 GLN 1606 12.884 -9.148 12.622 1.00 30.74 ATOM 1151 N VAL 1607 14.970 -8.602 13.281 1.00 29.59 ATOM 1153 CA VJAL 1607 14.996 -7.377 12.501 1.00 27.00 ATOM 1154 CB VAL 1607 16.235 -6.544 12.842 1.00 27.20 ATOM 1155 CG1 VAL 1607 16.382 -5.397 11.859 1.00 28.11 ATOM 1156 CG2 VAL 1607 16.113 -5.996 14.266 1.00 24.79 ATOM 1157 C VAL 1607 14.966 -7.725 11.014 1.00 28.02 ATOM 1158 0 VAL 1607 14.229 -7.108 10.241 1.00 28.28 ATOM 1159 N ALA 1608 15.736 -8.741 10.626 1.00 27.56 ATOM 1161 CA ALA 1608 15.787 -9.206 9.236 1.00 27.36 ATOM 1162 CB ALA 1608 16.801 -10.339 9.095 1.00 26.25 ATOM 1163 C ALA 1608 14.402' -9.674 8.779 1.00 28.58 ATOM 1164 0 ALA 1608 14.013 -9.446 7.624 1.00 29.11 ATOM 1165 N ARG 1609 13.660 -10.326 9.680 1.00 28.88 ATOM 1167 CA ARG 1609 12.306 -10.797 9.376 1.00 27.17 ATOM 1168 CB ARG 1609 11.797 -11.731 10.464 1.00 29.68 ATOM 1169 CG ARG 1609 12.458 -13.062 10.439 1.00 31.65 ATOM 1170 CD ARG 1609 11.612 -14.049 11.177 1.00 38.21 ATOM 1171 NE ARG 1609 10.856 -14.897 10.269 1.00 41.10 ATOM 1173 CZ ARG 1609 10.048 -15.872 10.667 1.00 41.97 ATOM 1174 NH1 ARG 1609 9.886 -16.125 11.959 3: 00 40.69 ATOM 1177 NH2 ARG 1609 9.411 -16.609 9.770 1.00 43.57 ATOM 1180 C ARG 1609 11.312 -9.654 9.183 1.00 25.38 ATOM 1181 0 ARG 1609 10.480 -9.693 8.260 1.00 25.75 ATOM 1182 N GLY 1610 11.365 -8.661 10.070 1.00 24.03 ATOM 1184 CA GLY 1610 10.4'80 -7.517 9.939 1.00 21.74 ATOM 1185 C GLY 1610 10.734 -6.864 8.592 1.00 23.32 ATOM 1186 0 GLY 1610 9.805 -6.540 7.850 1.00 23.39 ATOM 1187 N MET 1611 12.016 -6.714 8.265 1.00 24.48 ATOM 1189 CA MET 1611 12.453 -6.125 7.002 1.00 23.13 SSSD/55145. vOl WO "/107835 PCTIUS97/14885 221 ATOM 1190 CB MET 1611 13.949 -5.860 7.035 1.00 19.46 ATOM 1191 CG MET 1611 14.339' -4.671 7.910 1.00 22.46 ATOM 1192 SD MET 1611 13.457 -3.123 7.536 1.00 25.27 ATOM 1193 CE MET 1611 13.900 -2.801 5.876 1.00 22.25 ATOM 1194 C MET 1611 1.2.100 -7.005 5.811 1.00 24.87 ATOM 1195 0 MET 1611 11.699 -6.497 4.755 1.00 24.09 ATOM 1196 N GLU 1612 12.230 -8.321 5.975 1.00 25.48 ATOM 1198 CA GLU 16.12 11.894 -9.232 4.890 1.00 25.42 ATOM 1199 CB GLU 1612 12.155 -10.691 5.288 1.00 23.41 ATOM 1200 CG GLU 1612 11.664 -11.679 4.232 1.00 25.14 ATOM 1201 CD GLU 1612 11.872 -13.141 4.599 1.00 28.60 ATOM 1202 OE1 GLU 1612 11.637 -13.514 5.777 1.00 30.10 ATOM 1203 0E2 GLU 1612 12.244 -13.928 3.694 1.00 29.53 ATOM 1204 C GLU 1612 10.418 -9.021 4.521 1.00 26.92 ATOM 1205 0 GLU 1612 10.065 -8.928 3.343 1.00 29.61 ATOM 1206 N TYR 1613 9.576 -8.884 5.542 1.00- 27.88 ATOM 1208 CA TYR 1613 8.154 -8.675 5.337 1.00 23.'82 ATOM 1209 CB TYR 1613 7.415 -8.769 6. 667 1.00 24.17 ATOM 1210 CG TYR 1613 5.941 -8.492 6.545 1.00 23.73 ATOM 1211 CD1 TYR 1613 5.064 -9.483 6.096 1.00 22.17 ATOM 1212 CEl TYR 1613 3.698 -9.235 5.965 1.00 21.08 ATOM 1213 CD2 TYR 1613 5.419 -7.237 6.865 1.00 23.16 ATOM 1214 CE2 TYR 1613 4.054 -6.976 6.736 1.00 26.38 ATOM 1215 CZ TYR 1613 3.200 -7.981 6.287 1.00 23.16 ATOM '1216 OH TYR 1613 1.855 -7.725 6.149 1.00 25.50 ATOM 1218 C TYR 1613 7.885 -7.327 4.670 1.00 23.17 ATOM 1219 0 TYR 1613 7.147 -7.246 3.689 1.00 24.21 ATOM 1220 N LEU 1614 8.481 -6.266 5.206 1.00 2/-3 04 ATOM 1222 CA LEU 1614 8.316 -4.920 4.652 1.00 21.81 ATOM 1223 CB LEU 1614 9.107 -3.906 5.484 1.00 19.94 ATOM 1224 C G LEU 1614 8.609 -3.616 6.902 1.00 21.94 ATOM 1225 CD1 LJEU 1614 9.580 -2.719 7.654 1.00 14.28 ATOM 1226 CD2 LEU 1614 7.227 -2.977 6.814 1.00 17.45 ATOM 1227 C LEU 1614 8.764 -4.858 3.182 1.00 23.74 ATOM 1228 0 LEU 1614 8.169 -4.150 2.367 1.00 25.26 ATOM 1229 N ALA 1615 9.831 -5.587 2.862 1.00 25.00 ATOM 1231 CA ALA 1615 10.357 -5.644 1.502 1.00 23.04 ATOM 1232 CB ALA 1615 11.710 -6.360 1.483 1.00 20.02 ATOM 1233 C ALA 1615 9.351 -6.357 0.605 1.00 2-3.15 ATOM 1234 0 ALA 1615 9.076 -5.891 -0.503 1.00 25.25 ATOM 1235 N SER 1616 8.754 -7.441 1.104 1.00 23.64 ATOM 1237 CA SER 1616 7.758 -8.199 0.337 1.00 23.60 ATOM 1238 CB SER 1616 7.346 -9.453 1.107 1.00 22.46 ATOM 1239 OG SER 1616 6.531 -9.131 2.224 1.00 26.66 ATOM 1241 C SER 1616 6.505 -7.369 0.025 1.00 25.45 ATOM 1242 0 SER 1616 5.813 -7.607 -0.967 1.00 26.67 ATOM 1243 N LYS 1617 6.193 -6.436 0.916 1.00 25.47 ATOM 1245 CA LYS 1617 5.051 -5.551 0.781 1.00 25.04 ATOM 1246 CB LYS 1617 4.513 -5.183 2.163 1.00 26.30 ATOM 1247 CG LYS 1617 3.778 -6.318 2.851 1.00 28.58 ATOM 1248 CD LYS 1617 2.438 -6.530 2.169 1.00 33.00 ATOM 1249 CE LYS 1617 1.652 -7.676 2.764 '1.00 38.57 ATOM 1250 NZ LYS 1617 2.167 -8.987 '2.300 1.00 45.15 ATOM 1254 C LYS 1617 5.417 -4.293 0.002 1.00 26.34 145. vOl WO 98/07835 PCTIUS97/14885 222

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM'

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1255 1256 1258 1259 1260 1261 1262 1263 1267 1268 1269 1271 1272 1273 1274 1275 1276 1278 1279 1280 1281 1282 1283 1284 1285 1287 1288 1289 1290 1291 1293 1294 1296 1297 1298 1300 1301 1302 1303 1304 1306 1307 1310 1313 1314 1315 1317 1318 1319 1320 1321 1322 1323 1324 0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

SG

c 0

N

CA

CB

CG2 CG1 CD1

C

0)

N

CA

CB

CG

CD2 ND1 CEl NE2

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

CYS

CYS

CYS

CYS

CYS

CYS

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

HIS

HIS

HIS

HIS

HI S

HIS

HIS

HIS

HIS

HIS

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ASP

ASP

ASP

ASP

AS P

ASP

ASP

ASP

LEU

1617 1618 1618 1618 1618 1618 1618 1618 1618 1618 1619 1619 1619 1619 1619 1619 1620 1620 1620 1620 1620 1620 1620 1620 1621 1621 1621 1621 1621 1621 1621 1621 1621 1621 1622.

1622 1622 1622 1622 1622 1622 1622 1622 1622 1622 1623 1623 1623 1623 1623 1623 1623 1623 1624 4.649 6 .592 7.084 6.053 5.971 5 .573 5.636 4.621 7.466 7.556 7.753 8 .111 7.391 7.754 9.622 10.336 10.096 11.502 12.030 13.521 11.767 12.100 11.553 11.011 12 .193 12.297 13.081 12.848 12.224 13.260 12.909 12 .273 12 .963 12.408 14.162 14 .976 14.180 13 .673 12 .995 12.677 11.623 10.774 11.460 15.740 16.698 15.379 16 .114 15.562 16.481 15.971 17.721 16.203 15.845 16.735 -3.336 -4.319 -3.197 -2.819 -3.749 -5 .163 -6.087 -5.729 951 -0 .848 -2.130 1.022 -1.173 0 .105 -0 .841 -1.786 O0.378 0.761 1.*543 1 .806 o0.764 1.557 1.686 2 .792 1.210 1.967 1.174 1.633 1.02'7 2 .862 2 .993 1.891 3 .316 4 .328 3.315 4.520 5 .670 5.326 6 .494 6 .170 5.455 4 .994 5 .138 4 .993 5.757 4 .495 4.879 6.155 6.689 7.265 6 .514 3.763 3.927 2 .633 -0.034 -0.632 -1.447 -2 .528 -3.730 -3.364 -4 .570 -5.600 -0.643 -1.199 0.646 2 .522 2 .873 4.136 1.728 2 .072 1.457 1.625 0.381 0.506 -0.913 -2.164 2.855 2.833 3 .916 5.162 6.210 7.618 8 .656 8.088 9.356 9. 719 4. 976 5.349 4 .402 4.183 3 .558 2.202 1.551 0. 180 -0.197 0.711 -1.489 5.423 5.313 6 .596 7.788 8.430 9.533 10.514 9.423 8.812 9. 990 8.357 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1 .00 1.00 1.00 1.00 1 .00 1. 00 1.00 1 .0.0 1.00 1.00 1.00 1.00 1. 00 1. 00 1 .00 1. 00 1 .00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1. 00 1. 00 1 .00 1.00 1. 00 1.00 1.00 1.00 26 .77 27.17 28.20 28.42 26.'63 30.45 32 34 .89 28.78 28.78 29.26 28.32 26.33 27.82 29.15 29.55 29.39 27.44 25.37 19.80 25.40 27.51 26 .56 26 .68 26.31 25.00 23 .08 23.21 22.69 25.34 24 .18 25.86 25.09 28.21 26.09 26.50 23 .52 23 .81 28.42 32.52 32 .34 30.07 28.30 26.31 26.19 27.41 29.94 34.83 38 .84 44 .51 37.59 28.71 26.21 26 .82 145. vOl WO 98/07835 PCT/US97/14885 223 ATOM 1326 CA ATOM 1327 CB

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1328 1329 1330 1331 1332 1333 1335 1336 1337 1338 1339 1341 1342 1343 1344 1345 1347 1348 1349 1350 1351 1353 1354 1357 1360

CG

CD1 CD2

C

O

N

CA

CB

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

LEU 1624 LEU 1624 LEU 1624 LEU 1624 LEU 1624 LEU 1624 LEU 1624 ALA 1625 ALA 1625 ALA 1625 ALA 1625 ALA 1625 ALA 1626 ALA 1626 ALA 1626 ALA 1626 ALA 1626 ARG 1627 ARG 1627 ARG 1627 ARG 1627 ARG 1627 ARG 1627 ARG 1627 ARG 1627 ARG 1627 ARG 1627 16.905 17.025 17.089 15.824 17.282 18.136 19.235 17.912 18.945 19.271 18.351 17.135 19.197 18.708 19.860 17.835- 17.072 17.978 17.178 17.699 17.675 18.033 18.177 19.322 20.421 19.377 15.739 1.469 0.209 -1.107 -1.303 -2.215 1.640 1.897 1.557 1.702 3.174 1.116 0.928 0.815 0.266 -0.179 1.272 0.891 2.558 3.598 4.983 5.276 6.715 6.980 6.864 6.485 7.159 9.216 8.367 9.127 10.009 8.101 10.105 9.611 11.416 12.445 12.654 13.732 13.825 14.712 15.974 16.838 16.731 17.620 16.409 17.042 16.673 15.179 14.902 13.470 12.809 13.441 11.523 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 25.91 23.35 21.09 14.44 18.30 24.93 25.58 26.30 23.59 15.82 23.64 26.66 21.59 21.66 22.97 24.98 26..84 24.55 25.29 26.66 30.56 34.97 40.03 40.62 46.52 43.25 SSSD/55145.v01 WO 98/07835 PCTIUS97/14885 224

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1394 1395 1396 1397 1398 1400 1401 1402 1404 1405 1406 1407 1409 1410 1411 1412 1413 1414 1415 1416 1417 1419 1420 1421 1422 1423 1424 1425 1426 1428 1429 1430 1431 1432 1435 1436 1437 1439 1440 1441 1442 1443 1444 1445 1447 1448 1449 1450 1451 1452 1453 1454 1456 1457 CG1 CG2

C

0

N

CA

CB

OGi CG2

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

ODi ND2

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

VAL

VAL

VAL

VAL

THR

THR

THR

THR

THR

THR

THR

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

AS P AS P

ASP

ASP

ASP

AS P AS P AS P

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

VAL

VAL

VAL

VAL

VAL

VAL

VAL

MET

MET

MET

MET

MET

MET

MET

MET

LYS

LYS

LYS

1631 1631 1631 1631 1632 1632 1632 1632 1632 1632 1632 1633 1633 1633 1633 1633 1633 1633 1633 1633 1634 1634 1634 1634 1634 1634 1634 1634 1635 1635 1635 1635 1635 1635 1635 1635 1636 1636 1636 1636 1636 1636 1636 1637 1637 1637 1637 1637 1637 1637 1637 1638 1638 1638 12.995 14.197 10.450 10.198 9.697 8.516 7.466 7 .965 7 .154 8.896 10.002 7.939 8.156 6.893 7.031 8.048 8.104 8 .783 8 .561 9.227 8 .167 8.505 7.381 6.022 5 .726 5.253 9.804 10.141 10.528 11.795 12.801 13.343 13.499 13.679 11. 655 12.522 10.547 10.315 8.820 8.615 8.339 10.782 10.436 11. 609 12.140 13.397 14.480 15.050 15.074 11. 082 10.587 10.733 9.716 8.437 -5.469 -3.714 -3.773 -2.821 -4.863 -5.035 -5.941 -7.288 -5.414 -5.678 -6.189 -5 .706 -6.298 -6.182 -6.718 -5.959 -4.708 -6.612 -7.753 -8.292 -8.384 -9.787 -10.499 -10.349 11. 141 -9.439 -9.947 11. 049 -8.851 -8.864 -9.842 -9.359 -8.156 -10.300 -9.162 -9.811 -8.721 -8.910 -9.139 -9.182 -10.431 -7.630 -6.527 -7.792 -6.679 -7.138 -7.693 -6.490 -7.500 -6.264 -7.099 -4.983 -4.450 -4.120 23.243 21. 895 22 .885 23 .643 22 .827 23 .660 22 .962 22.881 21.551 24.989 25.146 25.913 27.224 28 .079 29.514 30.378 30.300 31.156 27.088 27.954 25.990 25.770 25.013 25.690 26 .617 25.295 25.007 24 .608 24 .799 24 .052 24 .678 26 .003 26.227 26 .874 22 .552 21.944 21.966 20.543 20.218 18 .712 20.838 19.863 20.301 18.832 18.060 17.330 18 .254 19.477 20.938 17.051 16.297 17.045 16 .143 16 .912 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 23 .92 24 .26 32 .64 33 .01 34 34.29 34 .62 34.40 31.61 35.41 34 .79 36.86 37.27 37.66 44.43 46.68 49.88 48.53 37.15 38.60 38.41 38 .86 44.27 50.18 52 .07 50.17 36 .23 35.82 36.51 37.41 38.49 37.71 38.09 39.63 36.37 36.41 33.79 30.59 28.83 26.13 25.67 30.18 27.86 30.93 28.34 30.84 30.73 32.20 28.71 27.29 27.32 27.19 26.38 27.09 SSSD/55145. vOl WO 98/07835 WO 980785PCTIUS97/14885" 225 ATOM 1458 CG LYS 1638 7.702 -5.351 17.407 1.00 29.71 ATOM 1459 CD LYS 1638 6.386 -5.018 18.109 1.00 31.48 ATOM 1460 CE LYS 1638 5.485 -6.263 18.202 1.00 27.09 ATOM 1461 NZ LYS 1638 4.888 -6.561 16.869 1.00 26.68 ATOM 1465 C LYS 1638 10.1-96 -3.208 15.416 1.00 26.56 ATOM 1466 0 LYS 1638 10.514 -2.194 16.040 1.00 27.40 ATOM 1467 N ILE 1639 10.211 -3.271 14.092 1.00 24.31 ATOM 1469 CA ILE 1639 10.649 -2.147 13.289 1.00 24.84 ATOM 1470 GB ILE 1639 10.924 -2.588 11.836 1.00 25.81 ATOM 1471 CG2 ILE 1639 11.248 -1.395 10.952 1.00 24.18 ATOM 1472 CG1 ILE 1639 12.094 -3.566 11.826 1.00 25.01 ATOM 1473 CD1 ILE 1639 12.075 -4.499 10.675 1.00 27.90 ATOM 1474 C ILE 1639 9.641 -0.999 13.348 1.00 24.90 ATOM 1475 0 ILE 1639 8.435 -1.186 13.170 1.00 25.24 ATOM 1476 N ALA 1640 10.167 0.183 13.635 1.00 25.70 ATOM 1478 CA ALA 1640 9.378 1.392 13.744 1.00 27.61 ATOM 1479 GB ALA 1640 9.699 2.094 15.070 1.00 26.37 ATOM 1480 C ALA 1640 9.637 2.348 12.576 1.00 28.35 ATOM 1481 0 ALA 1640 10.650 2.243 11.871 1.00 28.40 ATOM 1482 N ASP 1641 8.676 3.237 12.354 1.00 29.74 ATOM 1484 CA ASP 1641 8.760 4.272 11.325 1.00 32.13 ATOM 1485 GB ASP 1641 9.873 5.273 11.688 1.00 34.31 ATOM 1486 CG ASP 1641 9.507 6.158 12.896 1.00 36.31 ATOM 1487 ODi ASP 1641 10.299 7.056 13.258 1.00 42.18 ATOM 1488 0D2 ASP 1641 8.420 5.974 13.483 1.00 41.03 ATOM 1489 C ASP 1641 8.882 3.840 9.867 1.00 32.00 ATOM 1490 0 ASP 1641 9.339 4.617 9.021 1.00 32.65 ATOM 1491 N PEE 1642 8.415 2.634 9.563 1.00 30.61 ATOM 1493 CA PHE 1642 8,473 2.119 8.200 1.00 30.06 ATOM 1494 GB PHE 1642 8.248 0.606 8.189 1.00 24.46 ATOM 1495 CG PEE 1642 6.981 0.176 8.854 1.00 23.26 ATOM 1496 CD1 PEE 1642 5.7-99 0.075 8.125 1.00 19.66 ATOM 1497 CD2 PHE 1642 6.966 -0.134 10.209 1.00 22.88 ATOM 1498 GEl PEE 1642 4.609 -0.331 8.734 1.00 20.97 ATOM 1499 GE2 PEE 1642 5.785 -0.540 10.830 1.00 26.61 ATOM 1500 CZ PHE 1642 4.599 -0.639 10 083 1.00 24.82 ATOM 1501 C PEE 1642 7.512 2.830 7.225 1.00 33.14 ATOM 1502 0 PilE 1642 7.791 2.922 6.029 1.00 36.48 ATOM 1503 N GLY 1643 6.411 3.372 7.741 1.00 32.65 ATOM 1505 GA GLY 1643 5.462 4.059 6.876 1.00 32.28 ATOM 1506 C GLY 1643 5.629 5.560 6.913 1.00 32.19 ATOM 1507 0 GLY 1643 4.795 6.310 6.415 1.00 30.74 ATOM 1508 N LEU 1644 6.739 5.997 7.486 1.00 36.80 ATOM 1510 GA LEU 1644 7.052 7.406 7.630 1.00 41.95 ATOM 1511 GB LEU 1644 8.332 7.551 8.439 1.00 37.41 ATOM 1512 G G LET] 1644 8.377 8.746 9.369 1.00 38.98 ATOM 1513 GD1 LET] 1644. 7.384 8.548 10.493 1.00 40.45 ATOM 1514 CD2 LET] 1644 9.775 8.904 9.929 1.00 41.94 ATOM 1515 C LEU 1644 7.189 8.150 6.296 1.00 47.55 ATOM 1516 0 LEU 1644 7.787 7.648 5.341 1.00 50.55 ATOM 1517 N ALA 1645 6.637 9.356 6.247 1.00 52.59 ATOM '1519 GA ALA 1645 6.686 10.194 5.055 1.00 56.88 ATOM 1520 GB ALA 1645 5.3.91 10.999 4.942 1.00 58.01 ATOM 1521 C ALA 1645 7.880 11.135 5.178 1.00 58.95 145. vOl WO 98/07835 PCTIUS97/14885 226 ATOM 1522 0 ALA 1645 8.064 11.770 6.224 1.00 59.37 ATOM 1523 N ARG 1646 8.700 11.211 4.133 1.00 60.26 ATOM 1525 CA ARG 1646 9.870 12.088 4.165 1.00 63.04 ATOM 1526 CB ARG 1646 10.995 11.444 4.976 1.00 64.92 ATOM 1527 C ARG 1646 10.377 12.461 2.782 1.00 63.84 ATOM 1528 0 ARG 1646 10.361 11.641 1.864 1.00 63.55 ATOM 1529 N .ASP 1647 10.801 13.714 2.633 1.00 65.18 ATOM 1531 CA ASP 1647 11.332 14.190 1.361 1.00 67.26 ATOM 1532 CB ASP 1647 10.989 15.670 1.150 1.00 68.92 ATOM 1533 CG ASP 1647 11.164 16.124 -0.304 1.00 70.88 ATOM 1534 ODI ASP 1647 12.196 15.811 -0.943 1.00 70.33 ATOM 1535 0D2 ASP 1647 10.258 16.825 0.808 1.00 71.39 ATOM 1536 C ASP 1647 12.847 14.005 1.405 1.00 68.40 ATOM 1537 0 ASP 1647 13.545 14.711 2.142 1.00 68.66 ATOM 1538 N ILE 1648 13.347 13.055 0.621 1.00 68.48 ATOM 1540 CA ILE 1648 14.777 12.773 0.570 1.00 69.00 ATOM 1541 CB ILE 1648 15.091 11.535 -0.314 1.00 66.28 ATOM 1542 CG2 ILE 1648 14.231 10.352 0.131 1.00 65.14 ATOM 1543 CG1 ILE 1648 14.869 11.853 -1.799 1.00 63.01 ATOM 1544 CD1 ILE 1648 15.274 10.746 -2.738 1.00 60.11 ATOM 1545 C ILE 1648 15.542 13.990 0.046 1.00 71.12 ATOM 1546 0 ILE 1648 16.628 14.310 0.525 1.00 72.41 ATOM 1547 N HIS 1649 14.923 14.710 -0.883 1.00 73.09 ATOM 1549 CA HIS 1649 15.546 15.890 -1.469 1.00 74.66 ATOM 1550 CB HIS 1649 14.921 16.191 -2.835 1.00 76.00 ATOM 1551 CG HIS 1649 15.178 15.157 -3.867 1.00 78.03 ATOM 1552 CD2 HIS 1649 16.314 14.425 -4.151 1.00 78.85 ATOM 1553 ND1 HIS 1649 14.245 14.739 -4.795 1.00 78.49 ATOM 1555 CEl HIS 1649 14.765 13.835 -5.584 1.00 78.94 ATOM 1556 NE2 HIS 164-9 16.005 13.623 -5.226 1.00 78.22 ATOM 1558 C HIS 164-9 15.466 17.108 -0.549 1.00 75.04 ATOM 1559 0 HIS 1649 15.567 18.244 -1.007 1.00 75.49 ATOM 1560 N HIS 1650 15.265 16.860 0.743 1.00 76.11 ATOM 1562 CA HIS 1650 15.181 17.918 1.748 1.00 77.63 ATOM 1563 CB HIS 1650 13.723 18.327 1.995 1.00 81.10 ATOM 1564 CG HIS 1650 13.206 19.352 1.033 1.00 86.06 ATOM 1565 CD2 HIS 1650 13.662 20.592 0.730 1.00 88.74 ATOM 1566 ND1 HIS 1650 12.099 19.146 0.239 1.00 88.83 ATOM 1568 CEl HIS 1650 11.893 20.211 -0.511 1.00 90.51 ATOM 1569 NE2 HIS 1650 12.823 21.103 -0.238 1.00 90.75 ATOM 1571 C HIS 1650 15.824 17.482 3.064 1.00 77.39 ATOM 1572 0 HIS 1650 15.651 18.133 4.091 1.00 77.42 ATOM 1573 N ILE 1651 16.573 16.385 3.024 1.00 77.73 ATOM 1575 CA ILE 1651 17.241 15.864 4.212 1.00 77.02 ATOM 1576 CB ILE 1651 17.788 14.433 3.974 1.00 78.24 ATOM 1577 CG2 ILE 1651 18.647 13.963 5.153 1.00 77.92 ATOM 1578 CG1 ILE 1651 16.633 13.458 3.750 1.00 80.90 ATOM 1579 CD1 ILE 1651 17.094 12.032 3.483 1.00 82.41 ATOM 1580 C ILE 1651 18.411 16.748 .4.620 1.00 76.15 ATOM 1581 0 ILE 1651 19.269 17.078 3.803 1.00 76.52 ATOM 1582 N ASP 1652 18.432 17.150 5.882 1.00 75.13 ATOM 1584 CA ASP 1652 19.527 17.957 6.384 1.00 73.91 ATOM 1585 CB ASP 1652 19.068 18.781 7.592 1.00 76.30 ATOM 1586 CG ASP 1652 20.216 19.499 8.286 1.00 79.91 145. vOl WO 98/07835 WO 9807835PCT[US97I14885 227 ATOM 1587 ODi ASP 1652 ATOM 1588 0D2 ASP 1652 ATOM 1589 C ASP 1652 ATOM 1590 0 ASP 1652 ATOM 1591 N TYR 1653 ATOM 1593 CA TYR 1653 ATOM 1594 CB TYR 1653 ATOM 1595 CG TYR 1653 ATOM 1596 CD1 TYR 1653 ATOM 1597 CEl TYR 1653 ATOM 1598 CD2 TYR 1653 ATOM 1599 CE2 TYR 1653 ATOM 1600 CZ ATOM 1601 OH ATOM 1603 C ATOM 1604 0 ATOM 1605 N ATOM 1607 CA ATOM 1608 CB ATOM 1609 CG ATOM 1610 CD1 ATOM 1611 CEl ATOM 1612 CD2 ATOM 1613 CE2 ATOM 1614 CZ ATOM 1615 OH ATOM 1617 C ATOM 1618 0 ATOM 16.19 N ATOM 1621 CA ATOM 1622 CB ATOM 1623 CG ATOM 1624 CD ATOM 1625 CE ATOM 1626 NZ ATOM 1630 C ATOM 1631 0 ATOM 1632 N ATOM 1634 CA ATOM 1635 CB ATOM 1636 CG ATOM 1637 CD ATOM 1638 CE ATOM 1639 NZ ATOM 1643 C ATOM 1644 0 ATOM 1645 N ATOM 1647 CA ATOM 1648 CB ATOM 1649 OGI ATOM 1651 CG2 ATOM 1652 C ATOM 1653 0 ATOM 1654 N TYR 1653 TYR 1653 TYR 1653 TYR 1653 TYR 1654 TYR 1654 TYR 1654 TYR 1654 TYR 1654 TYR 1654 TYR 1654 TYR 1654 TYR 1654 TYR 1654 TYR 1654 TYR 1654 LYS 1655 LYS 1655 LYS 1655 LYS 1655 LYS 1655 LYS 1655 LYS 1655 LYS 1655 LYS 1655 LYS 1656 LYS 1656 LYS 1656 LYS 1656 LYS 1656 LYS 1656 LYS 1656 LYS 1656 LYS 1656 THR 1657 THR 1657 THR 1657 THR 1657 THR 1657 THR 1657 THR 1657 THR 1658 21.247 20.081 20.637 20.599 21.610 22.736 23 .655 23 .153 23 .881 23.434 21.960 21.500 22.241 21.781 23.557 24.197 23 .531 24.280 24.795 25.935 25.696 26 .750 27.256 28.314 28.057 29.111 23 .503 24.035 22.269 21.424 19. 955 18.978 17.581 16.517 15.139 21.738 21.900 21.815 22 .106 23.062 24.475 25.346 26.830 27.701 20.827 19.795 20.900 19.763 19.786 19. 780 16 .984 16.403 16 .805 15. 900 15. 849 14. 932 14. 757 13 .898 14.224 13 .363 13 .205 12.360 16 .227 15.351 17.488 17. 902 19.328 19.401 19.352 19.380 19.482 19.513 19.462 19.492.

17.763 18 .043 17.275 17 .108 17.124 17.239 17.513 17.244 17.478 15.834 14.751 15.977 14.857 15.296 15.599 16 .048 15.945 16 .322 14 .311 14 .991 13 .075 12.426 7.636 1.00 82.38 9.497 1.00 81.51 6.783 1.00 72.31 7.866 1.00 71.41 5.894 1.00 71.44 6.143 1.00 70.07 4.921 1.00 66.96 3.834 1.00 66.43 2.657 1.00 66.60 1.653 1.00 68.33 3.981 1.00 66.58 2.990 1.00 68.84 1.823 1.00 69.34 0.833 1.00 69.88 7.391 1.00 70.80 7.975 1.00 70.62 7.802 1.00 70..76 8.972 1.00 70.97 8.783 1.00 69.27 7.787 1.00 69.68 6.415 1.00 69.51 5.498 1.00 70.15 8.221 1.00 69.92 7.316 1.00 70.26 5.958 1.00 70.22 5.069 1.00 69.67 10.272 1.00 72.19 11.344 1.00 73.21 10.183 1.00 73.05 11.363- 1.00 74.81 10.953 1.00 75.63 12.102 1.00 79.16 11.576 1.00 84.09 12.634 1.00 87.56 12.097 1.00 89.36 12.156 1.00 75.72 11.586 1.00 77.14 13.477 1.00 75.08 14.363 1.00 73.36 15.477 1.00 72.88 15.007 1.00 72.87 16.167 1.00 74.66 15.828 1.00 74.84 16.981 1.00 73.74 14.982 1.00 72.45 15.007 1.00 72.74 15.469 1.00 71.26 16.107 1.00 70.05 16.206 1.00 68.30 17.060 1.00 69.34 14.839 1.00 66.16 17.504 1.00 70.37 17.892 1.00 71.47 18.263 1.00 70.80 19.969- 10.886 21.084 10.598 20.244 10.292 19.707 13.019 20.608 13.761 18.669 12.691 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 228

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

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1656 1657 1658 1659 1660 1662 1663 1664 1665 1666 1669 1670 1671 1673 1674 1675 1676 1678 1679 1680 1681 1682 1684 1685 1688 1691 1692 1693 1695 1696 1697 1698 1699 1700 1701 1702 1703 1704 1705 1706 1707 1708 1709 1711 1712 1713 1714 1715 1716 1717 1719 1720 1721 1722

CA

CB

C

0

N

CA

CB

CG

OD1 ND2

C

0

N

CA

C

0

N

CA

CB

CG

CD

NE

Cz NH1 NH2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CD

CA

CB

CG

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0

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CA

CB

CG1 CG2

C

0

N

CA

CB*

CG

CD

THR

THR

THR

THR

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

GLY

GLY

GLY

GLY

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

LEW-

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PRO

PRO

PRO

PRO

PRO

PRO

PRO

VAL

VAL

VAL

VAL

VAL

VAL

VAL

LYS

LYS

LYS

LYS

LYS

1658 1658 1658 1658 1659 1659 1659' 1659 1659 1659 1659 1659 1660 1660 1660 1660 1661 1661 1661 1661 1661 1661 1661 1661 1661 1661 1661 1662 1662 1662 1662 1662 1662 1662 1662 1663 1663 1663 1663 1663 1663 1663 1664 1664 1664 1664 1664 1664 1664 1665 1665 1665 1665 1665 18. 559 17.334 19. 844 20.429 20. 331 21. 537 21. 602 22 .419 22.261 23 .278 22.830 23. 917 22. 706 23 .859 24. 553 25. 659 23. 909 24. 504 24.255 24. 811 24. 542 24. 942 24. 731 24-.124 25.145 24. 015 22. 916 24.839 24. 503 25. 762 26.351 27. 780 25.484 23 .867 24 .548 22 .546 21.659 21. 794 20.433 20.282 22 .445 22.265 23 .200 23 .889 24 .757 23 .912 25.521 24.812 25. 157 25.211 26 .102 26 .749 27.811 28 .189 13.205 19.626 1.00 71.54 12.600 12 .865 11.639 11.157 9.635 9.032 9.410 8 .069 11 .749 11 .351 12 .654 13 .307 12 .593 12 .979 11.573 10 .826 9.334 8 .744 7 .267 6.599 5.306 4 .559 4 .754 11.288 11.812 11.080 11.481 12 .020 13 .306 13 .512 14.499 10.346 9.406 10.428 11.519 9.423 10.095 10 .901 9.059 7 .949 9. 989 9. 722 10 .916 11.929 11.554 8 .511 7 .903 8.171 7 .044 7.153 8.231 8.628 20.325 20.394 21.063 20.199 20. 871 20.796 21.916 23 .076 21.583 20.318 20.733 19.348 18.750 17.597 17.199 17.037 15.928 16 .092 17.365 17.361 18.595 18.826 17.901 19.965 14 .560 14.429 13 .542 12 .186 11.492 12.088 11.641 11. 705 11.370 10.957 11.118 11.561 10.351 10.158 11.414 9. 012 8 .521 8.426 7.160 6.659 5. 968 7.792 7.266 6.257 8.489 8.726 10.098 10.140 11.548 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 71.20 70.91 71.25 68.87 65 .52 67.39 69.42 71.70 68 .93 62.51 61.47 59.76 57.70 56. 98 57.55 55.34 52.28 50.68 49.61 52 53.64 56 .32 54 .04 54.48 49.89 51.43 45 .78 43 42 40.60 38.14 42 .00 41.81 40.46 40.49 40.60 38.17 38.43 40.65 35.40 33 .01 34 .56 32.91 33 .13 33.44 33 .68 30.58 29.20 28 .02 24. 24.39 28.36 29.24 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 229 ATOM 1723 CE ATOM 1724 NZ ATOM 1728 C ATOM 1729 0 ATOM 1730 N ATOM 1732 CA ATOM 1733 CE ATOM 1734 CG ATOM 1735 CD2 ATOM 1736 CE2 ATOM 1737 CE3 ATOM 1738 CD1 ATOM 1739 NEI ATOM 1741 CZ2 ATOM 1742 CZ3 ATOM 1743 CH2 ATOM 1744 C ATOM 1745 0 ATOM 1746 N ATOM 1748 CA ATOM 1749 CE ATOM 1750 CG ATOM 1751 SD ATOM 1752 CE ATOM 1753 C ATOM 1754 0 ATOM 1755 N ATOM 17 57 CA ATOM 1758 CB ATOM 1759 C ATOM 1760 0 ATOM 1761 N ATOM 1762 CD ATOM 1763 CA ATOM 1764 CB ATOM 1765 CG ATOM -1766 C ATOM 1767 0 ATOM 1768 N ATOM 1770 CA ATOM 1771 CE ATOM 1772 CG ATOM 1773 CD ATOM 1774 OE1 ATOM 1775 0E2 ATOM 1776 C ATOM 1777 0 ATOM 1778 N ATOM 1780 CA ATOM 1781 CE ATOM 1782 C ATOM 1783 0 ATOM 1784 N ATOM 1786 CA LYS 1665 LYS 1665 LYS 1665 LYS 1665 TRP 1666 TRP 1666 TRP 1666 TRP 1666 TRP 1666 TRP 1666 TRP 1666 TRP 1666 TRP 1666 TRP 1666 TRP 1666 TRP 1666 TRP 1666 TRP 1666 MET 1667 MET 1667 MET 1667 MET 1667 MET 1667 MET 1667 MET 1667 MET 1667 ALA 1668 ALA 1668 ALA 1668 ALA 1668 ALA 1668 PRO 1669 PRO 1669 PRO 1669 PRO 1669 PRO 1669 PRO 1669 PRO 1669 GLU 1670 GLU 1670 GLU 1670 GLU 1670 GLU 1670 GLU 1670 GLU 1670 GLU 1670 GLU 1670 A.LA 1671 ALA 1671 ALA 1671 ALA 1671 ALA 1671 LEU 1672 LEU 1672 29.269 29.639 25.440 26 .096 24.138 23 .414 22 .157 22.428 22.930 23 .063 23 .286 22.276 22.659 23 .535 23 .758 23.877 23 .048 22 .573 23.355 23.022 22 .828 21.704 21.567 20.959 23.984 25.182 23 .420 24 .186 23 .272 24.738 24 .044 25 .972 26.867 26.571 27.814 28.193 25.647 25.496 24. 993 24.110 23.680 22 .662 23 .280 22.488 24 .526 22.896 22.348 22.477 21.342 20.751 21.826 21.159 23 .013 23 .636 9.690 10. 194 5. 692 4. 671 5.698 4.46.1 4 .412 3.,931 4. 714 3. 837 6. 057 2 .656 2 .592 4 .264 6.484 5.587 4.345 3.301 5.390 5 .444 6 .893 7.630 9.283 8 .858 4.807 5. 047 4 .034 3.398 2 .509 4 .528 5 .521 4 .374 3.214 5.418 4 .731 3 .809 5. 909 7.107 4 .997 5 .423 4 .233 3 .294 2 .162 1.309 2 .114 6.229 7 .037 6 .009 6 .744 5.989 8 .124 9 .135 8.139 9 .352 11.489 1.00 31.15 12.836 1.00 35.47 8.543 1.00 25.16 8.627 1.00 24.34 8.286 1.00 25.16 8.053 1.00 26.61 8.917 1.00 28.17 10.330 1.00 30.26 11.426 1.00 26.92 12.537 1.00 26.34 11.598 1.00 24.69 10.800 1.00 26.44 12.118 1.00 25.65 13.779 1.00 24.97 12.837 1.00 22.23 13.908 1.00 24.97 6.572 1.00 27.24 6.116 1.00 29:'16 5.811 1.00 26.70 4.398 1.00 25.21 3.963 1.00 28.81 4.637 1.00 35.42 3.924 1.00 42.64 2.369 1.00 41.32 3.417 1.00 25.03 3.446 1.00 24.24 2.501 1.00 26.70 1.441 1.00 27.82 0.601 1.00 25.36 0.575 1.00 28.42 0.321 1.00 27.52- 0.065 1.00 28.95 0.170 1.00 27.98 -0.775 1.00 28.76 -1.326 1.00 28.58 -0.209 1.00 30.22 -1.893 1.00 27.08 -2.093 1.00 28.31 -2.595 1.00 25.42 -3.673 1.00 27.02 -4.542 1.00 27.18 -3.911 1.00 27.66 -3.112 1.00 27.75 -2.647 1.00 27.12 -2.944 1.00 21.64 -3.189 1.00 26.88 -3.929 1.00 24.52 -1.948 1.00 29.43 -1.392 1.00 29.29 -0.217 1.00 26.98 -0.939 1.00 31.14 -1.143 1.00 31.67 -0.343 1.00 32.31 0.154 1.00 33.79 SSSD/55145. vOl WO 98/07835 PCT/US97/14885' 230

ATOM

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ATOM

ATOM

ATOM

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ATOM

ATOM

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ATOM

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ATOM

ATOM

1787 1788 1789 1790 1791 1792 1793 1795 1796 1797 1798 1799 1800 1801 1802 1803 1804 1805 1807 1808 1809 1810 1811 1812 1813 1814 1816 1817 1818 1819 1820 1822 1823 1826 1829 1830 1831 i833 1834 1835 1836 1837 1838 1839 1840 1842 1843 1844 1845 1846 1847 1848 1849 1850

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD1 CD2 CEl CE2 cz

C

0

N

CA

CB

CG

OD1 0D2

C

0

N

CA

CB

CG.

CD

NE

CZ

NH1 NH2

C

0

N

CA

CB

CG1 CD1

C

0

N

CA

CB

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OH

LEU

LEU

LEU

LEU

LEU

LEU

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PilE PilE

PHE

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PHE

PilE

ASP

ASP

AS P

ASP

ASP

AS P

ASP

ASP

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ARG

ARG

ARG

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ARG

ARG

ARG

ARG

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

1672 1672 1672 1672 1672 1672 1673 1673 1673 1673 1673 1673 1673 1673 1673 1673 1673 1674 1674 1674 1674 1674 1674 1674 1674 1675 1675 1675 1675 1675 1675 1675 1675 1675 1675 1675 1676 1676 1676 1676 1676 1676 1676 1676 1677 1677 1677 1677 1677 1677 1677 1677 1677 1677 24. 841 25.. 585 24 .713 26. 863 24. 078 23 .789 24 .770 25. 266 26 .553 27 .661 28.313 28. 055 29. 346 29. 090 29. 736 24.273 24. 135 23. 584 22.650 22 .917 24 .362 25. 030 24 .828 21.162 20.315 20. 840 19. 445 18 .832 19.413 19. 516 20. 060 19.652 18.695 20. 177 18.617 17.447 19.235 18. 545 19. 358 18.-552 19. 708 20. 799 18.315 19. 245 17. 082 16 .701 15 .771 16.457 16.598 17.212 16. 952 17. 567 17. 688 18.238 8 .986 10 .166 10 .840 9.665 10 .280 11 .478 9 .723 10 .504 9. 874 9.761 8.545 10.867 8 .419 10 .757 9.525 10 .670 11 .754 9. 588 9.601 8 .392 8 .288 9.340 7.145 9.632 9. 506 9.745 9. 791 11 .137 12 .299 13 .551 14 .664 15.925 16 .253 16 .855 8.639 8 .808 7.475 6 .313 5 .644 4.529 6 .663 6 .200 5 .315 4 .632 5 .279- 4 .371 5 .074 6 .136 7 .432 8 .424 5 .857 6 .842 8 .125 9 .118 1.008 1.618 2 .666 2.237 -0.972 -0.949 -1.957 -3.075 -3.625 -2.617 -2.419 -1.861 -1.484 *-0.919 -0.732 -4.217 -4.765 -4.572 -5.698 -6.600 7. 041 -7.194 -7.251 -5.360 -6.257 -4.077 -3.650 -4.039 -3.269 -4 .127 -3.349 -3.453 -4.312 -2.665 -4.221 -4.557 -4.351 -4.874 -5.976 -6.602 -7.050 -7.962 -3.743 -3.300 -3.246 -2.173 -1.208 -0.406 -0.905 -0.159 0.863 1.621 1.110 1.888 1.00 1.00 1.00 1. 00 1.00 1.00 1.00' 1.00 1.00.

1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 34.49 37.16.

42.22 33 .93 36.30 39.09 34.39 33.81 33 33.44 32 .17 34. 87 31.*98 36.31 34.55 34.79 35 .74 37.31 35.61 37.01 41.02 43 .07 42 .24 37.06 36.37 37.78 39.41 44.39 54 63 .84 73.69 77.10 79.65 79.31 37.46 38.57 34.37 32.99 33 .98 35.04 34.92 41.16 31.55 30.65 30.88 27.10 28.30 30.61 30.82 30.75 29.75 32.62 34.51 38.89 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 231

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1852 1853 1854 1856 1857 1858 1860 1861 1862 1863 1865 1866 1867 1868 1869 1871 1872 1874 1875 1876 1878 1879 1880 1881 1882 1883 1886 1887 1888 1890 1891 1892 1894 1895 1896 1898 1899 1900 1901 1902 1903 1904 1905 1907 1908 1909 1910 1911 1912 1913 1915 1916 1917 1918

C

0

N

CA

CB

OGi CG2

C

0

N

CA

CB

CG

CD2

NDI

CEl NE2

C

0

N

CA

CB

CG

CD

OE 1 NE2

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

ODI

0D2

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

-CB

CG

CD2

TYR

TYR

THR

THR

THR

THR

THR

THR

THR

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

SER

SER

SER

SER

SER

SER

AS P

ASP

ASP

ASP

ASP

ASP

AS P

ASP

VAL

VAL

VAL

VAL

VAL

VAL

VAL

TRP

TRP

TRP

TRP

TRP

1677 1677 1678 1678 1678 1678 1678 1678 1678 1679 1679 1679 1679 1679 1679 1679 1679 1679 1679 1680 1680 1680 1680 1680 1680 1680 1680 1680 1681 1681 1681 1681 1681 1681 1682 1682 1682 1682 1682 1682 1682 1682 1683 1683 1683 1683 1683 1683 1683 1684 1684 1684 1684 1684 16.029 15. 132 16.459 15. 942 16.830 18. 165 16. 843 15. 979 16. 379 15. 569 15. 591 14. 853 13. 390 12.627 12. 532 11. 310 11.339 17. 056 17.419 17. 898 19. 341 19. 998 19. 741 19.212 18. 683 19. 357 19. 998 20. 925 19. 533 20. 133 19.821 18.445 19.696 20.439 18.530 18. 054 16.607 15. 603 14.410 15. 976 18. 926 19. 121 19.433 20.300 20. 562 21. 724 19.292 21. 584 22. 030 22 .141 23 .349 23.659 24. 802 26 .114 3.149 3 .264 1. 983 0. 701 0. 123 -0.008 1.009 -0.297 0.036 -1.530 -2 .560 -3.812 592 -3 .758 -3.137 -3 .028 -3 .400 -2 .846 -3.179 -2.604 -2.800 781 -4 .050 -3.763 -2 .686 -4 .713 -1.767 2 094 -0.521 0.480 1. 919 2 .126 0.189 0.455 -0.436 -0.816 -1.293 -0.165 -0.425 0 .960 -1.941 -2 .057 -2 .788 -3 .888 -4 .881 -5.802 -5.713 -3.298 -3.688 -2 .320 -1.633 -0.446 0.410 0.468 -2.743 -3.578 -2 .272 734 -3.853 -3.349 -5.085 577 -0.465 -1.844 818 -1.298 -1.536 -2 .643 -0.551 -1.04.1 -2.307 -0.514 0.613 -1.516 -1.406 782 -3 577 949 -5.187 -5.867 -0.514 0.224 562 0.303 151 -0.425 1.741 2.681 1.900 3.231 3 .180 3.352 3.108 3 .757 3 .777 4. 990 2.884 3.302 2.141 2.459 1.889 3.860 4. 938 3 .154 3.611 2.680 3.145 2. 587 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 00 1.00 1.00 1.00 1.00 1.00 1.00 25.47 26.00 24.27 24.09 24.19 27.81 24.15 25. 02 27.65 25.04 24.35 23.78 27.24 28.22 30.64 28.13 28.52 22.52 22. 58 24.34 23.52 25.36 33.28 34.68 41.24 32.10 23 .38 25 .12 20.87 20.53 19.58 20.67 22 .22 23.62 22.44 22 24.24 28.23 28.14 25.23 23. 92 26.24 23.67 22.42 23. 19. 73 19.85 21. 94 22.69 20.51 20.31 19.01 20.67 22.26 145. vOl WO 98/07835 PCTUS97/14885 232 ATOM 1919 CE2 TRP 1684 26.890 1.316 3.408 1.00 21.22 ATOM 1920 CE3 TRP 1684 26.718 -0.127 1.463 1.00 22.51 ATOM 1921 CD1 TRP 1684 24.825 1.229 4.248 1.00 19.91 ATOM 1922 NEl TRP 1684 26.079 1.763 4.414 1.00 18.59 ATOM 1924 CZ2 TRP 1684 28.236 1.586 3.148 1.00 20.81 ATOM 1925 CZ3 TRP 1684 28.059 0.141 1.204 1.00 22.01 ATOM 1926 CH2 TRP 1684 28.806 0.992- 2.047 1.00 23.34 ATOM 1927 C TRP 1684 23.131 -1.150 5.069 1.00 21.49 ATOM 1928 0 TRP 1684 23.958 -1.412 5.954 1.00 23.34 ATOM 1929 N SER 1685 22.015 -0.463 5.308 1.00 21.84 ATOM 1931 CA SER 1685 21.652 0.042 6.634 1.00 20.02 ATOM 1932 CB SER 1685 20.310 0.773 6.559 1.00 19.12 ATOM 1933 OG SER 1685 20.335 1.791 5.578 1.00 21.62 ATOM 1935 C SER 1685 21.551 -1.111 7.648 1.00 22.64 ATOM 1936 0 SER 1685 21.908 -0.946 8.829 1.00 22.09 ATOM 1937 N PHE 1686 21.043 -2.266 7.202 1.00 22.44 ATOM 1939 CA PHE 1686 20.939 -3.438 8.075 1.00 22.91 ATOM 1940 CB PHE 1686 20.196 -4.588 7.380 1.00 23.75 ATOM 1941 CG PHE 1686 20.027 -5.808 8.256 1.00 23.61 ATOM 1942 CDI PHE 1686 19.220 -5.757 9.388 1.00 21.21 ATOM 1943 CD2 PHE 1686 20.731 -6.976 7.990 1.00 23.91 ATOM 1944 CEl PHE 1686 19.118 -6.836 10.240 1.00 20.66 ATOM 1945 CE2 PHE 1686 20.636 -8.074 8.841 1.00 22.47 ATOM 1946 CZ PHE 1686 19.828 -7.999 9.972 1.00 23.35 ATOM 1947 C PHE 1686 22.339 -3.904 8.522 1.00 22.60 ATOM 1948 0 PHE 1686 22.526 -4.382 9.646 1.00 22.83 ATOM 1949 N GLY 1687 23.312 -3.770 7.626 1.00 23.82 ATOM 1951 CA GLY 1687 24.682 -4.140 7.941 1.00 22.58 ATOM 1952 C GLY 1687 25.175 -3.262 9.071 1.00 21.49 ATOM 1953 0 GLY 1687 25.832 -3.749 9.990 1.00 21.62 ATOM 1954 N VAL 1688 24.849 -1.968 9.008 1.00 21.15 ATOM 1956 CA VAL 1688 25.229 -1.008 10.052 1.00 20.56 ATOM 1957 CB VAL 1688 24.894 0.479 9.647 1.00 17.69 ATOM 1958 CG1 VAL 1688 25.408 1.456 10.690 1.00 15.11 ATOM 1959 CG2 VAL 1688 25.518 0.821 8.314 1.00 11.54 ATOM 1960 C VAL 1688 24.494 -1.398 11.346 1.00 22.60 ATOM 1961 0 VAL 1688 25.083 -1.407 12.428 1.00 25.23 ATOM 1962 N LEU 1689 23.215 -1.755 11.229 1.00 26.09 ATOM 1964 CA LEU 1689 22.423 -2.175 12.387 1.00 25.16 ATOM 1965 CB LEU 1689 20.976 -2.455 11.965 1.00 25.91 ATOM 1966 CG LEU 1689 19.913 -2.560 13.068 1.00 27.54 ATOM 1967 CD1 LEU 1689 18.557 -2.241 12.496 1.00 28.11 ATOM 1968 CD2 LEU 1689 19.898 -3.940 13.704 1.00 31.67 ATOM 1969 C LEU 1689 23.055 -3.426 13.018 1.00 27.49 ATOM 1970 0 LEU- 1689 23.128 -3.532 14.246 1.00 28.99 ATOM 1971 N LEU 1690 23.485 -4.374 12.180 1.00 27.67 ATOM 1973 CA LEU 1690 24.149 -5.596 12.643 1.00 26.76 ATOM 1974 CB LEU 1690 24.616 6.453 11.456 1.00 28.58 ATOM 1975 CG LEU 1690 23.651 -7.406 10.733 1.00 29.46 ATOM 1976 CD1 LEU 1690 24.372 -8.064 9.565 1.00 27.79 ATOM 1977 CD2 LEU 1690 23.130 -8.488 11.691 1.00 28.15 ATOM 1978 C LEU 1690 25.362 -5.176 13.476 1.00 26.19 ATOM 1979 0 LEU 1690 25.565 -5.670 14.597 1.00 25.29 ATOM 1980 N TRP 1691 26.124 -4.217 12.946 1.00 25.89 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 233

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1982 1983 1984 1985 1986 1987 1988 1989 1991 1992 1993 1994 1995 1996 1998 1999 2000 2001 2002 2003 2004 2005 2006 2008 2009 2010 2011 2012 2013 2014 2015 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2029 2030 2031 2033 2034 2035 2036 2038 2039 2040 2041 2042

CA

CB

CG

CD2 CE2 CE3 CD1

NEI

CZ2 CZ3 CH2

C

0

N

CA

CB

CG

CD

OE1 OE2

C

0

N

CA

CP

CG2 CG1 CD1 c 0

N

CA

CB

CG

CD1 CD2

CEI

CE2 Cz

C

0

N

CA

CB

OG1 CG2

C

0

N

CA

CB

CG

CDI

CD2

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

THR

THR

THR

THR

THR

THR

THR

LEU

LEU

LEU

LEU

LEU

LEU

1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1692 1692 1692 1692 1692 1692 1692 1692 1692 1693 1693 1693 1693 1693 1693 1693 1693 1694 1694 1694 1694 1694 1694 1694 1694 1694 1694 1694 1695 1695 1695 1695 1695 1695 1695 1696 1696 1696 1696 1696 1696 27.302 27.979 29.338 29.606 31.001 28.792 30.562 31.557 31.617 29.398 30.802 26.947 27.708 25.808 25 .349 24.120 24.273 22.982 22.224 22.696 24.958 25.099 24.421 24.02.7 23.205 22.983 21.840 21.005 25.259 25.320 26.273 27.473 28.143 27.223 26.628 26.809 25.625 25.805 25.210 28.429 29.376 28.157 28.934 29.412 28.287 30.305 28.053 28.430 26.898 25.915 26.356 26.658 27.205 25.398 -3.682 -2.628 -2.170 -1.060 -0.988 -0.118 -2.712 -2.010 -0.011 0.851 0.900 -3.088 -3 .245 -2.400 -1.817 -0.935 0.221 0.989 0.744 1.816 -2.918 2.753 -4.023 -5.125 -6.226 -7.469 -5.658 6.585 -5.750 -5.902 -6.043 -6.677 7.525 -8.574 -8.424 -9.630 -9.294 -10.508 -10.337 -5.784 -6.273 -4.480 -3.532 -2.333 -1.652 -2.800 -3.034 -2.103 -3.687 -3.364 -3.886 -5.379 -5.717 -6.150 13.631 12.755 13.257 14.134 14.297 14.778 12.944 13.567 15.097 15.573 15.719 15.012 15.974 15.104 16.371 16.171 15.219 15.100 14.148 15.982 17.352 18.557 16 .844 17.712 16. 944 17.842 16 .508 15.635 18.. 357 19.575 17.552 18.095 17.011 16.463 15.220 17.269 14.801 16.857 15.628 18.890 19.509 18.897 19.670 18.823 18.274 17.706 20.822 21.548 20.988 22.029 23.394 23.476 24.849 23.191 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 27.31 25.21 27.00 24 .28 23 .03 22.80 24.10 23.41 25.00 26.78 27.78 28.70 29.56 29.51 27.55 28.35 24.70 25.44 24.34 27.57 28.74 28.76 29.23 27.48 26.80 22.98 27.36 24.84 27.27 28.15 27.83 29.88 28.66 29.92 30.20 30.81 32 .42 32.30 31.13 31.07 33 .16 29.20 27.38 24 .77 26.27 20.18 29.84 32.77 28.52 28.82 32.50 33.24 34.15 37.24 SSSD/55145. vOl WO 98/07835 PCT/US97/14885' 234 ATOM 2043 C LEU 1696 25.553 -1.888 22.131 1.00 26.98 ATOM 2044 0 LEU 1696 25.579 -1.297 23.207 1.00 27.59 ATOM 2045 N GLY 1697 2S. 14 E -1.317 21.007 1.00 27.86 ATOM 2047 CA GLY 1697 24.767 0.074 20.980 1.00 27.40 ATOM 2048 C GLY 1697 25.927 0.962 20.618 1.00 27.47 ATOM 2049 0 GLY 1697 25.957 2.132 20.998 1.00 28.78 ATOM 2050 N GLY 1698 26.888 0.416 19.885 1.00 27.26 ATOM 2052 CA GLY 1698 28.031 1.212 19.482 1.00 29.54 ATOM 2053 C GLY 1698 27.651 2.301 18.492 1.00 31.17 ATOM 2054 0 GLY 1698 26.669 2.177 17.755 1.00 33.73 ATOM 2055 N SER 1699 28.418 3.380 18.481 1.00 29.96 ATOM 2057 CA SER 1699 28.168 4.491 17.577 1.00 29.37 ATOM 2058 CB SER 1699 28.438 5.810 18.319 1.00 31.77 ATOM 2059 OG SER 1699 28.575 6.919 17.431 1.00 38.42 ATOM 2061 C SER 1699 29.093 4.350 16.369 1.00 27.98 ATOM 2062 0 SER 1699 30.299 4.310 16.529 1.00- 28.18 ATOM 2063 N PRO 1700 28.537 4.240 15.153 1.00 29.62 ATOM 2064 CD PRO 1700 27.104 4.-259 14.794 1.00 31.22 ATOM 2065 CA PRO 1700 29.381 4.107 13.958 1.00 28.95 ATOM 2066 CB PRO 1700 28.356 4.003 12.807 1.00 27.21 ATOM 2067 CG PRO 1700 27.095 3.556 13.460 1.00 29.33 ATOM 2068 C PRO 1700 30.205 5.379 13.773 1.00 '28.78 ATOM 2069 0 PRO 1700 29.737 6.469 14.110 1.00 30.04 ATOM 2070 N TYR 1701 31.426 5.239 13.264 1.00 28.35 ATOM 2072 CA TYR 1701 32.296 6.390 12.987 1.00 30.77 ATOM 2073 CB TYR 1701 31.921 6.987 11.615 1.00 31.67 ATOM 2074 CG TYR 1701 32.060 6.037 10.454 1.00 34.:61 ATOM 2075 CD1 TYR 1701 30.952 5.673 9.686 1.00 -38.26 ATOM 2076 CEl TYR 1701 31.083 4.806 8.587 1.00 40.99 ATOM 2077 CD2 TYR 1701 33.301 5.520 10.106 1.00 38.16 ATOM 2078 CE2 TYR 1701 33.449 4.662 9.020 1.00 41.04 ATOM 2079 CZ TYR 1701 32.343 4.312 8.263 1.00 43.11.

ATOM 2.080 OH TYR 1701 32.531 3.478 7.181 1.00 49.53 ATOM 2082 C TYR 1701 32.305 7.532 14.029 1.00 31.41 ATOM 2083 0 TYR 1701 32.026 8.689 13.698 1.00 33.59 ATOM 2084 N PRO 1702 32.635 7.230 15.296 1.00 30.92 ATOM 2085 CD PRO 1702 32.998 5.938 15.888 1.00 32.30 ATOM .2086 CA PRO 1702 32.656 8.283 16.314 1.00 30.05 ATOM .2087 CB PRO 1702 33.123 7.548 17.561 1.00 27.77 ATOM 2088 CG PRO 1702 32.676 6.174 17.338 1.00 32.34 ATOM 2089 C PRO 1702 33.659 9.366 15.944 1.00 31.42 ATOM 2090 0 PRO 1702 34.769 9.055 15.513 1.00 30.95 ATOM 2091 N GLY 1703 -33.257 10.627 16.117 1.00 31.30 ATOM 2093 CA GLY 1703 34.122 11.751 15.817 1.00 29.66 ATOM 2094 C GLY 1703 34.172 12.138 14.351 1.00 31.00 ATOM 2095 0 GLY 1703 34.752 13.165 13.999 1.00 30.69 ATOM 2096 N VAL 1704 33.551 11.331 13.491 1.00 31.11 ATOM 2098 CA VAL 1704 33.553 11.610 12.059 1.00 29.88 ATOM 2099 CB VAL 1704 33.539 10.310 11.244 1.00 28.41 ATOM 2.100 CG1 VAL 1704 33.585 10.624 9.750 1.00 26.24 ATOM 2101 CG2 VAL 1704 34.702 9.429 11.649 1.00 24.10 ATOM 2102 c VAL 1704 32.396 12.508 11.604 i.00 30.80 ATOM 2103 0 VAL 1704 31.224 12.146 11.712 1.00 32.50 ATOM 2104 N PRO 1705 32.718 13.705 11.104 1.00 30.86 S5SD/55 145. vOl WO 98/07835 PCT/US97/14885 235

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM-

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2105 2106 2107 2108 2109 2110 2111 2113 2114 2115 2116 2117 2118 2119 2121 2122 2123 2124 2125 2127 2128 2129 2130 2131 2132 2133 2134 2135 2137 2138 2139 2140 2141 2142 2143 2144 2146 2147 2148 2149 2150 2151 2152 2153 2154 2155 2156 2158 2159 2160 2161 2162 2163 2167

CD

CA

CB

CG

C

0

N

CA

CE

CG1 CG2

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD1 CD2 CEl CE2

CZ

C

0

N

CA

CB

CG

CD

CE

NZ

C

PRO

PRO

PRO

PRO

PRO

PRO

VAL

VAL

VAL

VAL

VAL

VAL

VAL

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

1705 1705 1705 1705 1705 1705 1706 1706 1706 1706 1706 1706 1706 1707 1707 1707 1707 1707 1708 1708 1708 1708 1708 1708 1708 1708 17*08 1709 1 709 1709 1709 1709 1709 1709 1709 1710 1710 1710 1710 1710 1710 1710 1710 1710 1710 1710 1711 1711 1711 1711 1711 1711 1711 1711 34.039 31. 682 32 .400 33.774 31. 258 31. 974 30. 124 29. 560 28 .483 28.022 27. 309 30.518 30.. 682 31. 326 32.329 33.021 33.381 33. 740 33.902 34.909 35. 57.0 36. 190 37.442 38.117 37.770 34. 276 34. 927 32.997 32.285 30. 862 30. 015 30. 541 28. 563 32.222 32.412 31. 918 31. 82 8 31.531 30. 162 29. 150 29. 882 27. 873 28.611 27. 603 33.13 1 33. 134 34.231 35. 582 36. 588 38. 008 38.912 40. 311 41. 036 35.867 14 .350 14 .625 15. 971 15.607 14.264 13 .536 14.814 14 .576 15.632 15.538 15.455 14 .560 13 .585 15.649 15. 788 17.148 14 .678 14 .183 14.316 13 .268 13 .244 14.575 14. 962 14 .067 16.176 11.921 11.038 11. 774 10.532 10.563 9.363 8. 071 9.580 10.283 9.152 11.332 11.248 12.622 13 .132 12.268 14.480 12 .742 14.966 14.086 10. 739 9. 931 11.224 10.860 11. 755 11.669 12.582 12.648 11.360 9.375 11 .077 10.645 10.680 10.289 9.239 8.549 8.806 7 .474 7.172 5.738 8.106 6.320 5.570 6.189 5.139 5.267 5 .114 4.050 6.279 6.352 7.730 8 .165 7.383 6 .816 7.355 6.043 5.489 6 .374 6. 108 6.685 6.231 6.853 6.568 4 .606 4.156 3 .844 2.388 1.787 2.082 2.469 1. 984 2.764 2.274 2.670 1.803 0.877 2.373 1 .947 2.675 2.182 3.001 2.418 2.556 2.215 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1 .00 1.00 1 .00 1 .00 1 .00 1 .00 1.00 1 .00 1.00 1 .00 1.00 1.00 1 .00 1 .00 1 .00 1 .00 1 .00 1.00c 1 .00 1 .00 1.00 1.00- 1.00 1.00 *I..00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1 .00 1.00 30.59 31.47 32.75 32. 59 32.19 33 .91 32.57 31.80 34 .66 39.06 36.62 31.58 32.35 31.46 31.68 32 .59 32.23 33.47 32 33 .86 38. 54 47.63 58.35 62.88 64. 79 33.56 34.18 32 .91 13. 83 32.'28 32 .92 28.37 31.90 34.15 34 33.83 32.90 34.85 38.60 43.69 45.10 46.23 48.15' 46 31.84 29.97 32.45 34 .53 36.17 41.07 46.23 51.79 57.27 33 .82 145. vOl WO 98/07835 PCTUS97/14885 236 ATOM 2168 0 LYS 1711 36.451 8.688 1.376 1.00 33.20 ATOM 2169 N LEU 1712 35.439 8.885 3.382 1.00 34.52 ATOM 2171 CA LEU 1712 35.618 7.477 3.754 1.00 33.25 ATOM 2172 CB LEU 1712 35.094 7.211 5.189 1.00 30.99 ATOM 2173 CG LEU 1712 35.746 7.917 6.393 1.00 29.71 ATOM 2174 CD1 LEU 1712 35.047 7.552 7.678 1.00 24.11 ATOM 2175 CD2 LETJ 1712 37.208 7.552 6.497 1.00 32.21 ATOM 21 '76 C LEU 1712 34.83*3 6.631 2.744 1.00 32.16 ATOM 2177 0 LEU 1712 35.378 5.732 2.109 1.00 32.77 ATOM 2178 N LEU 1713 33.562 6.967 2.563 1.00 31.72 ATOM 2180 CA LEU 1713 32.700 6.259 1.637 1.00 33.60 ATOM 2181 CB LEU 1713 31.299 6.879 1.619 1.00 36.57 ATOM 2182 CG .LEt) 1713 30.522 6.711 2.930 1.00 37.60 ATOM 2183 CD1 LEt) 1713 29.284 7.575 2.927 1.00 35.03 ATOM 2184 CD2 LEt) 1713 30.182 5.246 3.157, 1.00 33.22 ATOM 2185 C LEt) 1713 33.285 6.248 0.236 1.00 35.33 ATOM 2186 0 LEU) 1713 33.318 5.203 -0.407 1.00' 36.00 ATOM 2187 N LYS 1714 33.741 7.405 0.234 1.00 36.24 ATOM 2189 CA LYS 1714 34.331 7.501 -1.566 1.00 36.35 ATOM 2190 CB LYS 1714 34.707 8.946 -1.900 1.00 35.82 ATOM 2191 CG LYS 1714 33.520 9.837 -2.168 1.00 37.23 ATOM 2192 CD LYS 1714 32.712 9.324 -3.337 1.00 40.53 ATOM 2193 CE LYS 1714 31.506 10.198 -3.600 1.00 44.51 ATOM 2194 NZ LYS 1714 30.747/ 9.724 -4.804 1.00 50.76 ATOM 2198 C LYS 1714 35.559 6.613 -1.701 1.00 37.60 ATOM 2199 0 LYS 1714 35.808 6.039 -2.764 1.00 40.82 ATOM 2200 N GLU 1715 36.299 6.452 -0.615 1.00 35.61 ATOM 2202 CA GLU 1715 37.49 6 5.630 -0.658 1.00 34.65 ATOM 2203 CB GLU 1715 38.517 6.188 0.320 1 00 37.83 ATOM 2204 CG GLU 1715 38.897 7.613 -0.036 1.00 42.28 ATOM 2205 CD GLU 1715 39.634 8.342 1.061 1.00 45.64 ATOM 2206 OE1 GLU 1715 39.928 7.726 2.114 1.00 43.09 ATOM 2207 0E2 GLt) 1715 39.918 9.544 0.853 1.00 47.56 ATOM 2208 C GLU 1715 37.244 4.145 -0.419 1.00 32.94 ATOM 2209 0 GLU 1715 38.177 3.348 -0.419 1.00 33.31 ATOM 2210 N GLY 1716 35.983 3.779 -0.213 1.00 29.12 ATOM 2212 CA GLY 1716 35.634 2.391 0.004 1.00 26.02 ATOM 2213 C GLY 1716 35.946 1.895 1.396 1.00 29.60 ATOM 2214 0 GLY 1716 36.223 0.715 1.588 1.00 29.81 ATOM 2215 N HIS 1717 35.879 2.783 2.379 1.00 29.97 ATOM 2217 CA HIS 1717 36.158 2.409 3.763 1.00 30.78 ATOM 2218 CB HIS 1717 36.369 3.659 4.623 1.00 33.25 ATOM 2219 CG HIS 1717 36.653 3.360 6.067 1.00 34.70 ATOM 2220 CD2 HIS 1717 37.820 3.155 6.715 1.00 32.77 ATOM 2221 NDl HIS 1717 35.656 3.219 7.010 1.00 36.90 ATOM 2223 CEl HIS 1717 36.200 2.932 8.180 1.00 35.87 ATOM 2224 NE2 HIS 1717 37.513 2.887 8.027 1.00 31.93 ATOM 2226 C HIS 1717 35.035 1.577 4.375 1.00 29.63 ATOM 2227 0 HIS 1717 33.861 1.847 4.133 1.00 30.82 ATOM 2228 N ARG 1718 35.406 0.600 5.201 1.00 27.92 ATOM 2230 CA ARG 1718 34.436 -0.258 5.878 1.00 27.30 ATOM 2231 CB ARG 1718 -34.379 -1.641 5.236 1.00 24.10 ATOM 2232 CG ARG 1718 33.939 -1.655 3.789 1.00 26.52 ATOM 2233 CD ARG 1718 32.469 -1.288 3.627 1.00 26.96 145. vOl WO 98/07835 WO 9807835PCTF1US97/14885 237 ATOM 2234 NE .ARG 1718 32.020 -1.374 2.232 1.00 24.41 ATOM 2236 CZ ARG 1718 32.090 -0.377 1.352 1.00 25.51 ATOM 2237 NH1 ARG 1718 32.611 0.801 1.706 1.00 23.61 ATOM 2240 N112 ARG 1718 31.553 -0.521 0.149 1.00 21.28 ATOM 2243 C ARG 1718 34.881 -0.384 7.330 1.00 28.81 ATOM 2244 0 ARG 1718 36.080 -0.425 7.611 1.0.0O 29.77 ATOM 2245 N MET 1719 33.920 -0.377 8.250 1.00 30.40 ATOM 2247 CA MET 1719 34.215 -0.485 9-.673 1.00 30.62 ATOM 2248 CB MET 1719 32.942 -0.339 10.497 1.00 28.91 ATOM 2249 CG MET 1719 32.235 1.003 10.316 1.00 30.85 ATOM 2250 SD MET 1719 30.829 1.237 11.432 1.00 33.27 ATOM 2251 CE MET 1719 29.521 0.416 10.561 1.00 31.81 ATOM 2252 C MET 1719 34.900 -1.793 10.005 1.00 31.32 ATOM 2253 0 MET 1719 34 .755 -2.769 9.278 1.00 31.47 ATOM 2254 N ASP 1720 35.651 -1.799 11.103 1.00 33.78 ATOM 2256 CA ASP 1720 36.387 -2.983 11.550 1.00 33.45 ATOM 2257 CB ASP 1720 37.478 -2.580 12.546 1.00 36.99 ATOM 2258 CG ASP 1720 38.585 -1.762 11.908 1.00 41.56 ATOM 2259 ODI ASP 1720 38.403 -1.339 10.742 1.00 48.43 ATOM 2260 0D2 ASP 1720 39.634 -1.546 12.568 1.00 40.99 ATOM 2261 C ASP 1720 35.473 -4.001 12.211 1.00. 32.12 ATOM 2262 0 ASP 1720 34.381. -3.657 12.668 1.00 30.89 ATOM 2263 N LYS 1721 35.944 -5.241 12.328 1.00 31.82 ATOM 2265 CA LYS 1721 .35.127 -6.270 12.953 1.00 31.71 ATOM 2266 CB LYS 1721 35.691 -7.6-79 12.747 1.00 32.34 ATOM 2267 CG LYS 1721 34.762 -8.738 13.344 1.00 34.85 ATOM 2268 CD LYS 1721 35.111 -10.155 12.961 1.00 37.39 ATOM 2269 CE LYS 1721 36.266 -10.674 13.765 1.00 41-42 ATOM 2270 NZ LYS 1721 36.348 -12.154 13.635 1.00 46-55 ATOM 2274 C LYS 1721 35.007 -6.'018 14.430 1.00 33:'40 ATOM 2275 0 LYS 1721 36.017 -5.879 15.121 1.00 34.26 ATOM 2276 N PRO 1722 33.768 -5.924 14.934 1.00 34.26 ATOM 2277 CD PRO 172*2 32.494 -6.002 14.203 1.00 32.16 ATOM 2278 CA PRO 1722 33.S46 -5.692 16.362 1.00 35.84 ATOM 2279 CB PRO 1722 32.027 -5.682 16.473 1.00 35.35 ATOM 2280 CG PRO 1722 31.575 5.255 15.108 1.00 35.35 ATOM 2281 C PRO 1722 34.105 -6.904 17.099 1.00 40.41 ATOM 2282 0 PRO 1722 34.010 -8.038 16.607 1.00 41.14 ATOM 2283 N SER 1723 34.739 -6.680 18.240 1.00 43.60 ATOM 2285 CA SER 1723 35.260 -7-.808 18.999 1.00 45.51 ATOM 2286 CE SEP 1723 36.078 -7.324 20.191 1.00 45.30 ATOM 2287 OG SER 1723 35.384 -6.300 20.879 1.00 49.62 ATOM 2289 C SER 1723 34.031 -8.589 '19.460 1.00 46.39 ATOM 2290 0 SER 1723 32.939 -8.028 19.614 1.00 45.16 ATOM 2291 N ASN 1724- 34.199 -9.891 19.631 1.00 48.53 ATOM 2293 CA ASN 1724 .33.088 -10.723 20.065 1.00 51.13 ATOM 2294 CB ASN 1724 32.509 -10.194 21.390 1.00 56.87 ATOM 2295 CG ASN 1724 33.595 -9.892 22.427 1.00 61.65 ATOM 2296 ODi ASN 1724 34.503 -10.702 22.649 1.00 63.73 ATOM 2297 ND2 ASN 1724 33.526 -8.713 23.039 1.00 64.64 ATOM 2300 C ASN 1724 32.034 -10.743 18.941 1.00 48.83 ATOM 2301 0 ASN 1724 30.846 -10.534 19.145 1 .00 50.50 ATOM 2302 N CYS 1725 32.511 -10.977 17.734 1.00 45.23 ATOM 2304 CA CYS 1725 31.654 -11.056 16.570 1.00 42.33 145. vOl WO 98/07835 PCT/US97I4885 238 ATOM 2305 CB CYS 1725 31.570 -9.702 15.854 1.00 41.48 ATOM 2306 SG CYS 1725 30.711 -9.751 14.275 1.00 40.38 ATOM 2307 C CYS 1725 32.383 -12.077 15.725 1.00 39.64 ATOM 2308 0 CYS 1725 33:.601 -12.004 15.579 1.00 42.00 ATOM 2309 N THR 1726 31.664 -13.090 15.263 1.00 35.96 ATOM 2311 CA THR 1726 32.275 -14.139 14.459 1.00 33.61 ATOM 2312 CB THR 1726 31.301 15.326 14.326 1.00 33.29 ATOM 2313 OGI THR 1726 30.071 -14.904 13.711 1.00 34.53 ATOM 2315 CG2 THR 1726 30.981 -15.861 15.696 1.00 25.84 ATOM 2316 C THR 1726 32.720 -13.629 13.092 1.00 32.27 ATOM 2317 0 THR 1726 32.257 -12.593 12.643 1.00 33.04 ATOM 2318 N ASN 1727 33.643 -14.315 12.434 1.00 32.98 ATOM 2320 CA ASN 1727 34.050 -13.850 11.114 1.00 34.97 ATOM 2321 CB ASN 1727 35.198 -14.680 10.541 1.00 39.89 ATOM 2322 CG ASN 1727 36.540 -14.271 11.103 1.00 45.37 ATOM 2323 ODI ASN 1727 37.044 -13.177 10.826 1.00 48.43 ATOM 2324 ND2 ASN 1727 37.125 -15.141 11.909 1.00 45.88 ATOM 2327 C ASN 1727 32.846 -13.947 10.192 1.00 33.97 ATOM 2328 0 ASN 1727 32.646 -13.088 9.341 1.00 35.07 ATOM 2329 N GLU 1728 32.024 -14.973 10.414 1.00 31.69 ATOM 2331 CA GLU 1728 30.814 -15.210 9.620 1.00 30.27 ATOM 2332 CB GLU 1728 30.141 -16.493 10.083 1.00 32.53 ATOM 2333 CG GLU 1728 28.932 -16.878 9.273 1.00 32.81 ATOM 2334 CD GLU 1728 28.353 18.190 9.711 1.00 36.43 ATOM 2335 OE1 GLU 1728 28.339 -18.466 10.932 1.00 36.75 ATOM 2336 OE2 GLU 1728 27.908 -18.945 8.829 1.00 41.92 ATOM 2337 C GLU 1728 29.814 -14.049 9.681 1.00 28.70 ATOM 2338 0 GLU 1728 29.234 -13.655 8.660 1.00 28.51 ATOM 2339 N LEU 1729 29.594 -13.517 10.880 1.00 26.77 ATOM 2341 CA LEU 1729 28.687 -12.393 .Ll.040 1.00 26.80 ATOM 2342 CB LEU 1729 28.228 -12.274 12.490 1.00 27.91 ATOM 2343 CG LEU 1729 27.233 -13.355 12.93.3 1.00 30.71 ATOM 2344 CD1 LEU 1729 27.095 -13.345 14.428 1.00 35.79 ATOM 2345 CD2 LEU 1729 25.885 -13.141 12.253 1.00 25.70 ATOM 2346 C LEU 1729 29.319 -11.089 10.540 1.00 27.06 ATOM 2347 0 LEU 1729 28.610 -10.177 10.126 1.00 30.27 ATOM 2348 N TYR 1730 30.650 -11.004 10.549 1.00 27.03 ATOM 2350 CA TYR 1730 31.328 -9.812 10.039 1.00 26.21 ATOM .2351 CB TYR 1730 32.792 -9.778 10.474 1.00 25.31 ATOM 2352 CG TYR 1730 33.538 -8.553 9.982 1.00 24.89 ATOM 2353 CD1 TYR 1730 33.012 -7.270 10.169 1.00 23.59 ATOM 2354 CEI TYR 1730 33.655 -6.148 9.665 1.00 24.74 ATOM 2355 CD2 TYR 1730 34.739 -8.675 9.285 1.00 22.11 ATOM 2356 CE2 TYR 1730 35.399 -7.560 8.775 1.00 22.32 ATOM 2357 CZ TYR 1730 34.853 -6.295 8.962 1.00 26.07 ATOM 2358 OH TYR 1730 35.484 -5.181 8.418 1.00 22.70 ATOM 2360 C TYR 1730 31.227 -9.878 8.509 1.00 27.71 ATOM 2361 0 TYR 1730 30.960 -8.875 7.843 1.00 28.05 ATOM 2362 N MET 1731 31.409 -11.081 7.977 1.00 27.92 ATOM 2364 CA MET 1731 31.306 -11.355 6.548 1.00 28.89 ATOM 2365 CB MET 1731 31.506 -12.853 6.317 1.00 35.84 ATOM 2366 CG MET 1731 31.068 -13.379 4.975 1.00 45.50 ATOM 2367 SD MET 1731 31.347 -15.167 4.865 1.00 56.40 ATOM 2368 CE MET 1731 32.106 -15.263 3.217 1.00 56.88 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 239

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2369 2370 2371 2373 2374 2375 2376 2377 2378 2379 2380 2382 2383 2384 2385 2386 2387 2388 2389 2391 2392 2393 2394 2395 2397 2398 2401 2404 2405 2406 2408 2409 2410 2411 2412 2413 2414 2415 2417 2418 2419 2420 2421 2422 2424 2425 2426 2427 2428 2429 2430 2431 2433 2434

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

0

N

CA

CB

CG

OD1 0D2

C

0

N

CA

CB

SG

C

0

N

CA

CB

CG

CD2 CE2 CE3 CD1 NEl CZ2 CZ3

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ASP

ASP

ASP

ASP

AS P

ASP

ASP

ASP

CYS

CYS

CYS

CYS

CYS

CYS

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

1731 29.916 1731 29.755 1732 28.915 1732 27.546 1732 26:598 1732 25.153 17732 24.008 1732 23.798 1732 27.470 1732 26.889 1733 28.068 1733 28.092 1733 28.931 1733 28.342 1733 29.456 1733 28.927 1733 28.741 1733 28.192 1734 29.922 1734 30.664 1734 32.027 1734 32.968 1734 33.247 1734 33.911 1734 35.233 1734 36.054 1734 35.732 1734 29.859 1734 29.920 1735 29.095 1735 28.259 1735 27.634 1735 28.664 1735 29.785 1735 28.356 1735 27.159 1735 26.846 1736 26.590 1736 25.547 1736 24.968 1736 23.885 1736 26.119 1736 25.386 1737 27.432 1737 28.104 1737 29.146 1737 28.572 1737 29.226 1737 28.315 1737 30.506 1737 27.319 1737 27.158 1737 28.641 1737 30.825 -10.928 -10.345 -11.203 -10.804 -11.317 -10.911 -11.593 -13.272 -9.273 -8 .729 -8.587 -7.124 -6.6.00 -6.769 -6.094 -7.051 -6.628 -5.771 -7.160 -6 .775 -7.482 -7.109 -5.621 -5.210 -5.220 5.601 9G7.

7 034 -6 .242 -8.124 -8.423 -9.813 -10.926 -10.660 -12 .068 -7.368 -6 .932 -6.951 -5.930 -5.765 -7.101 -4.595 -3.725 -4.437 -3.210 -2 .820 -2.493 -2.602 -2.159 -3.026 -2.012 -1.807 -2.127 -2 .993 6 .102 5 .041 6.932 6.639 7.718 7.492 8.684 8.002 6.559 5.620 7.537 7.545 8.700 10.058 11.295 12.693 6.270 5. 581 5. 966 4.762 4.716 5.866 5.882 4.647 4 .466 5.445 3 .277 3 478 2 .538 3.448 2.287 2.408 2.283 1.798 2.687 2.155 1.050 3.288 3.314 4.731 5.281 2.847 2.368 3.002 2.605 3 .640 4.947 6.212 7.196 6.614 5.201 6.551 8.563 7.971 1 .00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 27.79 30.68 28.02 25. 74 24-.94 22.96 24.39 18 .04 25.81 26.85 24 .84 25.27 25. 97 28.69 29.06 28.07 26. 97 28.37 28. 77 29.66 29.05 25.00 29.27 35.43 38.24 36.47 38 .57 29. 57 29.55 28.07 27. 96 28.60 31.34 31.12 36.07 27.24 25.79 26.53 24.35 22.01 21.52 24.26 24.19 22 .94 21.91 19.26 20.89 23.33 21.59 25.00 19.90 20.77 1,9. 89 21.23 145. vOl WO 98107835 PCT[US97/14885 240 ATOM 2435 CH2 TRP 1737 29.896 -2.543 8.927 1.00 21.09 ATOM 2436 C TRP 1737 28.758 -3.266 1.232 1.00 23.54 ATOM 2437 0 TRP 1737 29.653 -2.477 0.939 1.00 24.68 'ATOM 2438 N HIS 1738 28.315 -4.185 0.382 1.00 24.37 ATOM 2440 CA HIS 1738 28.877 -4.287 -0.947 1.00 24.42 ATOM 2441 CB HIS 1738 28.243 -5.436 -1.728 1.00 23.72 ATOM 2442 CG HIS 1738 29.131 -5.985 -2.801 1.00 27.20 ATOM 2443 CD2 HIS 1738 29.595 -5.425 -3.948 1.00 26.45 ATOM 2444 ND1 HIS 1738 29.681 -7.255 -2.751 1.00 29.26 ATOM 2446 CEl HIS 1738 30.436 -7.441 -3.816 1.00 29.25 ATOM 2447 NE2 HIS 1738 30.409 -6.358 -4.556 1.00 27.32 ATOM 2449 C HIS 1738 28.716 -2.970 -1.713 1.00 25.82 ATOM 2450 0 HIS 1738 27.675 -2.314 -1.660 1.00 23.96 ATOM 2451 N ALA 1739 29.802 -2.564 -2.362 1.00 26.27 ATOM 2453 CA ALA 1739 29.825 -1.346 -3.158 1.00 25.46 ATOM 2454 CB ALA 1739 31.186 -1.180 -3.789 1.00 25.70 ATOM 2455 C ALA 1739 28.754 -1.443 -4.233 1.00 26.18 ATOM 2456 0 ALA 1739 28.116 -0.455 -4.574 1.00 29.14 ATOM 2457 N VAL 1740 28.570 -2.643 -4.774 1.00 25.71 ATOM 2459 CA VAL 1740 27.560 -2.875 -5.802 1.00 26.12 ATOM 2460 CB VAL 1740 28.063 -3.841 -6.903 1.00 25.99 ATOM 2461 CG1 VAL 1740 27.102 -3.832 -8.090 1.00 23.37 ATOM 2462 CG2 VAL 1740 29.450 -3.440 -7.349 1.00 22.07 ATOM 2463 C VAL 1740 26.247 -3.400 -5.191 1.00 25.43 ATOM 2464 0 VAL 1740 26.186 -4.550 -4.704 1.00 24.93 ATOM 2465 N PRO 1741 25.170 -2.585 -5.265 1.00 24.20 ATOM 2466 CD PRO 1741 25.151 -1.277 -5.953 1.00 18.88 ATOM 2467 CA PRO 1741 23.838 -2.914 -4.734 1.00 25.28 ATOM 2468 CB PRO 1741 22.953 -1.788 -5.294 1.00 22:'75 ATOM 2469 CG PRO 1741 23.903 -0.632 *-5.398 1.00 20.99 ATOM 2470 C PRO 1741 23.299 -4.296 -5.128 1.00 25..84.

ATOM 2471 0 PRO 1741 22.787 -5.036 -4.280 1.00 25.99 ATOM 2472 N SER 1742 23.425 -4.642 -6.407 1.00 26.48 ATOM 2474 CA SER 1742 22.942 -5.919 -6.930 1.00 25.19 ATOM 2475 CB SER 1742 23.151 -5.992 -8.440 1.00 25.68 ATOM 2476 OG SER 1742 24.530 -5.943 -8.769 1.00 27. .46 ATOM 2478 C SER 1742 23.644 -7.100 -6.289 1.00 25.24 ATOM 2479 0 SER 1742 23.124 -8.218 -6.300 1.00 26.09 ATOM 2480 N GLN 1743 24.826 -6.851 -5.731 1.00 23.88 ATOM 2482 CA GLN 1743 25.590 -7.917 -5.118 1.00 24.44 ATOM 2483 CB GLN 1743 27.069 -7.733 -5.437 1.00 27.26 ATOM 2484 CG GLN 1743 27.344 -7.784 -6.940 1.00 27.39 ATOM 2485 CD GLN 1743 26.803 -9.047 -7.581 1.00 26.46 ATOM 2486 OE1 GLN 1743 27.325 -10.136 -7.339 1.00 25.80 ATOM 2487 NE2 GLN 1743 25-'760 -8.914 -8.393 1.00 27.42 ATOM 2490 C GLN 1743 25.348 -8.151 -3.633 1.00 23.20 ATOM 2491 0 GLN 1743 25.810 -9.147 -3.083 1.00 22.90 ATOM 2492 N ARG 1744 24.628 -7.243 -2.984 1.00 22.15 ATOM 2494 CA ARG 1744 24.318 -7.398 -1.568 1.00 21.23 ATOM 2495 CB ARG 1744 23.767 -6.088 -0.998 1.00 19.01 ATOM 2496 CG ARG 1744 24.705 -4.916 -1.145 1.00 17.27 ATOM 2497 CD ARG 1744 24.091 -3.605 -0.6 79 1.00 '14.79 ATOM 2498 NE ARG 1744 24.914 -2.493 -1.157 1.00 19.72 ATOM 2500 CZ ARG 1744 24.482 -1.258 -1.391 1.00 19.23 145. vOl WO 98/07835 PCT/US97/14885 241 ATOM 2501 NHI ARG 1744 23.201 -0.931 -1.201 1.00 15.90 ATOM 2504 NH2 ARG 1744 25.343 -0.343 -1.821 1.00 19.43 ATOM 2507 C ARG 1744 23.259 -8.496 -1.438 1.00 21.95 ATOM 2508 0 ARG 1744 22.585 -8.827 -2.415 1.00 25.34 ATOM 2509 N PRO 1745 23.21.3 -9.184 -0.292 1.00 20.82 ATOM 2510 CD PRO 1745 24.191 -9.219 0.804 1.00 21.25 ATOM 2511 CA PRO 1745 22.204 -10.229 -0.127 1.00 21.39 ATOM 2512 CB PRO 1745 22.687 -10.980 1.117 1.00 21.69 ATOM 2513 CG PRO 1745 23.418 -9.916 1.886 1.00 22.62 ATOM 2514 C PRO 1745 20.833 -9.585 0.102 1.00 22.15 ATOM 2515 0 PRO 1745 20.739 -8.402 0.426 1.00 23.29 ATOM 2516 N THR 1746 19.771 -10.349 -0.109 1.00 20.93 ATOM 2518 CA THR 1746 18.440 -9.827 0.107 1.00 19.90 ATOM 2519 CB THR 1746 17.391 -10.554. -0.783 1.00 20.21 ATOM 2520 OGI THR 1746 17.484 -11.974 -0.584 1.00 22.03 ATOM 2522 CG2 THR 1746 17.609 10.242 -2.255 1.00 20.82 ATOM 2523 C THR 1746 18.112 -10.095 1.557 1.00 19.77 ATOM 2524 0 THR 1746 18.842 -10.823 2.228 1.00 19.19 ATOM 2525 N PHE 1747 17.010 -9.526 2.045 1.00 23.46 ATOM 2527 CA PEE 1747 16.582 -9.7.70 3.422 1.00 21.64 ATOM 2528 CB. PHE 1747 15.473 8.794 3.827 1.00 18.89 ATOM 2529 CG PHE 1747 15.987 -7.445 4.262 1.00 17.45 ATOM 2530 CD1 PHE 1747 16.757 -7.317 5.417 1.00 17.65 ATOM 2531 CD2 PHE 1747 15.712 -6.303 3.516 1.00 15.37 ATOM 2532 CEl PHE 1747 17.242 -6.073 5.819 1.00 16.17 ATOM 2533 CE2 PHE 1747 16.189 -5.056 3.907 1.00 14.53 ATOM 2534 CZ PHE 1747 16.959 -4.941 5.065 1.00 16.88 ATOM 2535 C PHE 1747 16.11.8 1i.227 3.522 1.00 23.18 ATOM 2536 0 PHE 1747 16.271 -11.873 4.548 1.00 24.04 ATOM 2537 N LYS 1748 15.570 -11.745 2.432 1.00 .24.13 ATOM 2539 CA LYS 1748 15.137 -13.132 2.385 1.00 26.35 ATOM 2540 CB LYS 1748 14.50.2 -13.424 1.024 1.00 27.52 ATOM 2541 CG LYS 1748 14.034 -14.849 0.836 1.00 33.88 ATOM 2542 CD LYS 1748 13.598 -15.062 -0.600 1.00 41.83 ATOM 2543 CE LYS 1748 13.190 -16.506 -0.881 1.00 50.05 ATOM 2544 NZ LYS 1748 12.084 -16.986 0.005 1.00 55.70 ATOM 2548 C LYS 1748 16.359 -14.037 2.636 1.00 27.50 ATOM 2549 0 LYS 1748 16.303 -14.950 3.459 1.00 31.18 ATOM 2550 N GLN 1749 17.467 -13.761 1.949 1.00 27.24 ATOM 2552 CA GLN 1749 18.699 -14.529 2.122 1.00 27.03 ATOM 2553 CB GLN 1749 19.797 -14.039 1.169 1.00 31.80 ATOM 2554 CG GLN 1749 19.501 -14.196 -0.323 1.00 38.57 ATOM 2555 CD GLN 1749 20.460 -13.385 -1.209 1.00 39.93 ATOM 2556 OE1 GLN 1749 20.025 -12.535 -1.974 1.00 39.90 ATOM 2557 NE2 GLN 1749 21.768 -13.620 -1.068 1.00 40.23 ATOM 2560 C GLN 1749 19.205 -14.380 3.552 1.00 25.98 ATOM 2561 0 GLN 1749 19.533 -15.371 4.198 1.00 27.18 ATOM 2562 N LEU 1750 19.293 -13.133 4.018 1.00 25.20 ATOM 2564 CA LEU 1750 19.774 -12.823 5.369 1.00 25.74 ATOM 2565 CB LEU 1750 19.722 -11.317 5.631 1.00 20.99 ATOM 2566 CG LEU 1750 20.708 -10.468 4.831 1.00 20.90 ATOM 2567 CDI LEU 1750 .20.302 -8.987 4.822 1.00 19.88 ATOM 2568 CD2 LEU 1750 22.071 -10.643 5.426 1.00 17.26 ATOM 2569 C LEU 1750 18.985 -13.555 6.441 1.00 27.10 SSSD/55145. vOl WO 98107835 PCT/US97114885 242 ATOM 2570 0 LEU 1750 19.553 -14.094 7.392 1.00 27.89 ATOM 2571 N VAL 1751 17.672 -13.598 6.265 1.00 29.40 ATOM 2573 CA VAL 1751 16.798 -14.262 7.210 1.00 26.80 ATOM 2574 CB VAL 1751 15.324 -14.030 6.843 1.00 26.94 ATOM 2575 CG1 VAL 1751 14.429 -14.941 7.657 1.00 29.93 ATOM 2576 CG2 VAL 1751 14.941 -12.575 7.117 1.00 24.10 ATOM 2577 C VAL 1751 17.136 -15.745 7.228 1.00- 27.80 ATOM 2578 0 VAL 1751 17.223 -16.359 8.285 1.00 26.77 ATOM 2579 N GLU 1752 17.408 -16.300 6.056 1.00 32.26 ATOM 2581 CA GLU 1752 17.749 -17.717 5.966 1.00 35.72 ATOM 2582 CB GLU 1752 17.721 -18.173 4.504 1.00 39.33 ATOM 2583 CG GLU 1752 16.306 -18.078 3.911 1.00 49*41 ATOM 2584 CD GLU 1752 16.209 -18.421 2.429 1.00 55.88 ATOM 2585 OE1 GLU 1752 15.141 -18.138 1.835 1.00 58.00 ATOM 2586 OE2 GLU 1752 17.180 -18.978 1.863 1.00 61.03 ATOM 2587 C GLU 1752 19.093 -18.002 6.635 1.00 34.59 ATOM 2588 0 GLU 1752 19.230 -18.975 7.393 1.00 33.95 ATOM 2589 N ASP 1753 20.057 -17.114 6.401 1.00 34.38 ATOM 2591 CA ASP 1753 21.393 -17.235 6.977 1.00 32.81 ATOM 2592 CB ASP 1753 *22.338 -16.227 6.334 1.00 31.-57 ATOM 2593 CG ASP 1753 22.628 -16.556 4.888 1.00 33.'68 ATOM 2594 OD. ASP 1753 22.573 -17.755 4.536 1.00 35.14 ATOM 2595 OD2 ASP 1753 22.914 -15.624 4.104 1.00 34.44 ATOM 2596 C ASP 1753 21.378 -17.058 8.489 1.00 32.04 ATOM 2597 0 ASP 1753 21.997 -17.837 9.214 1.00 31.21 ATOM 2598 N LEU 1754 20.648 -16.045 8.955 1.00 31.00 ATOM 2600 CA LEU 1754 20.528 -15.754 10.382 1.00 29.46 ATOM 2601 CB LEU 1754 19.822 -14.426 10.598 1.00 23..47 ATOM 2602 CG LEU 1754 20.816 -13.309 10.318 1.00 23.58 ATOM 2603 CD1 LEU 1754 20.114 -11.963 10.128 1.00 20.46 ATOM 26C4 CD2 LEU 1754 21.828 -13.282 11.462 1.00 19.18" ATOM 2605 C LEU 1754 19.806 -16.866 3.1.110 1.00 31.84 ATOM 2606 0 LEU 1754 20.125 -17.178 12.254 1.00 30.78 ATOM 2607 N ASP 1755 18.832 -17.471 10.445 1.00 34.03 ATOM 2609 CA ASP 1755 18.116 -18.578 11.044 1.00 35.22 ATOM 2610 CB ASP 1755 16.973 -19.027 10.148 1.00 38.40 ATOM 2611 CG ASP .1755 16.159 -20.119 10.779 1.00 41.85 ATOM 2612 ODI ASP 1755 15.560 -19.866 11.841 1.00 47.90 ATOM 2613 OD2 ASP 1755 16.142 -21.241 10.238 1.00 46.67 ATOM 2614 C ASP 1755 19.11:4 -19.724 11.222 1.00 36.79 ATOM 2615 0 ASP 1755 19.114 -20.411 12.250 1.00 38.33 ATOM 2616 N ARG 1756 19.973 -19.920 10.226 1.00 34.81 ATOM 2618 CA ARG 1756 20.982 -20.969 10.302 1.00 34.68 ATOM 2619 CB ARG 1756 21.688 -21.100 8.959 1.00 34.78 ATOM 2620 CG ARG 1756 22.746- -22.179 8.910 1.00 35.93 ATOM 2621 CD ARG 1756 23.297 -22.306 7.511 1.00 41.60 ATOM 2622 NE ARG 1756 23.786 -21.025 6.999 1.00 46.42 ATOM 2624 CZ ARG 1756 24.889 -20.419 7.427 1.00 48.38 ATOM 2625 NH1 ARG 1756 25.637 -20.976 8.381 1.00 48.10 ATOM 2628 NH2 ARG 1756 25.236 -19.242 6.909 1.00 46.62 ATOM 2631 C ARG 1756 22.002 -20.666 11.399 1.00 36.17 ATOM 2632 0 ARG 1756 22.372 -21.541 12.177 1.00 38.33 ATOM 2633 N ILE 1757 22.433 -19.413 11.478 1.00 37.00 ATOM 2635 CA ILE 1757 23.416 -18.998 12.468 1.00 35.60 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 243

ATOM

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2636 CB 2637 CG2 2638 CG1 2639 CD1 2640 C 2641 0 2642 N 2644 CA 2645 CB 2646 CG1 2647 C G2 2648 C 2649 0 2650 N 2652 CA 2653 CB 2654 C 2655 0 2656 N 2658 CA 2659 CB 2660 CG 2661 CD1 2662 CD2 2663 C 2664 0 2665 N 2667 CA 2668 CB 2669 OGi 2671 CG2 2672 C 2673 0 2674 N 2676 CA 2677 CE 2678 OG 2680 C 2681 0 3420 PA 3421 OlA 3422 02A 3423 05* 3424 PB 3425 OlD 3426 02B 3427 03A 3428 C3B 3429 C5* 3430 C4* 3431 '04* 3432 C1* 3433 N9 3434 C4

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ILE

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VAL

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ALA

ALA

ALA

ALA

ALA

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

THR

THR

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THR

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SER

SER

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PCP

PCP

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PCP

PCP

PCP

PCP

PCP

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1757 1757 1757 1757 1757 1757 1758 1758 1758 1758 1758 1758 1758 1759 1759 1759 1759 1759 1760 1760 1760 1.760 1760 1760 1760 1760 1761 1761 1761 1761 1761 1761 1761 1762 1762 1762 1762 1762 1762 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 23. 964 24. 921 24 .693 25.097 22.866 23.531 21.634 21.016 19.560 18.918 19.560 20.983 21.38'0 20.501 20.418 19.836 21.784 21.894 22. 823 24.175 24. 954 24.284 24 .993 24.260 24.911 26.078 24 .222 24.820 24.250 24 .444 24.962 24.636 23.566 25.706 25.706 27.155 27.232 24.965 25.080 62.748 62.509 61.832 62 .744 65.226 65.246 66.527 64.334 64.345 62.337 62.479 63 .713 63 .394 64.326 65.017 -17 .588 -17 .131 -17 .612 -16 .253 -19.048 -19.556 -18 .585 -18 .584 -18 .017 -18.144 -16.560 -19.997 -20.229 -20.932 -22.325 -23.150 -22.867 -23.72S -22.375 -22.831 -22.900 -23.864 -23.847 -25.277 21. 965 -22.214 -20.963 -20.060* -18.627 -18 .154 -17.680 -20.548 -21.021 -20.436 -20.833 -20.979 -21.544 -19.775 -18.563 10.301 10.036 11. 180 8.904 11.946 13.015 11. 458 10.725 12.502 8.684 7.204 6.745 5.459 5.101 3.903 12.141 13.217 10.794 10.287 13.891 14.779 14.088 15.421 15.403 16 .773 15.009 15.988 17.128 15.182 15.589 14.459 15. 976 16 .841 15 .319 15.592 14.280 13.295 11.948 13 .886 16.607 16.919 17.141 18 .111 17.979 16.644 18 .917 19.539 19.919 20.318 21.717 22.205 23.508 22.547 22.296 7.817 9.280 7.038 7 .142 8.294 7.264 8.830 7. 584 9.635 5.839 5.587 6.169 6.680 7.712 7.840 1.00 35.54 1.00 32.41 1.00 33.77 1.00 33.49 1.00 37.28 1.00 38.42 1.00 39.19 1.00 39.84 1.00 37.62 1.00 38.30 1.00 39.62 1.00 41.98 1.00 43.36 1.00 43.31 1.00 44.00 1.00 44.52 1.00 45.98 1.00 48.78 1.00 48.93 1.00 51.47 1.00 53.63 1.00 57.84 1.00 61.83 1.00 58.57 1.00 53.60 1.00 54.00 1.00 55.77 1.00 56.64 1.00 55.76 1.00 56..20 1.00 55.25 1.00 58.16 1.00 56.85 1.00 61-.74 1.00 64.50 1.00 68.82 1.00 73.15 1.00 63.87 1.00 63.22 1.00 90.90 1.00 92.35 1.00 90.49 1.00 83.57 1.00 101.51 1.00 102.85 1.00 99.88 1.00 96.64 1.00 102.94 1.00 71.21 1.00 64.48 1.00 60.9§1 1.00 54.96 1.00 47.26 1.00 46.24 SSSD/55145. vOl WO 98/07835 PCT[US97/1 4885 248

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3694 3695 3696 3697 3699 3700 3701 3702 3703 3704 3705 3706 3707 3708 3709 3710 3712 3713 3714 3715 3716 3717 3718 3719 3721 3722 3723 3724 3726 3727 3728 3729 3730 3732 3733 3734 3735 3737 3738 3739 3740 3741 3743 3744 3745 3746 3747 3749 3750 3751 3752 3754 3755 3756 CA GLY C *GLY 0 GLY N LYS CA LYS CB LYS C LYS O LYS N PRO CD PRO CA PRO CB PRO CG PRO C PRO 0 PRO N LEU.- CA LEU CE LEU CG LEU CD1 LEU CD2 LEU C LEU 0 LEU N GLY CA GLY C GLY O GLY N GLtJ CA GLU CB GLU C GLU O GLU N GLY CA GLY C GLY 0 GLY N ALA CA ALA CB A.LA C ALA 0 ALA N PHE CA PHE CB PHE C PHE O0

PHE

N GLY CA GLY C GLY O GLY N GLN CA GLN CB GLN CG GLN 481 481 481 482 482 482 482 482 483 483 483 483 483 483 483 484 484 484 484 484 484 484 484 485 485 485 485 4 86 486 486 486 486 487 487 487 487 488 488 488 488 488 489 489 489 489 489 490 490 490 490 491 491 491 491 73 .673 72.270 72.058 71. 306 69.910 69.061 69 .284 69. 37.3 68.676 68.708 68.044 67.701 67.573 66.801 66.012 66 .650 65 .514 65. 935 67 .132 67.620 66 .755 64.317 63.158 64 .599 63 .538 64. 057.

65.230 63 .178 63 .563 64.015' 62.435 61.281 62 .781 61.798 62.218 62.938 61.780 62.106 61.362 63.607 64 .124 64.297 65 .754 66 .134 66.563 67.622 66.067 66 .710 66 .619 65.608 67.659 67.732 68 .529 68.653 4.247 -1.727 1.00 40.21 4.806 -1.873 1.00 39.78 6.015 -1.810 1.00 41.68 3.914 -2.063 1.00 39.98 4.297 -2.249 1.00 42.13 3.056 -2.566 1.00 42.73 5.050 -1.084 1.00 43.13 4.625 0.060 1.00 44.49 6.204 -1.358 1.00 43.22 6.969 -2.613 1.00 44.40 6.973 -0.290 1.00 45.44 8.295 -0.980 1.00 45.01 7.923 -2.414 1.00 43.95 6.261 0.232 1.00 47.67 5.725 -0.547 1.00 46.76 6.242 1.552 1.00 49.68 5.598 2.196 1.00 54.51 5.026 3.555 1.00 52.70 4.066 3.530 1.00 51.83 3.766 4.933 1.00 50.19 2.788 2.825 1.00 52.22 6.554 2.357 1.00 58.82 6.138 2.244 1.00 60.07 7.831 2.609 1.00 61.91 8:'810 2.778 1.00 65.89 10.16.7 3.227 2.00 69.46 10.301 3.597 1.00 70.65 1 1.165 3.241 1.00 70.72 12.521 .3.624 1.00 71.32 13.298 2.389 1.00 73.69 13.26.9 4.312 1.0.0 '70.93 12.846 4.275 1.00 71.58 14.404 4.909 1.00 70.10 15.211 5.603 1.00 68.11 16.669 5.598 1.00 67.97 17.109 4.696 1.00 67.68 17.409 6.615 1.00 67..26 18.826 6.737 1.00 66.90 19.428 7.909 1.00 68.72 19.004 6.921 1.00 67.08 18.867 8.037 1.00 65.97 19.248 5.806 1.00 66.76 19.439 5.773 1.00 65.91 20.794 6.379 1.00 66.45 18.288 6.414 1.00 63.92 18.503 7.031 1.00 63.16 17.069 6.209 1.00 59.03 15.878 6.720 1.00 51.12 14.823 5.638 1.00 48.59 14.736 4.938 1.00 45.25 14.003 5.525 1.00 48.77 12.951 4.519 1.00 47.40 13.474 3.319 1.00 49.92 12.514 2.155 1.00 56.31 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 249

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM'

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3757 3758 3759 3762 3763 3764 3766 3767 3768 3769 3770 3771 3772 3774 3775 3776 3777 3778 3779 3780 3782 3783 3784 3785 3786 3787 3788 3789 3791 3792 3793 3794 3795 3797 3798 3799 3800 3801 3802 3803 3804 3805 3807 3808 3809 3810 3811 3813 3814 3815 3816 3817 3818 3819

CD

OE1 NE2

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG

CDI

CD2

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD

OE1 OE2

C

0

N

CA

CB

C

0

N

CA

CB

CG2 CG1 CD1

C

0

GLN

GLN

GLN

GLN

GLN

VAL

VAL

VAL

VAL

VAL

VA.L

VAL

VAL

VAL

VAL

VAL

VAL

VAL

VAL

LEU

LEU

LEU

LEU

LEU

LEUJ

LEU

LEU

ALA

ALA

ALA

ALA

ALA

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU-

GLU

ALA

ALA

ALA

ALA

ALA

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

491 491 491 491 491 492 492 492 492 492 492 492 493 493 493 493 493 493 493 494 494 494 4.94 494 494 494 494 495 495 495 495 495 496 496 496 496 496 496 496 496 496 497 497 497 497 497 498 498 498 498 498 498 498 498 69. 604 70.043 69.929 68.407 69.396 67.867 68.416 67.375 67.947 66.922 68.746 67.888 69.990 70.333 71. 237 70.836 72. 717 70.952 71.542 70.691 71.236 70.482 70.834 70.809 69. 840 72.683 72. 976 73.584 74.996 75.654 75.670 75.033 76.946 77.712 78.046 76.816 77.145 76.473 78.068 78.973 79.835 79.036 80.173 79.709 81.160 80.764 82.446 83.494 84.395 85.524 83.577 82924 84.352 84.818 13.020 14.171 12.161 11.693 11.782 10.527 9.247 8.458 7.127 9.267 8.396 8 .178 7.961 7.127 863 9.319 7.713 5.806 5.711 4.763 3.450 2.387 0.908 0.508 0.086 3.541 4.20.1.

2.922 2.954 4.162 1.669 0.818 1.515 0.347 -0.538 1.142 -2.262 -3.316 -2.091 0.773 1.437 0.439 0.786 1.104 -0.372 -1.525 -0.059 -1.068 -0.993 -2.006 -1.244 0.009 -0.877 0.230 1. 088 1 .130 0.122 5. 086 5. 806 4 .752 5.205 6.042 6 .524 7.210 3 .975 3 .115 3 .845 2 .711 1.643 1.524 1. 943 3 .156 4 .233 2 .380 2 .656 1 .851 2 .021 3.479 1.229 2 .202 1.207 2 .954 2.619 3.283 3 .080 3 .711 2 .731 3 .137 1.943 1.301 0.339 0.410 -0.482 3.860 3.302 5.136 5.959 7.366 5.962 5.814 6 .090 6 .114 4 .858 4 .954 3 .591 998 7.355 7.641 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 58.79 59.63 59.05 44.46 44.15 42. 39.22 39.40 40.17 36.12 37.57 35.70 36:27 37.61 37.45 38.29 36 .53 37.54 37.32 37.67 38.41 39.16 36.43 34.69 37.48 39.30 39.21 40.08 41.70 41.63 43 .92 45.20 44 .21 43.44 45.87 53 .11 56 .68 61.87 58.18 40.97 40.91 42 .07 43.69 40.90 46 .16 46.90 48 .78 49.59 49.46 51.16 48.96 52.50 51.33 50.42 SSSD/551 45. vOl WO 98/07835 PTU9/4 250 ATOM 3820 N GLY 499 84.506 -1.952 8.119 1.00 53.87 ATOM 3822 CA GLY 499 85.314 -1.909 9.324 1.00 58.16 ATOM 3823 C GLY 499 84.759 1.094 10.483 1.00 62.44 ATOM 3824 0 GLY 499 85.510 -0.400 11.175 1.00 65.17 ATOM 3825 N LEU 500 83.454 -1.187 10.720 1.00 62.92 ATOM 3827 CA LEU 500 82.83-9 -0.453 11.822 1.00 61.93 ATOM 3828 CB LEU 500 81.339 -0.752 11.888 1.00 58.77 ATOM 3829 CG LEU 500 80.501 -0.207 10.736 1.00 56.68 ATOM 3830 CD1 LEU 500 79.047 -0.547 10.964 1.00 55.05 ATOM 3831 CD2 LEU 500 80.682 1.298 10.635 1.00 56.30 ATOM 3832 C LEU 500 83.501 -0.820 13.149 1.00 63.28 ATOM 3833 0 LEU 500 83.623 -2.002 13.487 1.00 64.91 ATOM 3834 N PRO 505 87.387 -6.451 10.091 1.00 82.92 ATOM 3835 CD PRO 505 88.522 -6.966 10.874 1.00 83.74 ATOM 3836 CA PRO 505 87.618 -5.052 9.705 1.00 80.73 ATOM 3837 CB PRO 505 89.027 -4.770 10.247-. 1.00 81.95 ATOM 3838 CG PRO 505 8965 -6.133 10.342 1.00 83.54 ATOM 3839 C PRO 505 87.514 -4.794 8.205 1.00 77.60 ATOM 3840 0 PRO 505 87.44.5 -3.651 7. 761 1.00 77.24 ATOM 3841 N ASN 506 87.488 -5.863 7.424 1.00 75.24 ATOM 3843 CA ASN 506 87.380 -5.727 5.981 1.00 72.92 'ATOM 3844 CB ASN 506 88.435 -6.589 5.283 1.00 73.87 ATOM 3845 C ASN 506 85.978 -6.122 5.529 1.00 70.43 ATOM 3846 0 ASN 506 85.719 -6.281 4.340 1.00 70.01 ATOM 3847 N ARG 507 85.075 -6.273 6.491 1.00 68.31 ATOM 3849 CA ARG 507 83.697 -6.647 6.200 1.00 65.*59 ATOM 3850 CB ARG 507 83.112 -7.429 7.378 1.00 66.34 ATOM 3851 C ARG 507 .82.846 -5.413 5.941 -1.00 62.97 ATOM 3852 0 ARG 507 83.191 -4.313 6.3*75 1.00 63.16 ATOM 3853 N vAL 508 81.740 -5.599 5.231 1.00 60.02 ATOM 3855 CA VAL 508 80.840 -4.495 4.947 1.00 58.59 ATOM 3856 CB VAL 508 80.532 4.357 3.439 1.00 58.40 ATOM 3857 CG1 VAL 508 81.813 4.196 2.658 1.00 61.14 ATOM 3858 CG2 VAL 508 79.751 -5.553 2.938 1.00 61.01 ATOM 3859 C VAL 508 79.537 -4.682 5.707 1.00 57.24 ATOM 3860 0 VAL 508 79.031 -5.803 5.836 1.00 58.42 ATOM 3861 N THR 509 79.020 3579 6.237 1.00 54.22 ATOM 3863 CA THR 509 77.769 -3.572 6.973 1.00 48.99 ATOM 3864 CB THR 509 77.971 -3.100 8.428 1.00 49.59 ATOM 3865 OGI THR 509 78.932 -3.935 9.082 1.00 51.71 ATOM 3867 CG2 THR 509 76.665 -3.166 9.198 1.00 50.69 ATOM 3868 C THR 509 76.837 -2.606 6.253 1.00 46.51 ATOM 3869 0 THR 509 77.231 -1.503 5.886 1.00 44.91 ATOM 3870 N LYS 510 75.628 -3.059 5.966 1.00 45.65 ATOM 3872 CA LYS 510 74.6 '58 -2.208 5.314 1.00 43.61 ATOM 3873 CB LYS 510 73.598 -3.058 4.632 1.00 45.46 ATOM 3874 CG LYS 510 72.845 -2.306 3.568 1.00 54.00 ATOM 3875 CD LYS 510 73.022 -2.912 2.183 1.00 58.74 ATOM 3876 CE LYS 510 72.194 -4.184 2.007 1.00 59.63 ATOM 3877 NZ LYS 510 72.711 -5.323 2.815 1.00 61.62 ATOM 3881 C LYS 510 74.065 -1.359 6.450 1.00 42.05 ATOM 3882 0 LYS 510 73.566 -1.898 7.*439 1.00 41.29 ATOM 3883 N VAL 511 74.185 -0.038 6.333 1.00 40.34 ATOM 3885 CA VAL 511 73.719 0.894 7.359 1.00 35.38 SSSD/55145. vOl WO 98/07835 PTU9/48 PCTIUS97/14885 251 ATOM 3886 CB VAL 511 74.932 1.554 8.074 1.00 33.16 ATOM 3887 CG1 VAL .511 75.761 0 .5-;01 8.795 1.00 29.24 ATOM 3888 CG2 VAL 511 75.804 2.295 7.054 1.00 30.37 ATOM 3889 C VAL 511- 72.856 2.005 6.77G 1.00 33.90 ATOM 3890 0 VAL 511 72.722 2.110 5.558 1.00 32.53 ATOM 3891 N ALA 512 72.261 2.813 7.655 1.00 31.97 ATOM 3893 CA ALA 512 71.434 3.956 7.248 1.00 31.10 ATOM 3894 CB ALA 512 70.088 3.945 7. 952 1.00 27.38 ATOM 3895 C ALA 512 72.225 5.186 7. 660 1.00 30.49 ATOM 3896 0 ALA 512 72.775 5.235 8.766 1.00 30.10 ATOM 3897 N VAL 513 72.312 6.162 6.765 1.00 30.50 ATOM 3899 CA VAL 513 73.064 7.382 7.041 1.00 29.68 ATOM 3900 CB VAL 513 74.204 7.593 6.015 1.00 28.89 ATOM 3901 CG1 VAL 513 74.966 8.856 6.334 1.00 26.30 ATOM 3902 CG2 VAL 513 75.134 6.389 5.987 1.00 26.66 ATOM-- 3903 C VAL 513 72.171 8.607 7.012 1.00 28.50 ATOM 3904 0 VAL 513 71.536 8.893 5.994 1.00 26.27 ATOM 3905 N LYS 514 72.091 9.282 8.154 1.00 29.18 ATOM 3907 CA LYS 514 71.307 10.508 8.295 1.00 31.52 ATOM 3908 CB LYS 514 70.797 10.659 9.728 1.00 33.52 ATOM 3909 CG LYS 514 69.890 9.540 10.198 1.00 35.67 ATOM 3910 CD LYS 514 69.439 9.831 .11.618 1.00 44.89 ATOM 3911 CE LYS 514 68.313 8.909 12.060 1.00 51.12 ATOM 3912 NZ LYS 514 67.029 9.137 11.307 1.00 57.11 ATOM 3916 C LYS 514 72.233 11.681 7.956 1.00 30.75 ATOM 3-917 0 LYS 514 73.390 11..698 8.379 1.00 30.08 ATOM 3918 N MET '515 71.724 12.651 7.201 1.00 29.45 ATOM 3920 CA MET 515 72.511 13.814 6.786 1.00 28.74 ATOM 3921 CB MET 515. 73.342 13..466 5.552 1.00 27.72 ATOM 3922 CG MET 515 72.487 13.034 4.378 1.00 31.56 ATOM 3923 SD MET 515 73.442 12.549 2.945 1.00 34.98 ATOM 3924 CE MET 515 73.730 10.878 3.330 1.00 31.23 ATOM 3925 C MET 515 71.585 14.966 6.444 1.00 27.75 ATOM 3926 0 MET 515 70.369 14.794 6.359 1.00 29.07 ATOM 3927 N LEt] 516 72.152 16.145 6.247 1.00 28.33 ATOM 3929 CA LEt] 516 71.348 .17.313 5.912 1.00 31.16 ATOM 3930 CB LEU 516 72.052 18.605 6.339 1.00 28.70 ATOM 3931 CG LEU 516 72.312 18.866 7.826 1.00 28.33 ATOM 3932 CD1 LEU 516 73.098 20.156 7.949 1.00 28.45 ATOM 3933 CD2 LEt] 516 71.020 18.959 8.604 1.00 21.64 ATOM 3934 C LEt] 516 71.069 17.378 4.421 1.00 33.22 ATOM 3935 0 LEt] 516 71.762 16.760 3.619 1.00 35.00 ATOM 3936 N LYS 517 70.022 18.100 4.061 1.00 34.69 ATOM 3938 CA LYS 517 69.696 18.286 2.665 1.00 34.20 ATOM 3939 CE LYS 517 68.194 18.475 2.496 1-1*00 37.45 ATOM 3940 CG LYS 517 67.403 17.264 2.950 1.00 43.71 ATOM 3941 CD LYS 517 66.157 17.072 2.126 1.00 51.25 ATOM 3942 CE LYS 517 65.123 18.135 2.419 1.00 58.56 ATOM 3943 NZ LYS 517 64.010 18.049 1.438 1.00 63.12 ATOM 3947 C LYS 517 70.482 19.533 2.259 1.00 33.81 ATOM 3948 0 LYS 517 70.991 20.244 3.130 1.00 33.17 ATOM 3949 N SER 518 70.603 19.788 0.959 1.00 33.42 ATOM 3951 CA SER 518 71.369 20.938 0.4 72 1.00 33.33 ATOM 3952 CB SER 518 71.550 20.842 -1.042 1.00 33.23 145. vOl WO 98/07835 PCTUS97/1488 252 ATOM 3953 OG SER 518 70.306 20.624 -1.678 1.00 38.84 ATOM 3955 C SER 518 70.794 22.298 0.846 1.00 33.23 ATOM 3956 0 SER 518 71.509 23.305 0.865 1.00 34.14 ATOM 3957 N ASP 519 69.510 22.313 1.178 1.00 32.77 ATOM 3959 CA ASP 519 68.825 23.541 1.570 1.00 33.26 ATOM 3960 CB ASP 519 67.401 23.563 0.995 1.00 35.10 ATOM 3961 CG ASP 519 66.484 22.503 1.617 1.00 38.98 ATOM 3962 ODi ASP 519 66.958 21.430 2.042 1.00 37.30 ATOM 3963 OD2 ASP 519 65.261 22.754 1.674 1.00 43.65 ATOM 3964 C, ASP 519 68.793 23.747 3.091 1.00 33.05 ATOM 3965 0 ASP 519 68.114 24.648 3.580 1.00 35.19 ATOM 3966 N ALA 520 69.538 22.931 3.833 1.00 31.38 ATOM 3968 CA ALA 520 69.570 23.032 5.293 1.00 29.47 ATOM 3969 CB ALA 520 70.264 21.830 5.870 1.00 29.74 ATOM 3970 C ALA 520 70.229 24.301 5.812 1.00 29.83 ATOM 3971 0 ALA 520 71.004 24.952 5.106 1.00 30.23 ATOM 3972 N THR 521 69.938 24.616 7.071 1.00 31.57 ATOM 3974 CA THR 521 70.487 25.793 7.742 1.00 34.56 ATOM 3975 CB THR 521 69.361 26.736 8.302 1.00 38.37 ATOM 3976 OGI THR 521 68.670 26.082 9.376 1.00 41.75 ATOM 3978 CG2 THR 521 68.357 27.117 7.209 1.00 38.30 ATOM 3979 C THR 521 71.353 25.363 8.916 1.00 33.22 ATOM 3980 0 THR 521 71.320 24.2C7 9.327 1.00 32.31 ATOM 3981 N GLU 522 72.092 26.310 9.479 1.00 34.43 ATOM 3983 CA GLU 522 72.951 26.042 10.619 1.00 39.53 ATOM 3984 CB GLU 522 73.634 27.340 11.068 1.00 46.35 ATOM 3985 CG GLU 522 74.398 27..271 12.402 1.00 58.03 ATOM 3986 CD GLU 522 75.772 26.603 12.301 1.00 63.14 ATOM 3987 OE1 GLU 522 76.800 27.321 12.404 1.00 61.75 ATOM 3988 0E2 GLU 522 75.824 25.359 12.158 1.00 66.35 ATOM 3989 C GLU 522 72.130 25.428 11.765 '1.00 38.40 ATOM 3990 0 GLU 522 72.642 24.622 12.543 1.00 37.92 ATOM 3991 N LYS 523 70.853 25.792 11.849 1.00 36.43 ATOM 3993 CA LYS 523 69.995 25.261 12.893 1.00 36.83 ATOM 3994 CB LYS 523 68.703 26.065 13.008 1.00 40.88 ATOM 3995 CG LYS 523 67.793 25.636 14.152 1.00 44.55 ATOM 3996 CD LYS 523 66.584 24.898 13.607 1.00 52.68 ATOM 3997 CE LYS 523 65.629 24.483 .14.708 1.00 56.04 ATOM 3998 NZ LYS 523 64.537 23.646 14.123 1.00 58.13 ATOM 4002 C LYS 523 69.689 23.804 12.601 1.00 35.27 ATOM 4003 0 LYS 523 69.645 22.985 13.513 1.00 36.58 ATOM 4004 N ASP 524 69.496 23.473 11.326 1.00 32.27 ATOM 4006 CA ASP 524 69.235 22.089 10.963 1.00 27.18 ATOM 4007 CB ASP 524 68.952 21.953 9.480 1.00 26.32 ATOM 4008 CG ASP 524 67.635 22.555 9.089 1.00 25.22 ATOM 4009 ODi ASP 524 66.662 22.394 9.848 1.00 31.78 ATOM 4010 0D2 ASP 524 67.568 23.190 8.028 1.00 24.00 ATOM 4011 C ASP 524 70.445 21.268 11.342 1.00 26.-83 ATOM 4012 0 ASP 524 70.312 20.165 11.851 1.00 28.65 ATOM 4013 N LEU 525 71.633 21.827 11.129 1.00 28.69 ATOM 4015 CA LEU 525 72.872 21.148 11.473 1.00 26.96 ATOM 4016 CB LEU 525 7*4.077 21.981 11.049 1.00 22.80 ATOM 4017 CG LEU 525 75.445 21.355 11.341 1.00 22.32 ATOM 4018 CD1 LEU 525 75.522 19.883 10.858 1.00 18.89 SSSD/55145. vOl WO 98/07835 WO 9807835PCT/US97/14885 253 ATOM 4019 CD2 LEU 525 76.504 22.212 10.704 1.00 17.44 ATOM 4020 C LEU 525 72.886 20.926 12.980 1.00 28.00 ATOM 4021 0 LEU 525 73.160 19.816 13.462 1.00 28.82 ATOM 4022 N SER 526 72.567 21.992 13.707 1.00 27.98 ATOM 4024 CA SER 526 72.496 21.994 15.168 1.00 30.78 ATOM 4025 CB SER 526 71.939 23.345 15.627 1.00 33.18 ATOM 4026 OG SER 526 71.624 23.347 17.009 1.00 42.73 ATOM 4028 C SER 526 71.599 20.865 15.704 1.00 30.56 ATOM 4029 0 SER 526 71.906 20.206 16.716 1.00 31.92 ATOM 4030 N ASP 527 70.484 20.665 15.018 1.00 28.19 ATOM 4032 CA ASP 527 69.516 19.651 15.366 1.00 27.41 ATOM 4033 CB ASP 527 68.207 19.932 14.632 1.00 27.63 ATOM 4034 CG ASP 527 67.492 21.172 15.149 1.00 27.37 ATOM 4035 ODi ASP 527 67.870 21.728 16.211 1.00 26.70 ATOM 4036 0D2 ASP 527 66.525 21.579 14.487 1.00 33.80 ATOM 4037 C ASP 527 70.007 18.241 15.063 1.00 27.36 ATOM 4038 0 ASP 527 69.722 17.309 15.816 1.00 30.13 ATOM 4039 N' LEU 528 70.716 18.077 13.952 1.00 25.76 ATOM 4041 CA LEU 528 71.245 16.765 13.588 1.00 25.29 ATOM 4042 CB LEU 528 71.777 16.771 12.143 1.00 23.65 ATOM 4043 CG LEU 528 72.283 .15.432 11.574 1.00 25.86 ATOM 4044 CD1 LEU 528 71.234 14.341 11.770 1.00 23.35 ATOM 4045 CD2 LEU 528 72.652 15.566 30.102 1.00 17.46 ATOM 4046 C LEU 528 72.351 16.368 14.578 1.00 25.66 ATOM 4047 C LEU 528 72 .418 15.210 15.015 1.00 24.02 ATOM 4048 N ILE 529 73.200 17.338 14.934 1.00 26.36 ATOM 4050 CA ILE 529 74.304 17.130 15.886 1.00 26.17 ATOM 4051 CB ILE 529 75.1-92 18.381 16.003 1.00 22.72 ATOM 4052 CG2 ILE 529 76.250 18.180 17.057 1.00 21.32 ATOM 4053 CG1 ILE 529 .75.876 18.666 14.685 1.00 20.71 ATOM 4054 CD1 ILE 529 76.621 19.965 14.675 1.00 25.60 ATOM 4055 C ILE 529 73.75,6 16.835 17.283 1.00 29.87 ATOM 4056 0 ILE 529 74.253 15.948 1.7.977 1.00 32.20 ATOM 4057 N SER 530 72.741 17.591 17.693 1.00 28.63 ATOM 4059 CA SER 530 72.143 17.381 18.991 1.00 32.21 ATOM 4060 CB SER 530 71.031 18.399 19.231 1.00 37.45 ATOM 4061 OG SER 530 70.065 18.342 18.195 1.00 49.52 ATOM 4063 C SER 530 71.598 15.956 19.075 1.00 30.96 ATOM 4064 0 SER 530 71.728 15.301 20.105 1.00 33.05 ATOM 4065 N GLU 531 70.996 15.476 17.996 1.00 29.13 ATOM 4067 CA GLU 531 70.468 14.117 17.987 1.00 29.84 ATOM 4068 CB GLU 531 69.672 13.847 16.709 1.00 30.29 ATOM 4069 CG GLU 531 69.093 12.445 16.666 1.00 27.39 ATOM 4070 CD GLU 531 68.521 12.074 15.331 1.00 31.34 ATOM 4071 OE1 GLU 531 67.929 10.981 15.228 1.00 35.90 ATOM 4072 0E2 GLO 531 68.660 12.860 14.376 1.00 38.37 ATOM 4073 C GLU 531 71.600 13.081 18.109 1.00 28.48 ATOM 4074 0 GLU 531 71.468 12.094 18.822 1.00 28.17 ATOM 4075 N MET 532 .72.682 13.281 17.364 1.00 28.12 ATOM 4077 CA MET 532 73.832 12.376 17.409 1.00 27.64 ATOM 4078 CB MET 532 74.953 12.899 16.499 1.00 .26.47 ATOM 4079 CG MET 532 76.267 12.125 16.601 -1.00 22.25 ATOM 4080 SD MET 532 77.406 12.610 15.286 1.00 30.32 ATOM 4081 CE MET 532 77.613 14.366 15.661 1.00 20.92 SS50/55 145. vOl WO 98/07835 PCT1US97/14885' 254

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4082 4083 4084 4086 4087 4088 4089 4090 4091 4092 4093 4094 4096 4097 4098 4099 4100 4101 4102 4103 4105 4106 4107 4108 4109 4110 4111 4112 4114 4115 4116 4117 4118 4119 4123 4124 4125 4127 4128 4129 4130 4131 4132 4133 4134 4136 4137 4138 4139 4140 4141 4142 4143 4145

C

0

"I

CA

CE

CG

CD

OE1 0E2

C.

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CE

CG

SD

CE

C

0

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

MET

MET

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

LYS

LYS

LYS

LYS

LYS

LYS

LYE

LYS

LYS

MET

MET

MET

MET

MET

MET

MET

MET

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

GLY

GLY

532 532 S33 533 533 533 533 533 533 533 533 534 534 534 534 534 534 534 534 535 535 535 535 535 535 535 535 536 536 536 536 536 536 536 536 536 537 537 537 537 537 537 537 537 538 538- 538 538 538 538 538 538 539 539 74.339 74 .640 74.439 74. 906 75. 071 76 .216 77.564 78. 001 78.202 73. 981 74. 455 72 .670 71.692 70 .258 69.311 67. 538 67.269 71.855 71.833 72. 048 72.239 72.347 71.089 71.160 71.251 73 .498 73 .564 '74 .515 75.757 76 .812 77.499 78.377 79.085 79.688 75.480 75.921 74 .742 74.384 73 .648 73 096 71.426 71 .684 73 .507 73 .744 72.496 71.568 70 .396 69.582 69.527 68 .399 72.236 71.. 983 73 .102 73 .744 12.328 18.832 1.00 11.267 19.364 1.00 13.497 19.442 1.00 13.594 20.802 1.00 15.064 21.177 1.00 15.745 20.433 1.00 15.070 20.661 1.00 14.969 21.823 1.00 14.643 19.678 1.00 12.850 21.774 1.00 12.093 22.637 1.00 13.014 21.588 1.00 12.346 22.444 1.00 12.751 22.082 1.00 12.594 23.278 0.50 12.682 22.961 0. 50 14.452 22.795 0.50 10.821 22.362 1.00 10.143 23.386 1.00 10.297 21.151 1.00 8.861 20.947 1.00 8.521 19.456 1.00 8.778 18.659 1.00 8.062 17.011 1.00 9.486 16.023 1.00 8.390 21.669 1.00 7.259 22.164 1.00 9.246 21.698 1.00 8.918 22.392 1.00 9.985 22.131 1.00 9.883 20.802 1.00 11.100 20.615 1.00 11.096 19.279 1.00 12.436 19.077 1.00 8.836 23.892 1.00 7.908 24.559 1.00 9.814 24.409 1.00 9.881 25.822 1.00 11.197 26.083 1.00 11.376 27.507 1.00 10.674 27.856 1.00 9.813 29.440 1.00 8.705 26.253 1.00 8.069 27.275 1.00 8.425 25.454 1.00 7.367 25.757 1.00 7.384 24.757 1.00 6.096 24.842 1.00 8.614 25.036' 1.00 8.787 24.058 1.00 6.006 25.804 1.00 5.227 26.713 1.00 5.718 24.848 1.00 4.422 24.850 1.00 27.87 30.31 27.08 28.50 29.09 28 31.08 34.15 33.60 29.91 29. 73 29.70 27.97 28.95 29.62. PRT1 29.87 PRT1 31.07 PRT1 28.36 27.02 26 .96 26.63 24.67 23.15 24 .57 24.79 27.66 28 .93 29.13 30.50 29.15 27. 71 28 .12 26.89 27.54 31.92 31.19 34.02 36.35 43 .33 54.60 67.38 62 .03 34.53 36.76 32.24 29.88 26.98 27.93 22.58 24.58 31.83 36.32 32.45 32.13 145. vOl WO 98/07835 PCTIUS9714885 255 ATOM 4146 C GLY 539 72.974 3.380 24.056 1.00 33.83 ATOM 4147 0 GLY 539 71.876 3.654 23.530 1.00 33.75 ATOM 4148 N LYS 540 73.539 2.173 24.010 1.00 33.36 ATOM 4150 CA LYS 540 72.980 1.054 23.256 1.00 37.04 ATOM 4151 CB LYS 540 74.110 0.181 22.709 1.00 39.21 ATOM 4152 CG LYS 540 74.865 0.893 21.623 1.00 48.72 ATOM 4153 CD LYS 540 75.818 0.009 20.850 1.00 56.84 ATOM 4154 CE LYS 540 76.225 0.693 19.516 1.00 62.14 ATOM 4155 NZ LYS 540 77.252 -0.102 18.805 1.00 71.02 ATOM 4159 C LYS 540 71.938 0.162 23.901 1.00 36.51 ATOM 4160 0 LYS 540 71.963 -0.096 25.113 1.00 38.52 ATOM 4161 N HIS 541 71.017 -0.295 23.058 1.00 32.98 ATOM 4163 CA HIS 541 69.963 -1.230 23.424 1.00 31.20 ATOM 4164 CB HIS 541 68.779 -0.561 24.095 1.00 30.35 ATOM 4165 CG HIS 541 67.815 -1.540 24.694 1.00 32.56 ATOM 4166 CD2 HIS 541 67.737 -2.058 25.941 1.00 32.45 ATOM 4167 ND1 HIS 541 66.795 -2.124 23.974 1.00 29.22 ATOM 4169 CEl HIS 541 66.134 -2.965 24.753 1.00 31.56 ATOM 4170 NE2 HIS 541 66.679 -2.932 25.957 1.00 32.22 ATOM 4172 C HIS 541 69.509 -1.937 22.152 1.00 32.00 ATOM 4173 0 HIS 541 69.409 -1.324 21.095 1.00 32.84 ATOM 4174 N LYS 542 69.187 -3.222 22.273 1.00 33.61 ATOM 4176 CA LYS 542 68.786 -4.061 21.154 1.00 31.54 ATOM 4177 CB LYS 542 68.653 -5.516 21.596 1.00 33.94 ATOM 4178 CG LYS 542 6.8.322 -6.451 20.437 1.00 42.34 ATOM 4179 CD LYS 542 68.083 -7.885 20.856 1.00 47.57 ATOM 4180 CE LYS 542 67.634 -8.726 19.658 1.00 52.70 ATOM 4181 NZ LYS 542 67.402 -10.146 20.023 1.00 59.51 ATOM 4185 C LYS 542 67.495 -3.611 20.487 1.00 29.57 ATOM 4186 0 LYS *542 67.268 -3.884 19.305 1.00 27.99 ATOM 4187 N ASN 543 66.649 -2.931 21.253 1.00 28.32 ATOM 4189 CA ASN 543 65.378 -2.476 20.714 1.00 28.86 ATOM 4190 CB ASN 543 64.231 -2.947 21.601 1.00 29.33 ATOM 4191 CG ASN 543 64.247 -4.452 21.811 1.00 29.64 ATOM 4192 ODI ASN 543 64.437 -4.926 22.930 1.00 33.86 ATOM 4193 ND2 ASN 543 64.106 -5.206 20.732 1.00 28.02 ATOM 4196 C ASN 543 65.252 -0.983 20.378 1.00 29.69 ATOM 4197 0 ASN 543 64.159 -0.413 20.457 1.00 30.02 ATOM 4198 N ILE 544 66.372 -0.357 20.011 1.00' 27.35 ATOM 4200 CA ILE 544 66.382 1.046 19.593 1.00 25.95 ATOM 4201 CB ILE 544 66.898 2.030 20.706 1.00 25.56 ATOM 4202 CG2 ILE 544 66.148 1.819 22.037 1.00 21.06 ATOM 4203 CG1 ILE 544 68.406 1.901 20.902 1.00 25.61 ATOM 4204 CD1 ILE 544 68.952 2.818 21.976 1.00 25.89 ATOM 4'205 C ILE 544 67.341 1.083 18.399 1.00 25.97 ATOM 4206 0 ILE 544 68.126 0.152 18.227 1.00 25.69 ATOM 4207 N ILE 545 67.226 2.095 17.537 1.00 27.27 ATOM 4209 CA ILE 545 68.129 2.243 .16.384 1.00 27.02 ATOM 4210 CB ILE 545 67.541 3.194 15.307 1.00 27.30 ATOM -4211 CG2 ILE 545 68.592 3.553 14.269 1.00 26.52 ATOM 4212 CG1 ILE 545 66.309 2.570 14.638 1.00 22.63 ATOM 4213 CD1 ILE 545 66.605 1.447 13.665 1.00 17.57 ATOM 4214 C ILE 545 69.383 2.873 16.979 1.00 28.55 ATOM 4215 0 ILE 545 69.346 4.014 17.451 1.00 29.47 SSSD/55145. vOl WO 98/07835 PCT/US97/l4885 256 ATOM 4216 N ASN 546 70.482 2.123 16.965 1.00 30.90 ATOM 4218 CA ASN 546 71.748 2.564 17.560 1.00 29.56 ATOM 4219 CB ASN 546 72.497 1.365 18.159 1.00 26.32 ATOM 4220 CG ASN 546 71.732 0.695 19.281 1.00 23.81 ATOM 4221 ODI ASN 546 71.580 1.252 20.362 1.00 27.34 ATOM 4222 ND2 ASN 546 71.267 -0.515 19.039 1.00 23.49 ATOM 4225 C ASN 546 72.700 3.330 16.653 1.00 30.99 ATOM 4226 0 ASN 546 72.679 3.169 15.430 1.00 30.98 ATOM 4227 N LEU 547 73.543 4.148 17.286 1.00 32.29 ATOM 4229 CA LEU 547 74.570 4.948 16.610 1.00 30.93 ATOM 4230 CB LEU 547 75.043 6.076 17.542 1.00 25..97 ATOM 4231 CG LEU 547 76.075 7.088 17.021 1.00 22.12 ATOM 4232 CD1 LEU 547 75.553 7.815 15.765 1.00 22.10 ATOM 4233 CD2 LEU 547 76.415 8.089 18.112 1.00 18.67 ATOM 4234 C LEU 547 75.756 4.039 16.264 1.00 30.70 ATOM 4235 0 LEU 547 76.284 3.361 17.137 1.00 34.46 ATOM 4236 N LEU 548 76-141 3.993 14.992 1.00 30.97 ATOM 4238 CA LEU 548 77.262 3.165 14.562 1.00 30.73 ATOM 4239 CB LEU 548 76.929 2.406 13.281 1.00 29.24 ATOM 4240 CG LEU 548 75.788 1.394 13.371 1.00 28.77 ATOM 4241 CD1 LEU 548 75.924 0.460 12.209 1.00 26.55 ATOM 4242 CD2 LEU 548 75.839 0.616 14.683 1.00 23.48 ATOM 4243 C JJEU 548 78.522 3.982 14.347 1.00 33.00 ATOM 4244 0 LEU 548 79.640 3.500 14.558 1. 0'0 35.92 ATOM 4245 N GLY 549 78.351 5.215 13.901 1.00 32.52 ATOM 4247 CA GIN 549 79.503 6.051 13.673 1.00 32.76 ATOM 4248 C GLY 549 79.092 7.411 13.1.80 1.00 33.72 ATOM 4249 0 GLY 549 77.895 7.707 13.092 1.00 35.01 ATOM 425.0 N ALA 550 80.089 8.226 12.840 1.00 33.47 ATOM 4252 CA ALA 550 79.848 9.566 12.337 1.00 30.69 ATOM 4253 CB ALA 550 79.555 10.509 13.497 1.00 28.66 ATOM 4254 C ALA 550 81.022 10.099 11.523 1.00 30.41 ATOM 4255 0 ALA 550 82.181 9.780 11.808 1.00 29.13 ATOM 4256 N CYS 551 80.695 10.817 10.446 1.00 30.29 ATOM 4258 CA CYS 551 81.675 11.490 9.584 1.00 28.44 ATOM 4259 CB CYS 551 81.432 11.214 8.096 1.00 27.25 ATOM 4260 SG CYS 551 81.639 9.508 7.566 1.00 28.89 ATOM 4261 C CYS 551 81.337 12.950 9.883 1. 00 27.07 ATOM 4262 0 CYS 551 80.293 13.441 9.467 1.00 29.86 ATOM 4263 N THR 552 82.184 13.616 10.658 '1.00 25.10 ATOM 4265 CA THR 552 81.952 14.997 11.047 1.00 24.37 ATOM 4266 CB THR 552 81.959 15.091 12.569 1.00 27.67 ATOM 4267 OGi THR 552 83.271 14.760 13.052 1.00 26.11 ATOM 4269 CG2 THR 552 80.951 14.120 13.164 1.00 30.41 ATOM 4270 C THR 552 83.003 15.980 10.557 1.00 24.51 ATOM 4271 0 THR 552 82.804 17.194 10.604 1.00 21.56 ATOM 4272 N GLN 553 84.151 15.441 10.162 1.0b 27.13 ATOM 4274 CA GLN 553 85.284 16.243 9.710 1.00 26.64 ATOM 4275 CB GLN 553 86.592 15.679 10.283 1.00 25.24 ATOM 4276 CG GLN 553 86.641 15.561 11.809 1.00 22.38 ATOM 4277 CD GLN .553 86.464 16.897 12.515 1.00 24.04 ATOM 4278 OE1 GLN 553 87.267 17.815 12.344 1.00 31,.50 ATOM 4279 NE2 GLN 553 85.403 17.017 13.304 1.00 21.59 ATOM 4282 C GLN 553 85.384 16.276 8.206 1.00 28.02 145. vOl WO 98/07835 PCTIUS97/14885 257 ATOM 4283 0 GLN S53 85.069 15.293 7.537 1.00 30.20 ATOM 4284 N ASP 554 85.794 17.430 7.695 1.00 28.08 ATOM 4286 CA ASP '554 86.000 17.652 6.263 1.00 30.14 ATOM 4287 CB ASP 554 87.330 17.034 5.833 1.00 29.82 ATOM 4288 CG ASP 554 88.451 17.470 6.707 1.00 31.79 ATOM 4289 0D1 ASP 554 88.699 18.666 6.767 1.00 36.45 ATOM 4290 OD2 ASP 554 89.066 16.623 7.364 1.00 33.06 ATOM 4291 C ASP 554 84.895 17.217 5.317 1.00 29.52 ATOM 4292 0 ASP 554 85.128 16.411 4.424 1.00 33.67 ATOM 4293 N GLY 555 83.709 17.793 5.488 1.00 29.02 ATOM 4295 CA GLY 555 82.586 17.476 4.621 1.00 26.05 ATOM 4296 C GLY 555 81.286 17.447 5.405 1.00 23.80 ATOM 4297 0 GLY 555 81.269 17.751 6.597 1.00 24.09 ATOM 4298 N PRO 556 80.175 17.117 4.740 1.00 23.29 ATOM 4299 CD PRO 556 80.094 16.804 3.304 1.00 18.93 ATOM 4300 CA PRO 556 78.860 17.045 5.378 1.00 23.45 ATOM 4301 CB PRO 556 77.943 16.643 4.226 1.00 22.35 ATOM 4302 CG PRO 556 78.889 15.931 3.261 1.00 24.94 ATOM 4303 C PRO 556 78.806 16.019 6.503 1.00 26.66 ATOM 4304 0 PRO 556 79.488 14.984 6.464 1.00 27.76 ATOM 4305 N LEU 557 78.006 16.324 7.522 1.00 29.14 ATOM 4307 CA LEU 557 77.842 15.440. 8.676 1.00 30.83 ATOM 4308 CB LEU 557 77.173 16.181 9.842 1.00 28.40 ATOM 4309 CG LEU 557 76.775 15.393 11.097 1.00 22.93 ATOM 4310 CD1 LEU 557 77.989 14.897 11.835 .1.00 23.02 ATOM 4311 CD2 LEU 557 75.970 16.285 11.984 1.00 23.53 ATOM 4312 C LEU 557 77.028 14.200 8,321 1.00 31.04 ATOM 4313 0 LEU 557 75.968 14.293 j.6:94 .1.00 31.89 ATOM 4314 N TYR 558 77.552 13.041 8 .700 1.00 29.8 ATOM 4316 CA TYR 558 76.891 11.773 8.460 1.00 27.80 ATOM 4317 CB TYR 558 77.741 10.878 7.562 1.00 28.04 ATOM 4318 CG TYR 558 77.895 11.339 6.122 1.00 29.98 ATOM 4319 CD 1 TYR 558 78.843 10.751 5.289 1.00 31.81 ATOM 4320 CEl TYR 558 78.980 11.140 3.956 1.00 32.22 ATOM 4321 CD2 TYR 558 77.086 12.335 5.584 1.00 31.50 ATOM 4322 CE2 TYR 558 77.214 12.729 4.256 1.00 31.57 ATOM 4323 CZ TYR 558 78.166 12.125 3.449 1.00 32.04 ATOM 4324 OH TYR 558 78.317 12.511 2'.134 1.00 33.34 ATOM 4326 C TYR 558 76.715 11.099 9.809 1.00 27.34 ATOM 4327 0 TYR 558 77.678 10.937 10.558 1.00 25.80 ATOM 4328 N VAL 559 75.464 10.798 10.147 1.00 28.06 ATOM 4330 CA VAL 559 75.118 10.118 11.394 1.00 '26.67 ATOM 4331 CB VAL 559 73.930 10.816 12.129 1.00 26.22 ATOM 4332 CG1 VAL 559 73.590 10.079 13.425 1.00 22.58 ATOM 4333 CG2 VAL 559 74.298 12.278 12.440 1.00 23.09 ATOM 4334 C VAL 559 74.745 8.715 10.943 1.00 24.32 ATOM 4335 0 VAL 559 73.665 8.464 10.412 1.00 26.37 ATOM 4336 N ILE 560 75.689 7.815 11.095 1.00 23.63 ATOM 4338 CA ILE 560 75.514 6.448 10.664 1.00 24.67 ATOM 4339 CB ILE 560 76.901 5.859 10.299 1.00 24.62 ATOM 4340 CG2 ILE 560 76.753 4.507 9.646 1.00 30.13 ATOM 4341 CG1 ILE 560 77.627 6.8610 9.326 1.00 21.87 ATOM 4342 CD1 ILE 560 79.114 6.538 9.162 1.00 22.25 ATOM 4343 C ILE 560 74.814 5.621 11.737 1.00 27.30 SSSD/55145. vOl WO 98/07835 PCTUS97/14885 258 ATOM 4344 0 ILE 560 75.306 5.505 12.865 1.00 28.80 ATOM 4345 N VAL 561 73.641 5.090 11.406 1.00 26.80 ATOM 4347 CA VAL 561 72.894 4.272 12.352 1.00 26.16 ATOM 4348 CB VAL 561 71.572 4.953 12.810 1.00 24.10 ATOM 4349 CG1 VAL 561 71.866 6.208 13.599 1.00 24.11 ATOM 4350 CG2 VAL 561 70.676 5.254 11.625 1.00 21.97 ATOM 4351 C VAL 561 72.572 '2.901 11.761 1.00 27.98 ATOM 4352 0 VAL 561 72.853 2.632 10.584 1.00 26.49 ATOM 4353 N GLU 562 71.998 2.039 12.599 .1.00 28.86 ATOM 4355 CA GLU 562 71.605 0.685 12.219 1.00 28.23 ATOM 4356 CB GLU 562 71.090 -0.068 13.440 1.00 25.86 ATOM 4357 CG GLU 562 72.170 -0.392 14.424 1.00 27.04 ATOM 4358 CD GLU 562 71.641 -0.969 15.714 1.00 28.37 ATOM 4359 OE1 GLU 562 72.389 -1.714 16.3-72 1.00 33.36 ATOM 4360 0E2 GLU 562 70.491 -0.6.65 16.092 1.00 31.60 ATOM 4361 C GLU 562 70.529 0.720 11.171 1.00 29.67 ATOM 4362 0 GLU 562 69.581 1.489 11.287 1.00 32.53 ATOM 4363 N TYR 563 70.666 -0.126 10.162 1.00 30.70 ATOM 4365 CA TYR 563 69.699 -0.209 9.083 1.00 30.65 ATOM 4366 CB TYR 563 70.419 -0.621 7.801 1.00 30.83 ATOM 4367 CG TYR 563 69.510 -0.905 6.633 1.00 32.10 ATOM 4368 CD1 TYR 563 68.545 0.018 6.236 1.00 .33.24 ATOM 4369 CEl TYR 563 67.715 0. 22? 5.160 1.00 34.65 ATOM 4370 CD2 TYR 563 69.609 -2.098 5.922 1.00 31.04 ATOM 4371 CE2 TYR 563 68.779 -2.353 4.838 1.00 33.12 ATOM 4312 CZ TYR 563 67.831 1.413 4.470 1. 00 34.22 ATOM 4373' OH TYR 563 67.002 1.650 3.400 1.00 34.76 ATOM 4375 C TYR 563 68.592 1.223 9.406 1.00 34.39 ATOM 4376 0 TYR 563 68.855 -2.325 9.884 1.00 34.87 ATOM 4377 N ALA 564 67.356 -0.861 9.091 1.00 35.49 ATOM 4379 CA ALA 564 66.212 -1.726 9.324 1.00 35.41 ATOM 4380 CB ALA 564 65.213 -1.000 10.210 1.00 35.93 ATOM 4381 C ALA 564 65.585 -2.056 7.962 1.00 37.19 ATOM 4382 0 ALA 564 64.789 -1.276 7.434 1.00 38.08 ATOM 4383 N SER 565 65.931 -3.211 7.401 1.00 37.14 ATOM 4385 CA SER 565 65.433 -3.616 6.08 0 1.00 36.83 ATOM 4386 CB SER 565 66.151 -4.881 5.614 1.00 35.24 ATOM 4387 OG SER 565 66.105 -5.873 6.619 1.00 34.96 ATOM 4389 C SER 565 63.'932 -3..782 5.886 1.00 38.65 ATOM 4390 0 SER 565 63.428 -3.617 4.760 1.00 37.80 ATOM 4391 N LYS 566 63.212 -4.077 6.964 1.00 38.96 ATOM 4393 CA LYS 566 61.772 -4.271 6.851 1.00 37.83 ATOM 4394 CE LYS 566 61.357 -5.495 7.655 1.00 39.07 ATOM 4395 CG LYS 566 61.954 -6.765 7.078 1.00 43.73 ATOM 4396 CD- LYS 566 61.813 -7.950 7.996 1.00 47.07 ATOM 4397 CE LYS 566 62.258 -9.216 7.299 1.00 47.77 ATOM 4398 NZ LYS 566 62.361 -10.326 8.278 1.00 51.48 ATOM 4402 C LYS 566 60.899 -3.050 7.165 1.00 37.53 ATOM 4403 0 LYS 566 59.702 -3.180 7.442 1.00 38.55 ATOM 4404 N GLY 567 61.496. 1.866 7.066 1.00 35.23 ATOM 4406 CA GLY 567 60.788 -062.7 7.305 1.00 33.64 ATOM 4407 C GLY. 567 60.120 0.485 8.656 1.00 33.24 ATOM 4408 0 GLY 567 60.518 -1.133 9.627 1.00 33.80 ATOM 4409 N ASN 568 59.120 0.389 8.716 1.00 31.65 SSSD/55145. vOl WO 98/07835 WO 9807835PCT1US97/1488 259 ATOM 4411 CA ASN 568 58.407 0.623 9.952 1.00 33.38 ATOM 4412 CB ASN 568 57.831 2.055 10.025 1.00 37.10 ATOM 4413 CG ASN 568 56.624 2.272 9.116 1.00 37.78 A TOM 4414 OD1 ASN 568 55.552 1.708 9.337 1.00 41.15 ATOM 4415 ND2 ASN 568 56.780 3.147 8.124 1.00 35.74 ATOM 4418 C ASN 568 57.357 -0.435 10.263 1.00 33.33 ATOM 4419 0 ASN 568 56.917 -1.178 9.384 1.00 32.54 ATOM 4420 N LEU 569 56.971 -0.490 11.532 1.00 33.35 ATOM 4422 CA LEU 569 56.004 -1.455 12.040 1.00 32.38 ATOM 4423 CB LEU 569 55.838 -1.263 13.552 1.00 27.50 ATOM 4424 CG LEU 569 54.954 -2.259 14.291 1.00 26.34 ATOM 4425 CD1 LEU 569 55.452 -3.671 14.007 1.00 24.19 ATOM 4426 CD2 LEU 569 54.968 1.951 15.787 1.00 21.44 ATOM 4427 C LEU 569 54.641 -1.433 11.355 1.00 33.35 ATOM 4428 0 LEt) 569 54.060 -2.484 11.095 1.00 34.99 ATOM 4429 N ARG -570 54.130 -0.239 11.083 1.00 34.36 ATOM 4431 CA ARG 570 52.827 -0.091 10.445 1.00 36.82 ATOM 4432 CB ARG 570 52.548 1.393 10.188 1.00 37.28 ATOM 4433 CG ARG 570 51.210 1.689 9.539 1.00 43.90 ATOM 4434 CD ARG 570 51.212 3.099 8.967 1.00 50.39 ATOM 4435 NE ARG 570 52.273 3.268 7.973 1.00 54.99 ATOM 4437 CZ ARG 570 53.075 4.328 7.887 3.00 54.96 ATOM 4438 NHl ARG 570 52.947 5.343 8.735 1.00 54.71 ATOM 4441 NH2 ARG 570 54.030 4.357 6.966 1.00 56.12 ATOM 4444 C ARG 570 52.818 -0.877 9.133 1.00 36.53 ATOM 4445 0 ARG 570 51.968 -1L.737 8.909 1.00 34.68 ATOM 4446 N GLU 571 53.830 -0.611 8.320 1.00 37.14 ATOM 4448 CA GLU 571 53.994 -1.253 7.031 1.00 37.94 ATOM 4449 CB GLU 571 55.126 -0.5.58 6.274 1.00 39.-71 ATOM 4450 CG GLU 571 54.834 0.916 6.062 1.00 44.69 ATOM 4451 CD GLU 571 55.934 1.665 5.346 1.00 52.22 ATOM 4452 OE1 GLU 571 57.098 1.196 5.358 1.00 54.87 ATOM 4453 0E2 GLU 571 55.629 2.743 .4.777 1.00 56.-37 ATOM 4454 C GLU 571 54.258 -2.744 7.164 1.00 36.53 ATOM 4455 0 GLU 571 53.692 3.550 6.426 1.00 36.35 ATOM 4456 N TYR 572 55.105 -3.105 8.120 1.00 35.77 ATOM 4458 CA TYR 572 55.456 4.499 8.371 1.00 36.28 ATOM 4459 CB TYR 572 56.446 -4.555 9.534 1.00 30.27 ATOM 4460 CG TYR 572 56.859 -5.925 10.006 1.00 31.65 ATOM 4461 CDI TYR 572 57.889 -6.626 9.371 1.00 29.40 ATOM 4462 CEl TYR 572 58.354 -7.839 9.883 1.00 29.32 ATOM 4463 CD2 TYR 572 56.292 -6.480 11.161 1.00 35.17 ATOM 4464 CE2 TYR 572 56.749 -7.696 11.680 1.00 33.08 ATOM 4465 CZ TYR 572 57.780 -8.366 11.038 1.00 35.15 ATOM 4466 OH TYR 572 58.234 -9.559 11.558 1.00 36.91 ATOM 4468 C TYR 572 54.189 -5.321 8.672 1.00 37.70 ATOM 4469 0 TYR 572 53.942 -6.369- 8.068 1.00 36.82 ATOM 4470 N LEt) 573 53.368 -4.799 9.576 1.00 37.64 ATOM 4472 CA LEt) 573 52.126 -5.442 9.970 1.00 36.03 ATOM 4473 CB LEtJ 573 51.497 -4.659 11.122 1.00 36.17 ATOM 4474 CG LEt) 573 52.257 -4.641 12.445 1.00 36.39 ATOM 4475 CD1 LEt) 573 51.590 -3.665 13.412 1.00 36.17 ATOM 4476 CD2 LEU 573 52.311 -6.042 13.032 1.00 32.13 ATOM 4477 C IJEU 573 51.117 -5.562 8.822 1.00 36.33 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 260 ATOM 4478 0 ATOM 4479 N ATOM 4481 CA ATOM 4482 CB ATOM 4483 CG ATOM 4484 CD ATOM 4485 OEI ATOM 4486 NE2 ATOM 4489 C ATOM 4490 0 ATOM 4491 N ATOM 4493 CA ATOM 4494 CB ATOM 4495 C ATOM 4496 0 ATOM 4497 N ATOM 4499 CA ATOM 4500 CB ATOM 4501 CG ATOM 4502 CD ATOM 4503 NE ATOM 4505 CZ ATOM 4506 NHI ATOM 4509 NH2 ATOM 4512 C ATOM 4513 0 ATOM 4514 N ATOM 4516 CA ATOM 4517 CB ATOM -4518 CG ATOM 4519 CD ATOM 4520 NE ATOM 4522 CZ ATOM 4523 NHI ATOM 4526 NH2 ATOM 4529 C ATOM 4530 0 ATOM 4531 N ATOM 4533 CA ATOM 4534 CB ATOM 4535 C ATOM 4536 0 ATOM 4537 N ATOM 4539 CA ATOM 4540 CB ATOM 4541 CG ATOM 4542 CD1 ATOM 4543 CD2 ATOM 4544 C ATOM 4545 0 ATOM 4546 N ATOM 4548 CA ATOM 4549 CB ATOM 4550 OG LEU 573 GLN 574 GLN 574 GLN 574 GLN 574 GLN 574 GLN 574 GLN 574 GLN 574 GLN 574 ALA 575 ALA 575 ALA 575 ALA 575 ALA 575 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 576 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 ARG 577 GLN 594 GLN 594 GLN 594 GLN 594 GLN 594 LEU 595 LEU 595 LEU 595 LEU 595 LEU 595 LEU 595 LEU 595 LEU 595 SER 596 SER 596 SER 596 SER 596 50.477 50.975 50.024 49.798 48.898 48.871 49.456 48.207 50.401 49.532 51.695 52.165 53.597 52.088 52.437 51.630 51.538 52.600 53.991 55.052 56.384 56.897 56.204 58.112 50.165 50.013 49.156 47.794 46.896 47.206 46.402 46.172 45.447 44.882 45.256 47.241 47.297 53.44B 52.231 51.419 52.582 53.162 52.218 52.499 52.597 53.471 53.307 54.923 51.482 50.302 51.969 51.134 51.905 52.871 -6.596 -4.502 -4 514 -3.103 -2.273 -0.850 -0.506 0.001 -5.427 -5.898 -5.646 -6.516 -6.165 -7.970 -8.867 -8.197 -9.542 -9.708 -9.609 -9.625 -9.663 -8.714 -7.618 -8.863 .9.860 -10. 746 -9.146 -9.372 -8.226 -6.910 -5.766 -4.734 -3.641 -3.421 -2.789 -10.715 -11.015 -13.666 -13. 872 -15.042 -14.116 -15.145 -13.151 -13.187 -11.751 -10.905 -9.427 -11.324 -13.985 -14.026 -14.647 -15.447 -16.669 -16.309 8.64S 8.038 6.936 6.413 7.264 6.801 5.772 7.565 5.783 5.042 5.599 4.532 4.170 4 .971 4.210 6.202 6.761 7.846 7.284 8.356 7.760 6.983 6.689 6.491 7.321 8.169 6.844 7.309 6.951 7.525 6.941 7.948 7.752 6.574 8.747 6.821 5.627 7.976 8.759 8.200 10.224 10.583 11.058 12.480 12.987 12.051 12.322 12.175 13.290 12.951 14.338 15.222 15.721 16.698 1.00 35.19 1.00 37.66 1.CO 41.78 1.00 43.82 1.00 45.42 1.00 49.56 1.00 52.22 1.00 54.86 1.00 42.89 1.00 46.15 1.00 42.39 1.00 40.19 1.00 40.68 1.00 40.49 1.00 43.34 1.00 38.76 1.00 38.44 1.00 34.26 1.00 37.16 1.00 36.38 1.00 36.98 1.00 38.62 1.00 41.41 1.00 37.48 1.00 40.55 1.00 43.20 1.00. 41.98 1.00 43.12 1.00 44.21 1.00 45.21 1.00 47.50 1.00 47.58 1.00 47.63 1.00 49.05 1.00 49.88 1.00 43.10 1.00 43.86 1.00 64.97 1.00 66.30 1.00 67.44 1.00 66.02 1.00 67.47 1.00 62.86 1.00 59.77 1.00 59.35 1.00 61.70 1.00 64.61 1.00 62.38 1.00 57.49 1.00 56.36 1.00 55.62 1.00 54.72 1.00 55.13 1.00 54.98 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 261 ATOM 4552 C SER 596 50.723 -14.597 16.415 1.00 54.73 ATOM 4553 0 SER 596 51.348 -13.579 16.704 1.00 53.29 ATOM 4554 N SER 597 49.704 -15.051 17.137 1.00 55.09 ATOM 4556 CA -SER 597 49.215 -14.337 18.307 1.00 56.44 ATOM 4557 CB SER 597 48.178 -15.185 19.044 1.00 59.14 ATOM 4558 OG SER 597 47.455 16.009 18.138 1.0.0 65.57 ATOM 4560 C SER 597 50.387 -14.026 19.238 1.00 55.64 ATOM 4561 0 SER 597 50.430 -12.966 19.856 1.00 56.04 ATOM 4562 N LYS 598 51.345 -14.948 19.315 1.00 54.91 ATOM 4564 CA LYS 598 52.528 -14.773 20.161 1.00 54.25 ATOM 4565 CB LYS 598 53.287 -16.096 20.311 1.00 54.23 ATOM 4566 CG LYS 598 54.236 -16.138 21.494 1.00 55.12 ATOM 4567 CD LYS 598 55.009 -17.448 21.523 1.00 59.41 ATOM 4568 CE LYS 598 55.711 -17.679 22.858 1.00 58.10 ATOM 4569 NZ LYS 598 54.750 17. 983' 23.959 1.00 56.10 ATOM 4573 C LYS 598 53.439 -13.716 19.536 1.00 52.32 ATOM 4574 0 LYS 598 53.986 -12.869 20.249 1.00 52.23 ATOM 4575 N ASP 599 53.573 -13.768 18.208 1.00 47.57 ATOM 4577 CA ASP 599 54.389 -12.818 17.466 1.00 45.47 ATOM 4578 CB ASP 599 54.324 -13.101 15.959 1.00 49.05 ATOM 4579 CG ASP 599 55.245 -14.238 15.525 1.00 54.16 ATOM 4580 OD1 ASP 599 56.242 -14.503 16.223 1.00 61.34 ATOM 4581 0D2 ASP 599 54.992 -14.863 14.471 1.00 55.80 ATOM 4582 C ASP 599 .53.933 -11.383 17.721 1.00 43.55 ATOM 4583 0 ASP 599 54.762 -10.491 17.895 1.00 44.34 ATOM 4584 N LEU 600 52.622 -11.160 17.751 1.00 -39.73 ATOM 4586 CA LEU 600 52.104' 9.821 17.989 1.00 37.64 ATOM 4587 CE LEU 600 50.597 -9.743 17.719 1.00 35.42 ATOM 4588 CG LEU 600 50.075 -9.951 16.287 1.00 33.95 ATOM 4589 CD1 LEU 600 48.621 -9.552 16.262 1.00 36.59 ATOM 4590 CD2 LEU 600 50.841 -9.139 15.265 1.00 28.40 ATOM 4591 C LEU 600 52.429 -9.347 19.402 1.00 38.24 ATOM 4592 0 LEU 600 52.817 -8.193 19.590 1.00 38.28 ATOM 4593 N VAL 601 52.305 -10.235 20.391 1.00 38 .77 ATOM 4595 CA VAL 601 52.610 -9.855 21.772 1.00 38.87 ATOM 4596 CB VAL 601 52.121 -10.906 22.812 1.00 38.03 ATOM 4597 CG1 VAL 601 52.150 -10.303 24.223 1.00 36.21 ATOM 4598 CG2 VAL 601 50.710 -11.332 22.504 1.00 39.07 ATOM 4599 C VAL 601 54.123 -9.662 21.887 1.00 38.98 ATOM 4600 0 VAL 601 54.601 -8 .757' 22.580 1.00 39.93 ATOM 4601 N SER 602 54.861 -10.488 21.155 1.00 37.35 ATOM 4603 CA SER 602 56.311 -10.422 21.126 1.00 37.11 ATOM 4604 CB SER 602 56.853 -11.469 20.154 1.00 39.38 ATOM 4605 OG SER 602 58.265 -11.413 20.061 1.00 46.76 ATOM 4607 C SER 602 56.695 -9.020 20-*664 1.00 35.43 ATOM 4608 0 SER 602 57.493 -8.339 21.315 1.00 35.01 ATOM 4609 N CYS 603 56.091 -8.586 19.561 1.00 33.42 ATOM 4611 CA CYS 603 56.329 -7.254 19.015 1.00 32.18 ATOM 4612 CB CYS 603 55.449 -7.035 17.790 1.00 32.38 ATOM 4613 SG CYS 603 55.440 -5.365 17.123 0.50 35.11 PRT1 ATOM 4614 C CYS 603 56.074 -6.167 20.059 1.00 31.20 ATOM 4615 0 CYS 603 5682 -5.234 20.185 1.00 32.44 ATOM 4616 N ALA 604 55.001 -6.321 20.828 1.00 29.74 ATOM 4618 CA ALA 604 54.640 -5.363 21.872 1.00 32.26 145. vOl WO 98/07835 PCTIUS97/14886 2G2 ATOM 4619 CB ALA 604 53.232 -5.675 22.412 1.00 31.75 ATOM 4620 C ALA 604 55.656 -5.365 23.019 1.00 33.71 ATOM *4621 0 ALLA 604 55.933 -4.326 23.621 1.00 33.49 ATOM 4622 N TYR 605 56.186 -6.544 23.326 1.00 35.56 ATOM 4624 CA TYR 605 57.176 -6.709 24.388 1.00 35.49 ATOM 4625 CB TYR 605 57.447 -8.206 24.617 1.00 36.12 ATOM 4626 CG TYR 605 58.562 -8.495 25.591 1.00 34.75 ATOM 4627 CD1 TYR 605 58.415 -8.237 26.954 1.00 34.30 ATOM 4628 CEl TYR 605 59.444 -8.499 27.853 1.00 36.26 ATOM 4629 CD2 TYR 605 59.773 -9.021 25.150 1.00 37.39 ATOM 4630 CE2 TYR 605 60.812 -9.288 26.040 1.00 37.81 ATOM 4631 CZ TYR 605 60.641 -9.027 27.388 1.00 38.34 ATOM 4632 OH TYR 605 61.662 -9.324 28.265 1.00 42.09 ATOM 4634 C TYR 605 58.475 -5.972 24.027 1.00 34.98 ATOM 4635 0 TYR 605 58.981 -5.171 24.822 1.00 35.83 ATOM 4636 N GLN 606 58.996 6.247 22.828 1.00 33.99 ATOM 4638 CA GLN 606 60 218 -5.620 22.315 1.00 33.60 ATOM 4639 CB GLN 606 60.506 -6.111 20.894 1.00 31.37 ATOM 4640 CG GLN 606 60.858 -7.584 20.786 1.00 32.05 ATOM 4641 CD GLN 606 61.175 -8.015 19.354 1.00 30.33 ATOM 4642 OE1 GLN 606 62.145 -7.558 18.754 1.00 30.84 ATOM 4643 NE2 GLN 606 60.353 -8.895 18.810 1.00 33.75 ATOM 4646 C GLN 606 60.123 4.079 22.321 1.00 34.86 ATOM 4647 0) GLN 606 61.070 -3.390 22.702 1.00 37.54 ATOM 4648 N VAL 607 58.975 -3.555 21.904 1.00 32.89 ATOM 4650 CA VAL 607 58.748 -2.114 21.883 1.00 30.80 ATOM 4651 CB VAL 607 57.426 -1.777 21.120 1.00 28.82 ATOM 4652 C G1 VAL, 607 57.121 -0.299 21.191 1.00 25.36 ATOM 4653 CG2 VAL 607 57.-541 -2.204 19.661 1.00 23.37 ATOM 4654 C VAL 607 58.747 -1.532 23.312 1.00 30.48 ATOM 4655 0 VAL 607 59.359 -0.48-9 23.563 1.00 29.42 ATOM 4656 N ALA 608 58.106 -2.225 24.255 1.00 30..07 ATOM 4658 CA ALA 608 58.064 -1.761 25.646 1.00 30.14 ATOM 4659 CB ALA 608 57.027 -2.548 26.452 1.00 28.49 ATOM 4660 C ALA 608 59.-455 -1.849 26.305 1.00 31.25 ATOM 4661 0 ALA 608 59.791 -1.054 27.198 1.00 28.90 ATOM 4662 N ARG 609 60.257 -2.819 25.870 1.00 31.61 ATOM 4664 CA ARG 609 61.608 -2.979 26.393 1.00 31.99 ATOM 4665 CB ARG 609 62.253 -4.245 25.856 1.00 34.93 ATOM 4666 CG ARG 609 61.606 -5.507 26.317 1.00 40.82 ATOM 4667 CD ARG 609 62.633 -6 *606 26.397 1.00 42.68 ATOM 4668 NE ARG 609 63.275 -6.621 27.705 1.00 43.85 ATOM 4670 CZ ARG 609 64.332 -7.364 28.019 1.00 44.73 ATOM 4671 NHl ARG 609' 64.889 -8.162. 27.108 1.00 41.40 ATOM 4674 NH2 ARG 609 64.803 -7.341 29.260 1.00 44.85 ATOM 4677 C ARG 609 62.459 -1.796 25.966 1.00 33.70 ATOM 4678 0 ARG 609 63.130 -1.174 26.793 1.00 35.94 ATOM 4679 N GLY 610 62.459 -1.511 24.663 1.00 31.22 ATOM 4681 CA GLY 610 63.232 -0.391 24.157 1.00 27.21 ATOM 4682 C GLY 610 62.819 0.875 24.865 1.00 25.81 ATOM 4683 0 GLY 610 63.665 1.652 25.300 1.00 26.21 ATOM 4684 N MET 611' 61.511 1.056 25.015 1.00 27.12 ATOM 4686 CA MET 611 60.969 2.222 25.695 1.00 28.82 ATOM 4687 CB MET 611 59.457 2.288 25.524 1.00 29.29 145. vOl WO 98/07835 PCTIUS97/14885 263

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4688 4689 4690 4691 4692 4693 4695 4696 4697 4698 4699 4700 4701 4702 4703 4705 4706 4707 4708 4709 4 '710 4711 4712 4713 4715 4716 4717 4719 4720 4721 4722 4723 4724 4725 4726 4728 4729 4730 4731 4732 4734 4735 4736 4738 4739 4740 4742 4743 4744 4745 4746 4747 4751 4752

CG

SD

CE

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2

CZ

Oil

C

0

N

CA

CB

-CG

CD1 CD2

C

0

N

CA

CB

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

MET

MET

MET

MET

MET

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

TYR

TYR

TYR

TYR

TIYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

ALA

ALA

ALA

ALA

ALA

SER

SER

SER

SER

SER

SER

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

611 611 611 611 611 612 612 612 612 612 612 612 612 612 613 613 613 613 613 613 613 613 613 613 613 613 614 614 614 614 614 614 614 614 615 615 615 615 615 616 616 616 616 616 616 617 617 617 617 617 617 617 617 617 59. 004 59. 732 59.155 61.341 61 -596 61.347 61 .723 61.603 62.029 62.135 62.546 61.826 63 .178 63 .534 63.999 65.403 66.156 67.6] 2 68.584 69.930 68. 021 69.352 70 .307 71.632 65.539 66.256 64 .836 64.931 64.089 64.545 63 .594 65.983 64.499 65.110 63 .470 62 .955 61 .625 63.986 64 .112 64 .722 65.738 66.287 67.076 66.870 67.637 66 .971 67.975 68 .508 69.224 70.423 71.075 72.426 67.360 67.892 2.706 4.286 5.431 2.261 3.334 1.109 1.057 -0.370 -0.516 968 -2.834 -2.240 1.544 2.319 1.107 1.507 0.743 1. -i46 0.544 0.927 2.148B 2.540 1.927 2.318 3.005 3.682 3.536 4. 956 5.319 4.778 5.257 5.213 5.761 6.770 5.272 5 .945 5.314 5.913 6.885 4.809 4.703 3.277 2.935 5.678 6.061 6.060 7.010 6.620 5.302 24 .135 23 .617 24. 922 27.178 27.730 27.837 29.-253 29. 792 31.237 31.688 30.883 32.867 29.353 30.261 28 .391 28.334 27.241 27.132 27 .931 27.851 26.247 26.157 26.963 26.896 28 .088 28 .814 27. 090 26. 793 25.569 24 .208 23.125 23 .894 28 .001 28.345 28 .683 29.871 30 .314 31.007 31.753 31.134 32.175 32.285 31.165 31.865 32 .755 30.592 30.143 28.776 28. 797 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 *1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1. 00 1.00 1. 00 1.00 1.00 1. 00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 31.07 28.38 28.34 30.34 31.73 32 .72 35.46 34.70 32.31 33 .14 30.79 36 .13 36.43 35.38 35.47 33 .16 31.33 33.03 36.69 36.82 3 3. 4'9 34 .73 37.07 36.77 31.82 34. 76 28 .44 25.67 24 23 .73 20.54 23.21 28.30 27.09 32.73 34.10 33.68 33.84 34.95 32.69 33 28.27 25 .54 35.43 37.32 34.80 33 .01 33.18 35.64 40.31 43 .03 45 .54 32.87 34.06 5.380 '29.710 4.025 29.863 4.152 30-449 8.397 30.102 9.308 29.470 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 264 ATOM 4753 N LYS 618 66.221 8.542 30.772 1.00 33.53 ATOM 475S CA LYS 618 65.500 9.808 30.872 1.00 33.28 ATOM 4756 CB LYS 618 66.384 10.842 31.558 1.00 37.22 ATOM 4757 CG LYS 618 66.968 10.367 32.869 1.00 43.11 ATOM 4758 CD LYS 618 65.927 10.278 33.957 1.00 49.82 ATOM 4759 CE LYS 618 66.520 9.636 35.199 1.00 55.20 ATOM 4760 NZ LYS 618 65.669 9.853 36.415 1.00 61.31 ATOM 4764 C LYS 618 65.012 10.359 29.542 1.00 31.57 ATOM 4765 0 LYS 618 64.651 11.530 29.455 1.00 31.10 ATOM 4766 N CYS 619 64.953 9.506 28.524 1.00 31.04 ATOM 4768 CA CYS 619 64.519 9.922 27.196 1.00 29.21 ATOM 4769 CB CYS 619 65.213 9.065 26.125 1.00 28.55 ATOM 4770 SG CYS 619 64.782 9.400 24.392 1.00 26.31 ATOM 4771 C CYS 619 62.999 9.849 27.051 1.00 30.91 ATOM 4772 0 CYS 619 62.376 8.827 27.364 1.00 31.18 ATOM 4773 N ILE 620 62.411 10.967 26.632 1.00 29.48 ATOM 4775 CA ILE 620 60.981 11.073 26.416 1.00 29.34 ATOM 4776 CB ILE 620 60.402 12.344 27.060 1.00 28.12 ATOM 4777 CG2 ILE 620 58.944 12.535 26.645 1.00 28.76 ATOM 4778 CG1 ILE 620 60.521 12.267 28.581 1.00 28.36 ATOM 4779 CD1 ILE 620 60.062 13.522 29.270 1.00 25.55 ATOM 4780 C ILE 620 60.852 11.188 24.908 1.00 30.97 ATOM 4781 0 ILE 620 61.254 12.193 24.336 1.00 33.88 ATOM 4782 N HIS 621 60.307 10.147 24.284 1.00 31.55 ATOM 4784 CA HIS 621 .60.148 10.080 22.831 1.00 31.85 ATOM 4785 CB HIS 621 59.72.1 8.668 22.425 1.00 28.27 ATOM 4786 CG HIS 621 59.913 8.373 20.979 1.00 24.68 ATOM 4787 CD2 HIS 621 60.608 7.383 20.356 1.00 24.39 ATOM 4788 ND1 HIS 621 59.354 9.130 19.973 1.00 25.87 ATOM 4790 CEl HIS 621 59.691 8.623 18.798 1.00 27.65 ATOM 4791 NE2 HIS 621 60.444 7.571 19.007 1.00 25.80 ATOM 4793 C HIS 621 59.187 11.096 22.224 1.00 34.38 ATOM 4794 0 HIS 621 59.387 11.539 21.104 1.00 38.74 ATOM 4795 N ARG 622 .58.080 11.374 22.898 1.00 37.17 ATOM 4797 CA ARG 622 57.093 12.346 22.425 1.00 37.27 ATOM 4798 CB ARG 622 57.718 13.746 22.298 1.00 38.63 ATOM 4799 CG ARG 622 58.261 14.271 23.601 1.00 40.47 ATOM 4800 CD ARG 622 58.661 15.739 23.530 1.00 44.76 ATOM 4801 NE ARG 622 59.129 16.174 24.842 1.00 52.09 ATOM 4803 CZ ARG '622 60.299 15.821 25.375 1.00 56.86 ATOM 4804 NH1 ARG 622 61.132 15.041 24.699 1.00 61.20 ATOM 4807 NH2 ARG 622 60.606 16.167 26.624 1.00 58.19 ATOM 4810 C ARG 622 56.324 11.994 21.151 1.00 37.23 ATOM 4811 0 ARG 622 55.300 12.614 20.867 1.00 38.45 ATOM 4812 N ASP 623 56.805 11.035 20.364 1.00 36.55 ATOM 4814 CA ASP 623 56.075 10.652 19.160 1.00 36.52 ATOM 4815 CB ASP 623 56.581 11.403 17.910 1.00 39.68 ATOM 4816 CG ASP 623 55.635 11.247 16.687 1.00 48.75 ATOM 4817 ODi ASP 623 56.077 11.491 15.538 1.00 49.98 ATOM 4818 0D2 ASP 623 54.445 10.879 16.872 1.00 49.65 ATOM 4819 C ASP 623 56.126 9.143 18.967 1.00 33.37 ATOM 4820 0 ASP 623 56.325 8.650 17.864 1.00 31.77 ATOM 4821 N LEU 624 55.999 8.404 20.059 1.00 30.45 ATOM 4823 CA LEU 624 56.014 6.954 19.950 1.00 30.77 SSSD/55145. vOl WO 98/07835 WO 9807835PCT1US97/14885 265 ATOM 4824 CB LEU 624 55.983 6.307 21.342 1.00 27.43 ATOM 4825 CG LEU 624 55.949 4.778 21.441 1.00 28.69 ATOM 4826 CD). LEU 624 57.139 4.132 20.731 1.00 24.75 ATOM 4827 CD2 LEU 624 55.927 4.389 22.894 1.00 27.39 ATOM 4828 C LEU 624 54.803 6.532 19.109 1.00 31.22 ATOM 4829 0 LEU 624 53.680 6.952 19.380 1.00 33.44 ATOM 4830 N ALA 625 55.053 5.763 18.054 1.00 28.85 ATOM 4832 CA ALA 625 54.009 5.286 17.159 1.00 26.93 ATOM 4833 CB ALA 625 53.559 '6.400 16.227 1.00 25.03 ATOM 4834 C ALA 625 54.642 4.162, 16.356 1.00 28.44 ATOM 4835 0 ALA 625 55.863 4.065 16.317 1.00 31.32 ATOM 4836 N ALA 626 53.828 3.329 15.705 1.00 29.14 ATOM 4838 CA ALA 626 54.344 2.205 14.905 1.00 28.42 ATOM 4839 CB ALA 626 53.192 1.357 14.353 1.00 27.37 ATOM 4840 C ALA 626 55.231 2.698 13.771 1.00 26.38 ATOM 4841 0 ALA 626 56.195 2.041 13.395 1.00 26--12 ATOM 4842 N ARG 627 54.890 3.861 13.230 1.00 27.16 ATOM 4844 CA AP.G 627 55.669 4.474 12.158 1.00 28.44 ATOM 4845 CB ARG 627 55.022 5.794 11.733 1.00 28.19 ATOM .4846 CG ARG 627 54.889 6.793 12.867 1.00 30.34 ATOM 4847 CD ARG 627 54.456 8.155 12.361 1.00 34.08 ATOM 4848 NE ARG 627 54.081 9.024 13.471 1.00 35.58 ATOM 4850 CZ ARG 627 52.849 9.123 13.950 1.00 35.55 ATOM 4851 NH. ARG 627 51.860 8.422 13.420 1.00 35.67 ATOM 4854 NH2 ARG 627 52.618 9.898 14.993 1.00 40.81 ATOM 4857 C ARG 627 57.108 4.733 12.630 1.00 28.06 ATOM 4858 0 ARG 627 58.044 4.737 11.825 1.00 29.80 ATOM 4859 N ASN 628 57.272 4.935 13.940 1.00 28.50 ATOM 4861 CA ASN 628 58.582 5.195 14.544 1.00 26.14 ATOM 4862 CB ASN 628 58.494 6.340 15.551 1.00 23.55 ATOM 4863 CG ASN 628 58.319 7.681 14.874 1.00 27.48 ATOM 4864 OD. ASN 628 58.874 7.919 13.800 1.00 34.12 ATOM 4865 ND2 ASN 628 57.543 8.556 15.479 1.00 23.21 ATOM 4868 C ASN 628 59.263 3.965 15.153 1.00 26.76 ATOM 4869 0 ASN 628 60.202 4.078 15.948 1.00 26.90 ATOM 4870 N VAL 629 58.774 2.794 14.767 1.00 27.02 ATOM 4872 CA VAL 629 59.344 1.523 15.186 1.00 27.81 ATOM 4873 CB VAL 629 58.298 0.622 15.864 1.00 26.83 ATOM 4874 CG1 VAL 629 58.876 -0.766 16.115 1.00 20.74 ATOM 4875 CG2 VAL 629 57.836 1.259 17.165 1.00 22.49 ATOM 4876 C VAL 629 59.781 0.895 13.861 1.00 28.61 ATOM 4877 0 VAL 629 58.983 0.809 12.924 1.00 28.76 ATOM 4878 N LEU 630 61.059 0.557 13.746 1.00 30.35 ATOM 4880 CA LEU 630 61.576 -0.033 12.514 1.00 32.42 ATOM 4881 CB LEU 630 62.824 0.725 12.040 1.00 32.28 ATOM 4882 CG LEU 630 62.697 2.249 11.880 1.00 27.75 ATOM 4883 CD1 LEU 630 64.019 2.860 11.469 1.00 24.71 ATOM 4884 CD2 LEU 630 61.611 2.582 10.872 1.00 27.70 ATOM 4885 C LEU 630 61.895 -1.488 12.799 1.00 32.89 ATOM 4886 0 LEU 630 62.167 -1.838 13.943 1.00 32.32 ATOM 4887 N VAL 631 61.831 -2.336 11.774 1.00 34.81 ATOM 4889 CA VAL 631 62.087 -3.772 11.943 1.00 33.87 ATOM 4890 CB VAL 631 60.818 -4.616 11.597 1.00 31.60 ATOM 4891 CG1 VAL 631 60.929 -6.004 12.197 1.00 30.84 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885' 266 ATOM 4892 CG2 VAL 631 59.545 -3.916 12.089 1.00 25.53 ATOM 4893 C VAL 631 63.286 -4.256 11.109 1.00 34.95 ATOM 4894 0 VAL 631 63.365 -4.009 9-.892 1.00 37.01 ATOM 4895 N THR 632 64.215 -4.942 11.770 1.00 35.08 ATOM 4897 CA TNR 632 65.418 -5.444 11.104 1.00 35.96 ATOM 4898 CB THR 632 66.541 -5.711 12.116 1.00 34.29 ATOM 4899 OG1 THR 632 66.187 -6.818 12.953 1i.00 32.35 ATOM 4901 CG2 THR 63'2 66.750 -4.488 12.985 1.00 33.42 ATOM 4902 C THR 632 65.162 -6.712 10.300 1.00 39.32 ATOM 4903 0 THR 632 64.078 -7.302 10.382 1.00 41.24 ATOM 4904 N GLU 633 66.153 -7.123 9.511 1.00 42.32 ATOM 4906 CA GLU 633 66.030 -8.335 8.703 1.00 44.34 ATOM 4907 CB GLU 633 67.314 -8.609 7.912 1.00 46.06 ATOM 4908 CG GLI) 633 67.205 -9.767 6.898 1.00 49.87 ATOM 4909 CD GLU 633 66.380 -9.445 5.629 1.00 53.04 ATOM 4910 OE1 GLU 633 65.637 -8.430 5.570 1.00 51.31 ATOM 4911 0E2 GLU 633 66.479 -10.226 4.667 1.00 55.48 ATOM 4912 C GLU 633 65.708 -9.526 9.600 1.00 44.58 ATOM 4913 0 GLU 633 64.974 -10.423 9.207 1.00 46.56 ATOM 4914 N ASP 634 66.201 -9.493 10.833 1.00 44.12 ATOM 4916 CA ASP 634 65.961 -10.583 11.759 1.00 44.23 ATOM 4917 CB ASP 634 67.221 -10.867 12.580 1.00 50.17 ATOM 4918 CG ASP 634 68.443 -11.181 11.697 1.00 56.79 ATOM 4919 ODi ASP 634 68.363 -12.113 10.857 1.00 59.62 ATOM 4920 0D2 ASP 634 69.482 -10.490 11.837 1.00 58.62 ATOM 4921 C ASP 634 64.7.56 -10.331 12.644 1.00 43.26 ATOM 4922 0 ASP 634 64.652 -iO.879 13.733 1.00 43.58 ATOM 4923 N ASN4 635 63.858 -9.475 12.16G 1.00 43.97 ATOM 4925 CA ASN 635 62.612 -9.126 12.847 1.00 43.66 ATOM 4926 CB ASN 635 61.698 -10.355 i2.930 1.00 46.94 ATOM 4927 CG ASN 635 61.413 -10.958 11.572 1.00 48.29 ATOM 4928 ODi ASN 635 60.831 -10.314 10.702 1.00 51.42 ATOM 4929 ND2 ASN 635 61.832 -12.198 11.38G 1.00 49.44 ATOM 4932 C ASN 635 62.694 -8.463 14.216 1.00 43.03 ATOM 4933 0 ASN 635 61.774 -8.596 15.031 1.00 43.03 ATOM 4934 N VAL 636 63.763 -7.712 14.467 1.00 42.69 ATOM -4936 CA VAL 636 63.915 -7.034 15.756 1.00 38.30 ATOM 4937 CB VAL 636 65.406 -6.861 16.134 1.00 37.92 ATOM 4938 CG1 VAL 636 65.555 -6.040 17.421 1.00 37.14 ATOM 4939 CG2 VAL 636 66.052 -8.226 16.306 1.00 37.55 ATOM 4940 C VAL 636 63.251 -5.673 15.688 1.00 35.75 ATOM 4941 0 VAL 636 63.486 -4.926 14.746 1.00 36.28 ATOM 4942 N MET 637 62.355 -5.396 16.628 1.00 34.73 ATOM 4944 CA MET 637 61.672 -4.103 16.680 1.00 33.22 ATOM 4945 CB MET 637 60.456 -4.152 17.608 1.00 34.83 ATOM 4946 CG MET 637 59.364 -5.148 17.231 1.00 34.41 ATOM 4947 SD MET 637 58.661 -4.926 15.589 1.00 33.19 ATOM 4948 CE MET 637 58.869 -6.584 14.913 1.00 29.73 ATOM 4949 C MET 637 62.677 -3.107 17.250 1.00 33.75 ATOM .4950 0 MET 637 63.281 -3.357 18.308 1.00 31.79 ATOM 4951 N LYS 638 62.839 -1.980 16.558 1.00. 31'.83 ATOM -4953 CA LYS 638 63.774 -0.939 16.965 1 -00 28.17 ATOM 4954 CB LYS 638 64.986 -0.930 16.038 1.'00 24.98 ATOM 4955 CG LYS 638 66.006 -1.967 16.400 1.00 23.17 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 267 ATOM 4956 ATOM 4957 ATOM 4958 ATOM 4962 ATOM 4963 ATOM 4964 *ATOM 4966 ATOM 4967 ATOM 4968 ATOM -4969 ATOM 4970 ATOM 4971 ATOM 4972 ATOM 4973 ATOM 4975 ATOM 4976 ATOM 4977 ATOM 4978 ATOM 4979 ATOM 4981 ATOM 4982 ATOM 4983 ATOM 4984 ATOM 4985 ATOM 4986 ATOM 4987 ATOM 4988 ATOM 4990 ATOM 4991 ATOM 4992 ATOM 4993 ATOM 4994 ATOM 4995 ATOM 4996 ATOM 4997 ATOM 4998 ATOM 4999 ATOM 5000 ATOM 5002 ATOM 5003 ATOM 5004 ATOM 5005 ATOM 5007 ATOM 5008 ATOM 5009 ATOM 5010 ATOM 5011 ATOM 5012 ATOM 5013 ATOM 5014 ATOM 5016 ATOM 5017 ATOM 5018 ATOM 5019 SSSD/55145. vOl

CD

CE

NZ

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

C

0'

N

CA

CB

CG

OD1 0D2

C

0

N

CA

CB

CG

CD1 CDT)2 CE 1 CE2

CZ

C

0

N

CA

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

C

0 LYS 638 LYS 638 LYS 638 LYS 638 LYS 638 ILE 639 ILE 639 ILE 639 ILE 639 ILE 639 ILE 639 ILE' 639 ILE 639 ALA 640 ALA 640 ALA 640 ALA 640 ALA 640 ASP 641 ASP 641 ASP 641 ASP 641 ASP 641 ASP 641 ASP 641 ASP 641 PHE 642 PHE 642 PEE 642 PHE 642 PEE 642 PEE 642 PEE 642 PEE 642 PHE 642 PEE 642 PHE 642 GLY 643 GLY 643 GLY 643 GLY 643 LEU 644 LEU 644 LEU 644 LEU 644 LEU 644 LEU 644 LEU 644 LEU 644 ALA 645 ALA 645 ALA 645 ALA 645 ALA 645 67.193 68.212 68.747 63.165 62.803 63 .052 62 .508 62 .589 61.875 62.019 60.517 63.387 64 .619 62.758 63.477 63.222 63 .042 61.996 63.863 63.545 62.217 62 .346 63.409 61.356 63.455 62.825 64.080 64.044 64.32? 65.673 66.812 65.806 68.072 67.051 68.195 65. 024 64.990 65.910 66.888 66.634 67.482 65.461 65.131 63.832 63.823 62.527 65.004 65. 027 64.488 65.534 65.505 66.539 64.112 63 .393 -1.916 -2.969 -2.765 0.445 0.958 1. 031 2 .376 2 .863 4 .189 1.827 1.667 3 .338 3.283 4 .231 5.218 -4 .964 6 .643 6 .828 7.637 9.052 9 .443 9 .762 9.478 10.299 9.442 10 .446 8 .658 94.3 7. 664 7 .063 7.539 6 .026 6 .990 5 .471 5 .954 10 .045 10. 503 10 .433 11.455 12.768 13 .652 12.921 14 .144 13 .975 12 .967 13 .134 13.228 15.396 15 .356 16 .505 17 .794 18.741 18.407 18 .500 15.470 15.847 17.220 16 .986 15.936 18 .181 18 .351 19.839 19. 984 20.826 20.792 17.543 17 .642 16 .783 15 .976 14 .506 16 .344 16.974 15.993 16 .245 15 .593 14.107 13 .500 13 .548 17. 700 18 .041 18 .564 19.992 20.787 20.505 21.163 19.576 20.900 19.305 19.970 20.414 21.563 19.500 19.799 19.093 19.132 18 .484 17.748 16 .969 15.836 15.070 14.934 18 .605 19.715 18.068 18 .759 18.156 18.667 19.663 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1. 00 1. 00 1. 00 1.0*0 1.00 1'.00 1.00 1.00 1.00 1.00 1.00.

1.00 1.00 1.00 1. 00 1.00 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1.00 25.04 24 .79 24.91 26.04 24 .44 25.14 25.68 27.40 18. 94 26 25 .07 25.82 25.76 25 .92 26.12 26.-54 26 .33 26.20 26.39 28.09 31.43 36 .81 40.24 40.49 28.40 29.30 30. 27 30.97 24.64 20.96 16.89 16 .23 18 18 .76 17.91 34.53 35..23 36.40 38. .28 41.44 44 45.44 49.14 46.26 42 42 .68 45 53.90 56 .54 57.59 60.15 55.55 61.90 63.83 WO 98/07835 PCTIUS97/14885 268

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5020 5022 5023 5024 5025 5026 5027 5028 5029 5031 5032 5033 5034 5035 5036 5037 5038 5039 5041 5042 5043 5045 5046 5047 5048 5049 5050 3051 .9052 5053 5055 5056 5057 5059 5060 .5061 5062 5063 5064 5068 5069 5070 5072 5073 50-74 5075 5076 5077 5081 5082 5083 5085 5086 5087

N

CA

CB

CG

OD1 '0D2

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2 cz

OH

C

0

N

CA

CB

CG

CDI

GEl CD2 CE2

-:H

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

C

0 ASP 652 ASP 652 ASP 652 ASP 652 ASP 652 ASP 652 ASP 652 ASP 652 TYR 653 TYR 653 TYR 653 TYR 653 TYR 653 TYR 653 TYR 653 TYR 653 TYR 653 TYR 653 TYR 653 TYR 653 TYR 654 TYR 654 TYR 654 TYR 654 TYR 654 TYR 654 TYR 654 TYR 654 TYR 654 TYR 654 TYR 654 TYR 654 LYS 655 LYS 655 LYS 655 LYS 655 LYS 655 LYS 655 LYS 655 LYS 655 LYS 655 LYS 656 LYS 656 LYS 656 LYS 656 LYS 656 LYS 656 LYS 656 LYS 656 LYS >-656 GLY 660 GLY .660 GLY 660 GLY 660 52.090 50.913 51.314 50. 109 49.028 50.252 50-.145 50.434 49.145 48.318 47.272 47.804 47. 017 47.477 49.083 49.558 48. 748 49.220 47.602 47.045 47.632 46.954 46.205 45.275 45.776 44.929 43.895 43.032 43.557 42.710 47.857 47.396.

49.139 50.056 51.508 52.504 53.932 54.898 56.325 49.884 49.904 49.670 49.500 48.628 47.155 46.402 44. 926 44.202 50.859 51. 823 48.651 47.*932 47.241 46.183 22.191 22 .199 22.428 22.557 22 .996 22.222 20.890 19.899 20.905 19.730 20.048 20. 185 20.757.

20.885 19.738 19.860 20.435 20.554 19.231 18.131 20.031 19.673 20.893 21.499 22 .140 22 .655 21.396 21. 912 22.538 23 .034 19.080 18 .772 18 .919 18.356 18. 713 18 .133 18 .585 17.833 18.246 16 .847 16 .182 16.320 14 .886 14.620 14 .874 14 .709 14.449 14.327.

14.225 14 .878 9.665 10 .910 10.937 11.552 14.865 14 .007 12.537 11.607 12 .052 10.411 14 .156 13.483 15.027 15 .277 16 .344 17.755 18.752 20.058 18.101 19.406 20.378 21.669 14.021 14 .012 12 .962 11.727 I1. .18 12.209 1.343 14 .312 12.067 13 .033 .14 .153 15.117 10.651 9.552 10 .959 9.982 10.311 9.315 9 .562 8.637 8 .821 9.935 10.972 8.735 8.545 7.320 7.542 6.241 6.473 5.173 8.368 7.956 5.782 6 .012 7 .364 7.525 1.00 89.91 1.00 89.75 1.00 88.08 1.00 87.09 1.00 86.85 1.00 86.69 1.00 89.98 1.00 90.19 1.00 90.26 1.00 90.78 1.00 91.65 1.00 93.43 1.00 94.60 1.00 95.35 1.00 93.46 1.00 94.36 1.00 95.26 1.00 95.00 1.00 90.47 1.00 91.33 1.00 89.21 1.00 89.09 1.00 88.23 2.00 87.65 1.00 86.76 1.00 87.17 1.00 88.61 1.00 89.32 1.00 88.66 1.00 89.35 1.00 89.49 1.00 88.37 1.00 90.80 1.00 93.18 1.00 95.66 1.00 99.82 1.00103 .58 1. 00106 1.00108.43 1.00. 93.56 1.00 93.72 1.00 94.19 1.00 94.84 1.00 94.64 1.00 95.54 1.00 99.56 1.00101.77 1. 00103 .77 1.00 95.18 1.00 95.74 1.00 58.76 1.00 56.04 1.00 53.90 1.00 53.92 SSSD/55145. vOl WO 98/07835 WO 9807835PCT/US97/1488 269 ATOM 5088 ATOM 5090 ATOM 5091 ATOM 5092 ATOM 5093 ATOM 5094 ATOM 5096 ATOM 5097 ATOM 5100 ATOM 5103 ATOM 5104 ATOM 5105 ATOM 5107 ATOM 5108 ATOM 5109 ATOM 5110 ATOM S111 ATOM 5112 ATOM 5113 ATOM 5114 ATOM 5115 ATOM 5116 ATOM 5117 ATOM *5118 ATOM 5119 ATOM 5120 ATOM 5121 ATOM 5123 ATOM 5124 ATOM 5125 ATOM 5126 ATOM 5127 ATOM 5128 ATOM 5129 ATOM .5131 ATOM .5132 ATOM .5133 ATOM 5134 ATOM 5135 ATOM 5136 ATOM 5140 ATOM 5141 ATOM 5142 ATOM 5144 ATOM 5145 ATOM 5146 ATOM 5147 ATOM 5148 ATOM 5149 ATOM 5150 ATOM 5151 ATOM 5153 ATOM 5154 ATOM 5155

N

CA

CB

CG

CD

NE

Cz NH1 NH2

C

0

N

CA

CE

CG

CD1 CD2

C

0

N

CD

CA

CE

CG

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CE

CG

CD2 CE2 CE3 CD1

NEI

CZ2 CZ3 CH2 ARG 661 ARG 661 ARG 661 ARG 661 ARG 661 ARG 661 ARG 661 ARG 661 ARG 661 ARG 661 ARG 661 LEU 662 LEU 662 LEU 662 LEU 662 -LEU 662 LEU 662 LEU 662 LEU 662 PRO 663 PRO 663 PRO 663 PRO 663 PRO 663 PRO 663 PRO 663 VAL' 664 VAL 664 VAL 664 VAL 664 VAL 664 VAL 664 VAL 664 LYS 665 LYS 665 LYS 665 LYS 665 LYS 665 LYS 665 LYS 665 LYS 665 LYS 665 TRP 666 TRP 666 TRP 666 TRP 666 TRP 666 TRP 666 TRP 666 TRP 666 TRP 666 TRP 666 TRP 666 TRP 666 47.838 47.297 47.755 47. 506 47. 561 47.584 48.035 48.503 48 .036 47. 722 48.658 47. 019 47.310 46.021 45.301 43.852 46.041 47. 973 47.327 49.260 50.086 50; *052 51.367 51.479 49.412 49.683 48. 566 47. 874 46. 953 47.779 46.089 47.072 46 866 46.710 45. 956 45.411 44.242 43.. 905 42.684 42.266 46.718 46. 152 47.994 48.825 50.123 49. 946 49.407 49.418 48.924 50.257 49.937 48.962 48.466 48.491 10.243 10.177 8 .891 7.620 6.390 5 .155 3 .988 3 .884 2 .926 11.401 12 .103 11.656 12.799 13 .533 14 .149 14.428 15.407 12.330 11.718 12 .655 13 .389 12 .281 13 .003 12 .966 12.665 J.2 .036 13 .697 14 .092 15 .327 16.583 15 .154 12 .896 12.760 11 .978 10.788 2-0.083 10.835 10.431 11.228 10.902 9.830 8 .869 10.123 9. 296 8 .906 7 .781 7 .853 6 .546 8.899 6.475 5.729 6 .245 8.604 7.282 8.328 9.679 10.377 9. 566 10.446 9.663 10.117 11.356 9.327 10.483 10.104 11.579 12. 437 12.783 11.588 11 .937 11. 163 13.716 14.568 13 .892 12. 924 15 .068 14 .833 13 .328 16.399 17.426 16.387 17. 613 17.396 17.252 16 .155 18.150 19.360 17.255 17.638 26.397 15.797 14.397 13.931 12 .545 18.537 19.046 18.765 19.628 18.917 17.966 16 .638 16.116 15.835 18.186 17.086 14.832 14.548 14.060 1. 00 1. 00 1. 00 1. 00 1. 00 1.00 1 .00 1 .00 1. 00 1. 00 1. 00 S. 00 1. 00 1.00 1.00 1. 00 1. 00 1. 00 S. 00 1.00 1.00 1 .00 1. 00 1 .00 .1.00 1. 00 1 .00 1. 00 1 Go 1 .00 1 .00 1 .00 1.00 1 .0.0 1 .00 1 .00 1.00 1.00 1.00 1 .00 1 .00 1 .00 1.00 1 .00 1 .00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 51.87 48.23 49.74 47.59 51.85 52.94 52.19 52.10 54.43 43.67 41.45 40.27 37.15 37.39 37.67 35.38 39.79 34 .68 33.33 34.11 33.67 33.55 32. 99 36.09 33.55 34.12 32.63 32.24 33.24 35.01 35.44 31.08 31.49 29.75 28.83 29.52 27.21 27.25 28.63 25.33 29.03 28.37 30.40 31.10 29.53 27. 03 25.06 23.83 26.08 20.75 24.92 23.95 29.09 29.22 145. v01 WO 98/07835 PCT/US97/14885 270 ATOM 5156 C TRP 666 49.174 10.049 20.896 1.00 33.20 ATOM 5157 0 TRP 666 49.701 9.469 21.849 1.00 34.39 ATOM 5158 N MET 667 48.862 11.340 20.910 1.00 34.82 ATOM 5160 CA MET 667 49.169 12.175 22.056 1.00 36.31 ATOM 5161 CB MET 667 49.205 13.645 21.651 1.00 40.08 ATOM 5162 CG MET 667 50.475 14.047 20.931 1.00 42.41 ATOM 5163 SD MET 667 50.555 15.818 20.713 1.00 51.31 ATOM 5164 CE MET 667 50.957 15.928 18.949 1.00 45.44 ATOM 5165 C MET 667 48.299 12.003 23.287 1.00 37.81 ATOM 5166 0 MET 667 47.081 11.871 23.195 1.00 38.91 ATOM 5167 N ALA 668 48.958 11.964 24.442 1.00 36.47 ATOM 5169 CA ALA 668 48.286 11.846 25.718 1.00 37.06 ATOM 5170 CB ALA 668 49.308 11.654 26.835 1.00 35.76 ATOM 5171 C ALA 668 47.548 13.161 25.893 1.00 38.76 ATOM 5172 0 ALA 668 48.000 14.201 25.414 1.00 38.04 ATOM 5173 N PRO 669 46.416 13.142 26.608 1.00 41.60 ATOM 5174 CD PRO 669 45.819 11.981 27.282 1.00 41.64 ATOM 5175 CA PRO 669 45.614 14.347 26.841 1.00 43.25 ATOM 5176 CB PRO 669 44.478 13.827 27.718 1.00 45.08 ATOM 5177 CG PRO 669 44.383 12.368 27.325 1.00 44.04 ATOM 5178 C PRO 669 46.390 15.486 27.526 1.00 44.68 ATOM 5179 0 PRO 669 46.304 16.644 27.111 1.00 43.79 ATOM 5180 N GLU 670 47.135 15.164 28.580 1 00 44.29 ATOM 5182 CA GLU 670 47.905 16.195 29.266 1.00 45.36 ATOM 5183 CB GLU 670 48.596 15.637 30.509 1.00 46.97 ATOM 5184 CG GLU 670 49.858 14.819 30.243 1.00 50.04 ATOM 5185 CD GLtJ 670 49.588 13.345 30.070 1.00 51.35 ATOM 5186 OE1 GLU 670 .50.512 12.552 30.327 1.00 50.99 ATOM 5187 0E2 GLU 670 48.458 12.975. 29.700 1.00 52.70 ATOM 5188 C GLU 670 48.942 16.802 28.320 1.00 45.63 ATOM 5189 0 GLU 670 49.174 18.006 28.340 1.00 44.75 ATOM 5190 N ALA 671 49.546 15.962 27.482 1.00 46.18 ATOM 5192 CA ALA 671 50.555 16.406 26.531 1.00 46.44 ATOM 5193 CB ALA 671 51.218 15.203 25.860 1.00 43.27 ATOM 5194 C ALA 671 49.931 17.3-13 25.483 .1.00 47.85 ATOM 5195 0 ALA 671 50.485 18.355 25.150 1.00 47.61 ATOM 5196 N LEU 672 48.748 16.928 25.018 1.00 51.40 ATOM 5198 CA LEU 672 48.010 17.657 23.990 1.00 54.25 ATOM 5199 CB LEU 672 46.996 16.705 23.346 1.00 55.60 ATOM 5200 CG LEU 672 46.202 17.113 22.105 1.00 58.92 ATOM 5201 CD1 LEU 672 47.114 17.425 20.932 1.00 58.60 ATOM 5202 CD2 LEU 672 45.269 15.977 21.753 1.00 60.32 ATOM 5203 C LEU 672 47.315 18.925 24.514 1.00 55.91 ATOM 5204 0 LEU 672 47.289 19.958 23.837 1.00 55.72 ATOM 5205 N PHE 673 46.782 18.846 25.730 1.00 57.88 ATOM 5207 CA PHlE 673 46.089 19.977 26.342 1.00 60.07 ATOM 5208 CB PRlE 673 44.873 19.484 27.127 1.00 57.08 ATOM 5209 CG PHE 673 43.876 18.742 26.290 1.00 56.39 ATOM 5210 CD1 PHlE 673 43.191 17.653 26.813 1.00 57.67 ATOM 5211 CD2 PHE 673 43-.633 19.116 24.970 1.00 55.36 ATOM 5212. CEl PHlE 673 42.281 16.939 26.036 1.00 57.42 ATOM 5213 CE2 PHE 673 42.724 18.410 24.183 1.00 55.91 ATOM 5214 CZ PHE 673 42.049 17.317 24.720 1.00 56.42 ATOM 5215 C PHE 673 46.974 20.854 27.238 1.00 63.00 145. vOl WO 98/07835 PCTUS97/14885 271

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5216 5217 5219 5220 5221 5222 5223 5224 5225 5226 5228 5229 5230 5231 5232 5234 5235 5238 5241 5242 5243 5245 5246 5247 5248 5249 5250 5251 5252 5254 5255 5256 5257 5258 5259 5260 5261 5262 5264 5265 5266 5268 5269 5270 5272 5273 5274 5275 5277 5278 5279 5280 5281 5283 0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD

NE

Cz NH1 NH2

C

0

N

CA

CB

CG2

CGI

CD1

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2

CZ

OH

C

0

N

CA

CB

OG).

CG2

C

0

N

CA

CB

CG

CD2 ND1 CE1

PHE

AS P

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

THR

THR

THR

THR

THR

THR

THR

HIS

HIS

HIS

HIS

HIS

HIS

HIS

673 674 674 674 674 674 674 674 674 675 675 675 675 675 675 675 675 675 675 675 676 676 676 676 676 676 676 676 677 677 677 677 677 677 677 677 677 677 677 677 678 678 678 678 678 678 678 679 679 679 679 679 679 679 46. 926 47. 786 48.656 48. 545 47. 128 46. 684 46.462 50. 132 50. 984 50.441 51. 829 52. 321 51.491 52. 094 53.382 54.159 53. 788 55.324 52. 780 53. 960 52.248 53. 016 52. 175 52.871 51. 920 51. 038 53.494 52.727 54.760 55. 340 56.240 55.488 55. 187 54.534 55.113 54.458 54.177 53.557 56. 124 57. 040 55.733 56.397 55. 524 54. 302 55.190 56.634 56.207 57.312 57.532 58.441 59.869 60.630 60.694 61. 903 22. 085 20.223 20. 954 20.375 20.358 19. 283 21.416 20. 971 21. 304 20. 585 20. 550 21. 970 22 .685 24 .034 23. 911 24. 939 26 .182 24. 720 19. 864 20. 208 18 .903 18. 162 17. 904 16. 904 19.224 19-.096 16 .828 15.869 16 .773 15 .556 15.868 16.315 17 .660 18. 086 15 .395 15 .809 17 .159 17.589 14 .854 15.430 13 .621 12 .834 12.726 12 .045 14. 1 G5 11.432 11.085 10.616 9.248 8 .546 8 .997 9.668 8 .726 9.201 27.155 28.081 28 .999 30.409 30.923 31.372 30. 869 28.603 29.434 27.365 26. 883 26 .576 25.531 25.146 24.457 24.122 24.408 23.524 27.876 27.966 28.627 29.623 30.891 31.807 31.614 32.835 29.070 28.985 28.680 28 .143 26 .954 25.719 25.512 24.353 24.738 23.571 23.385 22.230 29.224 29.812 29.510 30.524 31.791 31. 475 32.327 29.992 28.892 30.784 30.390 31.391 31.331 32.233 30.263 30.510 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1.00 1 .00 1.00 1 .00 1.00 1.00 2. .00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 65.31 64 .08 64.97 65.13 67.33 66.68 69.20 66.38 68.44 65.68 63.71 63 .67 67.65 73 74.09 73 .41 72.90 71. 96 61.41 62 .62 59.15 56.88 56 .26 53 .11 57.86 61. .56 .58 58.12 54.34 51 .14 52 .37 56. 21 56.78 57.54 57.82 59.32 59.59 60.15 48.64 50.45 44.59 42.21 43.55 47.42 48.74 39.94 39.34 38 .54 38.29 39.51 43.13 43.49- 43.00 43.62 145. vOl WO 98/07835 PCT1US97/1488 272

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5284 5286 5287 5288 5290 5291 5292 5293 5294 5295 5298 5299 5300 5302 5303 5304 5306 5307 5308 5310 5311 5312 5313 5314 5315 5316 5317 5319 5320 5321 5322 5323 5324 5325 5327 5328 5329 5330 5331 5332 5333 5334 5336 5337 5338 5339 5340 5341 5343 5344 5345 5347 5348 5349 NE2

C

0

N

CA

CB

CG

CD

OE1 NE2

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG

CD2 CE2 CE3 CD1 NE1 CZ2 CZ3 CH2

C

0

N

CA

CB

OG

C

0

N

HIS

HIS

HIS

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

SER

SER

SER

SER

SER

SER

ASP

ASP

AS P

ASP

AS P

ASP

AS P

ASP

VAL

'VAL

VAL

VAL

VAL

VAL

VAL

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

SER

SER

SER

SER

SER'

SER

PHE

679 679 679 680 680 680 680 680 680 680 680 680 681 681 681 681 681 681 682 682 682 682 682 68B2 682 682 683 683- 683 683 683 683 683 684 684 684 684 684 684 684 684 684 684 684 684 684 684 685 685 685 685 685 685 686 61.889 56 .147 55 .898 55.228 53 .867 53 .214 53 .835 53 .677 52 .595 54 .767 53 .013 51.968 53.427 52.665 52 929 54 .307 53 .066 52-289 54 .281 54 .800 56..284 57.224 58.445 56. 763 54 .015 53 .788 53 .653 52.879 52.725 51.653 54.050 51.506 51.008 50.919 49.638 49.158 47.913 46.573 45.755 45.978 47 .850 46.560 44.380 44 .611 43.830 49.876 49.254 50.815 51.174 52 .444 52.355 51.399 50.968 52 .065 9.778 8.599 7.667 9.156 8.649 9.010 8.278 6.756 6.225 6.050 9.099 8.505 10.155 10.571 12. 034 12.286 9.620 9.366 9.077 8.106 7.820 8.732 8.537 9.620 6 .810 6.087 6.499 5.293 5.095 4.059 4.649 5.338 4.311 6.531 6.686 8.137 8.423 8.593 8.888 8.528 8.612 8.894 9.118 8.759 9.048 6.294 5.356 6.992 6.738 7.504 8.874 5.249 4.709 4.582 31.695 30.359 29. 593 31.142 31.209 32.543 33 .732 33.660 33 .908 33 .348 30.036 29. 758 29.349 28.182 27.813 27.620 27.051 26.136 27.162 26.205 26 .464 25.677 25.826 24 .908 26.374 25.411 27.617 27.935 29.478 29. 790 30.088 27.245 26.779 27.147 26.464 26.525 25.694 26.187 25.064 27.452 24 .337 23.956 25.181 27.563 26.428 25.013 24.503 24.380 22.986 22.631 22.986 22.737 21.713 23.676 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1. 0.0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1. 0,0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 44.68 39.42 40.00 38.96 38.84 40.90 44.42 44.47 45.52 42 .06 38.25 39.27 37.00 38.02 40.29 47.29 37.43 37.86 35.23 33.24 31.85 34.18 31.79 29.15 31. i=2 31.-93 33.14 32 .79 34.56 32.39 28.08 31.45 30.37 31.04 31.23 34 .14 37.17 38.61 37. 91 37.63 37.39 34.76 34.79 38.53 37.59 29.99 30.82 28.28 27 .54 26.69 32.15 26.41 29.52 26.47 SSSD/551 45. vOl WO 98/07835 PCT/US97/14885 273 ATOM 5351 CA PHE 686 52.325 3.151 23.563 1.00 26.35 ATOM 5352 CB PHE 686 53.167 2.668 24.754 1.00 25.01 ATOM 5353 CG PHE 686 53.447 1.182 24.742 1.00 27.24 ATOM 5354 CD1 PHE 686 54.187 0.'600 23.712 1.00 24.88 ATOM 5355 CD2 PHE 686 52.915 0.351 25.729 1.00 24.99 ATOM 5356 CEl PHE 686 54.389 0.783 23.655 1.00 22.77 ATOM 5357 CE2 PHE 686 53.113 -1.036 25.679 1.00 28.39 ATOM 5358 CZ PHE 686 53.853 -1.601 24.631 1.00 22.71 ATOM 5359 C PHE 686 50.997 2.366 23.466 1.00 28.82 ATOM 5360 0 PHE 686 50.892 1.398 22.696 1.00 26.41 ATOM 5361 N GLY 687 49.988 2.797 24.229 1.00 29.65 ATOM 5363 CA GLY 687 48.692 2.134 24.194 1.00 29.88 ATOM 5364 C GLY 687 48.099 2.158 22.794 1.00 29.57 ATOM 5365 0 GLY 687 47.560 1.165 22.300 1.00 30.38 ATOM 5366 N VAL 688 48.222 3.310 22.147 1.00 29.19 ATOM 5368 CA VAL 688 47.718 3.478 20.795 1.00 25.09 ATOM 5369 CB VAL 688 47.747 4.956 20.359 1.00 22.52 ATOM 5370 CGI VAL 688 47.106 5.115 18.985 1.00 21.13 ATOM 5371 CG2 VAL 688 47.(01 5.810 21.366 1.00 22.50 ATOM 5372 C VAL 688 48.574 2.636 19.865 1.00 23.82 ATOM 5373 0 VAL 688 48.080 2.132 18.871 1.00. 25.39 ATOM 5374 1 LEU 689 49.849 2.463 20.208 1.00 24.46 ATOM 5376 CA LEU 689 50.764 1.655 19.401 1.00 25.68 ATOM 5377 CB LEU 689 52.222 1.893 19.834 1.00 25.93 ATOM 5378 CG LEU 689 53.374 1.307 19.004 1.00 25.01 ATOM 5379 CD! LEU 689 54.655 2.080 19.257 1.00 25.86 ATOM 5380 2D2 LEU 689 53.593 -0.145 19.318 1.00 24.90 ATOM 5381 C LEU 689 50.374 0.171 19.531 1.00 26.50 ATOM 5382 0 LEU 689 50.464 -0.578 18.558 1.00 27.13 ATOM 5383 N LEU 690 49.927 -0.234 20.724 1.00 27.76 ATOM 5385 CA LEU 690 49.481 -1.610 20.980 1.00 28.59 ATOM 5386 CB LEU 690 49.087 -1.800 22.447 1.00 30.38 ATOM 5387 CG LEU 690 50.121 -2.065 23.545 1.00 29.57 ATOM 5388 CD1 LEU 690 49.435 -1.966 24.907 1.00 27.40 ATOM 5389 CD2 LEU 690 50.744 -3.431 23.360 1.00 28.79 ATOM 5390 C LEU 690 48,242 -1.849 20.134 1.00 28.77 ATOM 5391 0 LEU 690 48.055 -2.922 19.573 1.00 28.07 ATOM 5392 N TRP 691 47.383 -0.838 20.075 1.00 29.58 ATOM 5394 CA TRP 691 46.166 -0.921 19.275 1.00 30.53 ATOM 5395 CB TRP 691 45.327 0.349 19.451 1.00 28.28 ATOM 5396 CG TRP 691 43.985 0.300 18.769 1.00 25.86 ATOM 5397 CD2 TRP 691 43.702 0.689 17.421 1.00 23.99 ATOM 5398 CE2 TRP 691 42.321 0.498 17.215 1.00 25.08 ATOM 5399 CE3 TRP 691 44.487 1.165 16.367 1.00 20.88 ATOM 5400 CD1 TRP 691 42.791 -0.090 19.314 1.00 23.72 ATOM 5401 NEI TRP 691 41.786 0.031 18.389 1.00 26.15 ATOM 5403 CZ2 TRP 691 41.704 0.788 15.997 1.00 25.07 ATOM 5404 CZ3 TRP 691 43.883 1.448 15.163 1.00 22.80 ATOM 5405 CH2 TRP 691 42.501 1.251 14.982 1.00 24.95 ATOM 5406 C TRP 691 46.566 -1.116 17.811 1.00 30.63 ATOM 5407 0 TRP 691 45.943 -1.892 17.093 1.00 33.02 ATOM 5408 N GLU 692 47.625 -0.431 17.386 1.00 31.00.

ATOM 5410 CA GLU 692 48.130 -0.545 16.018 1.00 29.00 ATOM 5411 CB GLU 692 4,9.285 0.426 15.778 1.00 26.55 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 274 ATOM 5412 CG GLU 692 48.873 1.876 15.651 1.00 29.90 ATOM 5413 CD GLU 692 50.040 2.781 15.316 1.00 29.83 ATOM 5414 OEI GLU 692 50.770 3.174 16.247 1.00 32.18 ATOM 5415 OE2 GLU 692 50.227 3.110 14.124 1.00 31.57 ATOM 5416 C GLU 692 48.622 -1.959 15.735 1.00 29.02 ATOM 5417 0 GLU 692 48.474 -2.467 14.627 1.00 29.22 ATOM 5418 N ILE 693 49.258 -2.573 16.724 1.00 29.54 ATOM 5420 CA ILE 693 49.766 -3.933 16.555 1.00 31.01 ATOM 5421 CB ILE 693 50.634 -4.360 17.757 1.00 32.36 ATOM 5422 CG2 ILE 693 51.006 -5.845 17.641 1.00 34.39 ATOM 5423 CG1 ILE 693 51.909 -3.506 17.815 1.00 30.30 ATOM 5424 CD1 ILE 693 52.696 -3.693 19.082 1.00 25.66 ATOM 5425 C ILE 693 48.638 -4.939 16.381 1.00 30.63 ATOM 5426 0 ILE 693 48.633 -5.738 15.451 1.00 31.10 ATOM 5427 N PHE 694 47.644 -4.858 17.248 1.00 32.60 ATOM 5429 CA PHE 694 46.543 -5.793 17.172 1.00 33.86 ATOM 5430 CB PHE 694 45.938 -5.970 18.563 1.00 35.66 ATOM 5431 CG PHE 694 46.941 -6.499 19.559 1.00 35.70 ATOM 5432 CD1 PHE 694 47.460 -5.684 20.556 1.00 37.18 ATOM 5433 CD2 PHE 694 47.449 -7.794 19.426 1.00 34.37 ATOM 5434 CEl PHE 694 48.473 -6.150 21.392 1.00 36.90 ATOM 5435 CE2 PHE 694 48.456 -8.265 20.255 1.00 31.89 ATOM 5436 CZ PHE 694 48.970 -7.446 21.234 1.00 34.95 ATOM 5437 C PHE 694 45.532 -5.576 16.049 1.00 34.26 ATOM 5438 0 PHE 694 44.702 -6.442 15.787 1.00 37.52 ATOM 5439 N THR 695 45.636 -4.441 15.359 1.00 32.23 ATOM 5441 CA THR 69'5 44.775 -4.160 14.215 1.00 28.08 ATOM 5442 CB THR 695 44.186 -2.728 14.241 1.00 25.71 ATOM 5443 OGI THR 695 45.237 -1.762 14.228 1.00 24.94 ATOM 5445 CG2 THR 695. 43.353 -2.528 15.468 1.00 23.07 ATOM 5446 C THR 695 45.615 -4.348 12.955 1.00 27.53 ATOM 5447 0 THR 695 45.166 4.066 11.845 1.00 30.89 ATOM 5448 N LEU 696 46.833 -4.848 13.145 1.00 27.73 ATOM 5450 CA LEU 696 47.781 -5.081 12.061 1.00 28.99 ATOM 5451 CB LEU 696 47.370 -6.297 11.226 1.00 27.78 ATOM 5452 CG LEU 696 47.379 -7.591 12.047 1.00 29.89 ATOM 5453 CD1 LEU 696 47.251 -8.823 11.164 1.00 29.96 ATOM 5454 CD2 LEU 696 48.668 -7.656 12.803 1.00 30.20 ATOM 5455 C LEU 696 48.044 -3.853 11.179 1.00 30.33 ATOM 5456 0 LEU 696 48.006 -3.926 9.948 1.00 29.41 ATOM 5457 N GLY 697 48.374 -2.738 11.831 1.00 30.92 ATOM 5459 CA GLY 697 48.655 -1.503 11.113 1.00 30.35 ATOM 5460 C GLY 697 47.420 -0.650 10.912 1.00 30.65 ATOM 5461 0 GLY 697 47.359 0.178 10.000 1.00 30.01 ATOM 5462 N GLY 698 46.428 -0.836 11.772 1.00 30.50 ATOM 5464 CA GLY 698 45.209 -0.063 11.656 1.00 30.36 ATOM 5465 C GLY 698 45.416 1.415 11.930 1.00 30.07 ATOM 5466 0 GLY 698 46.320 1.809 12.666 1.00 30.56 ATOM 5467 N SER 699 44.554 2.228 11.338 1.00 29.65 ATOM 5469 CA SER 699 44.597 3.674 11.485 1.00 28.42 ATOM 5470 CB SER 699 44.263 4.324 10.145 1.00 24.61 ATOM 5471 OG SER 699 43.960 5.693 10.280 1.00 31.25 ATOM 5473 C SER 699 43.621 4.137 12.574 1.00 28.27 ATOM 5474 0 SER 699 42.406 3.930 12.474 1.00 27.14 SSSD/55145. vOl WO 98/07835 PCTUS97/14885 275

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5475 5476 5477 5478 5479 5480 5481 5482 5484 5485 5486 5487 5488 5489 5490 5491 5492 5494 5495 5496 5497 5498 5499 5500 5501 5502 5503 5505 5506 5507 5508 5510 5511 5512 5513 5514 5515 5516 5517 5518 5519 5520 5521 5522 5523 5525 5526 5527 5528 5529 5530 5531 5533 5534

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2 cz

OH

C

0

N

CD

CA

CB

CG

C

0

N

CA

C

0

N

CA

CB

CG1 CG2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

PRO

PRO

PRO

PRO

PRO

PRO

PRO

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

PRO

PRO

PRO

PRO

PRO

PRO

PRO

GLY

GLY

GLY

GLY

VAL

VAL

VAL

VAL

VAL

VAL

VAL

PRO

PRO

PRO

PRO

PRO

PRO

PRO

VAL

VAL

VAL

VAL

VAL

VAL

VAL

GLU

GLU

GLU

700 700 700 700 700 700 700 701 701 701 701 701 701 701 701 701 701 701 701 702 702 702 702 702 702 702 703 703 703 703 704 704 704 704 704 704 704 705 705 705 705 705 705 705 706 706 706 706 706 706 .706 707 707 707 44.160 45.587 43.303 44.319 45.531 42.413 42.800 41.204 40.246 40.559 40.321 41.323 41.092 39.084 38.845 39.845 39.584 40.173 40.356.

39.901 39.671 39.815 39.610 38.923 38.689 37.554 39.035 38.085 37.862 37.110 38.518 38.369 38.473 38.330 37.403 39.375 40.578 38.888 37.512 39. 745 38.863 37.478 40.164 39.549 41.198 41.764 42.803 43.483 43.836 40.740 40.761 39. 834 38.823 37.973 4 .682 4 .867 5. 155 5 .624 5. 982 6 .305 7. 096 6 .357 7 .419 8 .647 8.413 8 .638 8.412 7. 965 7. 738 7. 963 7.716 7.829 9. 001 6 .867 5.430 7.181 5.807 5. 036 8. 145 7. 953 9. 192 10.217 11.285 12 .231 11.149 12 .081 11. 360 12.350 10.295 13 .227 13 .028 14 .446 14. 763 15.628 16 .647 16.256 16 .081 15. 708 16 .912 17.417 18. 527 .18 .941 18. 038 .17. 934 .17.536 18.796 19.375 20.379 13 .675 13 .999 14 .764 15.812 14.985 14.306 13.446 14 .854 14.548 15.405 16.866 17.803 19.158 17.310 18.653 19.574 20.907 13 .088 12.760 12.191 12 .417 10.764 10.119 11.169 10.440 10.865 9.693 9 .295 10.351 10.108 11.505 12.619 13 .984 15.135 14.091 12.588 12.758 12.336 11.906 12.280 11.569 12.021 13.668 14.668 13.710 14 .954 14 .673 15.957 13.670 15.969 17.136 15.517 16.395 15.621 1. 00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1. 00 1.00 1.00 1 O0 1 .00 1.00 1.00 .1..00 1 .0,0 1.00.

1.00 1.00 1.00 1 .00 100 1. 00 1.00 1.00 1. 00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00o 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 29.29 26.09 29.30 27.68 27.85 29.71 31.38 29.51 30.25 33.50 37.84 40.05 42.28 41.54 43.70 42.63 45.31 28.45 29.03 28.05 26-.90 27.48 27 .06 28.28 26.81 26.26 28.48 26 .54 28 .03 28 .93 28 .16 29.55 28 28.07 29.78 32 .00 33 33.56 33.69 32.65 34 36.38 33 .22 33 .26 34.61 37.72 39.14 39.12 41. 07 38.70 38.42 40.43 40.66 43 145. vOl WO 98/07835 PCTIUS97/14885 276 ATOM 5535 C GLU 707 37.940 18.316 17.028 1.00 41.03 ATOM 5536 0 GLU 707 37.642 18.370 18.231 1.00 41.52 ATOM 5537 N GLU 708 37.560 17.327 16.224 1.00 41.62 ATOM 5539 CA GLU. 708 36.708 16.243 16.700 1.00 41.06 ATOM 5540 CB GLU 708 36.179 15.425 15.523 1.00 45.19 ATOM 5541 CG GLU 708 35.281 16.221 14.571 1.00 48.74 ATOM 5542 CD GLIU 708 34.063 16.825 15-.258 1.00 57.18 ATOM 5543 OE1 GLU 708 33.523 16.203 16.207 1.00 54.30 ATOM 5544 0E2 GLU 708 33.646 17.934 14.837 1.00 61.76 ATOM 5545 C GLU 708 37.443 15.363 17.694 1.00 38.39 ATOM 5546 0 GLU 708 36.867 14.927 18.696 1.00 36.76 ATOM 5547 N LEU 709 38.725 15.131 17.434 1.00 37.78 ATOM 5549 CA LEU 709 39.555 14.327 18.324 1.00 38.13 ATOM 5550 CB LIEU 709 41.007 14.255 17.820 1.00 35.45 ATOM 5551 CG LEU 709 41.984 13.560 18.786 1.00 35.57 ATOM 5552 CD1 LEU 709 41.825 12.049 18.729 1.00 32.33 ATOM 5553 CD2 LEU 709 43.407' 13.965 18.484 1.00 31.98 ATOM 5554 C LIEU 709 39.550 14.946 19.716 1.00 38.31 ATOM 5555 0 LEU 709 *39.362 14.250. 20.717 1.00 38.16 ATOM 5556 N PEE 710 39.776 16.254 19.770 1.00 40.09 ATOM 5558 CA PEE 710 39.807 16.973 21.036 1.00 43.61 ATOM 5559 CB PHE 710 39.997 18.475 20.797 1.00 48.22 ATOM 5560 CG PEE 710 41.328 18.834 20.192 1.00 51. 77 ATOM 5561 CD1 PEE 710 42.395 17.939 20.231 1.00 52.94 ATOM 5562 CD2 PEE 710 41.513 20.072 19.579 1.00 53.99 ATOM 5563 CEI PEE 710 43.632 18.275 19.679 1.00 56.48 ATOM 5564 CE2 PEE 710 42.746 20.422 19.021 1.00 55.72 ATOM 5565 C Z PEE 710 43.807 19.517 19.069 1.00 57.84 ATOM 5566 C PHE 710 38.519 16.726 21.796 1.00. 43.35 ATOM 5567 0 PEE 710 38.539 16.424 22.989 1.00 43.22 ATOM 5568 N LYS '711 37.399 16.804 21.083 1.00 44.68 ATOM 5570 CA LYS 711 36.095 16.587 21.690 1.00 43.47 ATOM 5571 CB LYS 711 34.977 16.878 20.687 1.00 44.33 ATOM 5572 CG LYS 711 33.601 16.765 21.299 1.00 47.63 ATOM 5573 CD LYS 711 32.510 17.206 20.362 1.00 49.97 ATOM 5574 CE LIYS 711 31.158 16.873 20.960 1.00 51.70 ATOM 5575 NZ LYS 711 30.038 17.412 20.150 1.00 57.55 ATOM 5579 C LYS 711 35.986 15.173 22.261 1.00 42.72 ATOM 5580 0 LIYS 711 35.589 14.999 23.420 1.00 41.16 ATOM 5581 N LIEU 712 36.392 14.176 21.471 1.00 42.52 ATOM 5583 CA LIEU 712 36.361 12.770 21.898 1.00 42.52 ATOM 5584 CB LEU 712 36.922 11.843 20.809 1.00 41.56 ATOM 5585 CG LIEU 712 36.090 11.528 19.560 1.00 41.87 ATOM 5586 CD1 LIEU 712 36.902 10.620 18.636 1.00 36.28 ATOM 5587 CD2 LIEU 712- 34.760 10.868 19.951 1.00 37.19 ATOM 5588 C LIEU 712 37.158 12.564 23.180 1.00 42.34 ATOM 5589 0 LIEU 712 36.697 11.886 24.107 1.00 40.77 ATOM 5590 N LIEU 713 38.366 13.121 23.208 1.00 42.68 ATOM 5592 CA LIEU 713 39.240 13.025 24.371 1.00 44.05 ATOM 5593 CB LIEU 713 40.581 13.710 24.100 1.00 45.45 ATOM 5594 CG LIEU 713 41.418 13.114 22.963 1.00 44.78 ATOM 5595 CD1 LIEU 713 42.676 13.945 22.750 1.00 41.89 ATOM 5596 CD2 LIEU 713 41.757 11.660 23.282 1.00 43.21 ATOM 5597 C LIEU 713 38.571 13.654 25.591 1.00 44.66 SSSD/55145. vOl WO 98/07835 WO 9807835PCT/tJS97/14885 277 ATOM 5598 0 ATOM 559 9 N ATOM 5601 CA ATOM 5602 CB ATOM 5603 CG ATOM 5604 CD ATOM 5605 CE ATOM 5606 NZ *ATOM 5610 C ATOM 5611 0 ATOM 5612 N ATOM 5614 CA ATOM 5615 CE ATOM 5616 CG ATOM 5617 CD ATOM 5618 OE1 *ATOM 5619 0E2 ATOM 5620 C ATOM 5621 0 ATOM 5622 N ATOM 5624 CA ATOM 5625 C ATOM 5626 0 ATOM 5627 N ATOM 5629 CA ATOM 5630 CE ATOM 5631 CG ATOM 5632 CD2 ATOM 5633 ND1 ATOM 5635 CEl ATOM 5636 NE2 ATOM 5638 C ATOM 5639 0 ATOM 5640 N ATOM 5642 CA ATOM 5643 CB ATOM 5644 CG ATOM 5645 CD ATOM 5646 NE ATOM 5648 CZ ATOM 5649 NH1 ATOM 5652 NH2 ATOM 5655 C ATOM 5656 0 ATOM 5657 N ATOM 5659 CA ATOM 5660 CB ATOM 5661 CG ATOM 5662 SD ATOM 5663 CE ATOM 5664 C ATOM 5665 0 ATOM 5666 N ATOM 5668 CA

LEU

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLY

GLY

GLY

GLY

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ARG

ARG

ARG

ARG

ARG

AR.G

ARG

ARG

ARG

ARG

ARG

MET

MET

MET

MET

MET

MET

MET

MET

ASP

ASP

713 714 714 714 714 714 714 714 714 714 715 715 715 715 715 715 715 715 715 716 716 716 716 717 717 717 717 717 717 717 717 717 717 718 718 718 718 718 718 718 718 718 718 718 719 719 719 719 719 719 719 719 720 720 38.562 37.980 37.300 36. 884 38. 076 37. 684 38.939 39.889 36. 104 35. 767 35.480 34. 342 33.408 32. 800 32. 032 32. 409 31. 061 34.793 33. 970 36. 102 36. 623 36.503 36. 603 36 30'7 36.167 35.800 35.745 34. 756 36. 818 36 .494 35.250 37.451 38.528 37.313 38.440 38.614 38. 976 40.284 40. 718 40.550 39. 940 41. 067 38.124 36. 953 39.145 38.925 40.198 40.575 42.000 43.317 38.415 38. 708 37.659 37.069 13.'051 26.662 14.839 25.418 15.510 26.524 16.921 26.127 17.828 25.918 19.259 25.589 20.097 25.292 20.148 26.459 14.728 27.054 14.824 28.237 13 .934 26.192 13.118 26.593 12.893 25.411 14.174 24.846 13.936 23.563 13.008 22.810 14'.677 23.304 11.773 27.157 10.907 27.450 11.585 27.286 10.336 27.819 9.140 26.887 7.994 27.340 9.404 25.592 8.353 24.579 8'.951 23.217 7.941 22.112 7.101 21.717 7.683 21.283 6.728. 20.426 6.357 20.670 7.567 24.413 8.152 24.295 6.247 24.337 5.345 24.170 4.496 25.434 5.308 26.687 6.065 26.476 6.856 27.630 8.173 27.744 8.859 26.784 8.826 28.777 4.474 22.952 4.243 22.645 4.077 22.204 3.253 21.029 3.125 20.185 4.399 19.441 4.225 18.368 4.219 19.511 1.877 21.418 1.393 22.517 1.267 20.498 -0.063 20.666 1.00 45.70 1.00 43.05 1. 00 42.19 1.00 42.41 1.00 46.10 1.00 49.86 1.00 52.55 1.00 50.17 1.00 42.39 1.00 43.44.

1.00 40.44 1.00 37.90 1.00 39.54 1.00 45.20 1.00 47.85 1.00 50.00 1.00 50.41 1.0.0 37.31 1.00 36 79 1.00 36.60 1.00 37.11 -I.00 38.'30 1.00 36.84 1.00 40.24 1.00 42.63 1.00 43.13.

1.00 44.69 1.00 45.13 .1.00 47.31 1.00 47.61 1.00 44.95 1.00 44.84 1. 00 46.79 1.00 45.44 1.00 45.36 1.00 43.'82 1.00 44.52 1.00 45.02 1.00 43.12 1.00 44.77 1.00 44.67 1.00 46.39 1.00 45.94 1.00 47.59 1.00 45.34 1.00 44.28 1.00 42.30 1.00 38.44 1.00 36.97 1.00 36.09 1.00 46.21 1.00 43.29 1.00 48.79 1.00 48.87 145. vOl WO 98107835 PCTIUS97/14885.

278 ATOM 5669 CB ASP 720 36.099 -0.369 19.513 1.00 54.01 ATOM 5670 CG ASP 720 34.766 0.374 19.632 1.00 59.30 ATOM 5671 OD1 ASP 720 34.762 1.583 19-981 1.00 62.96 ATOM 5672 0D2 ASP 720 33.716 -0.259 19.354 1.00 58.64 ATOM 5673 C ASP 720 38.126 -1.154 20.688 1.00 46.10 ATOM 5674 0 ASP 720 39.213 -0.992 20.125 1.00 44.13 ATOM 5675 N LYS 721 37.788 -2.272 21.322 1.00 45.27 ATOM 5677 CA LYS 721 38.689 -3.413 21.404 1.00 43.25 ATOM 5678 CB LYS 721 38.172 -4.436 22.416 1.00 42.02 ATOM 5679 CG LYS 721 39.072 -5.651 22.557 1.00 46.57 ATOM 5680 CD LYS 721 38.602 -6.576 23.666 1.00 49.96 ATOM 5681 CE LYS 721 38.300 -7.971 23.141 1.00 51.80 ATOM 5682 NZ LYS 721 37.937 -8.920 24.240 1.00 56.08 ATOM 5686 C LYS 721 38.769 -4.055 20.031 1.00 43.67 ATOM 5687 0 LYS 721 37.736 -4.313 19.394 1.00 44.02 ATOM 5688 N PRO 722 39.995 -4.233 19.513 1.00 43.94- ATOM 5689 CD PRO 722 41.281 -3.711 20.001 1.00 45.90 ATOM 5690 CA PRO 722 40.159 -4.853 18.198 1.00 43.96 ATOM 5691 CB PRO 722 41.665 -4.720 17.941 1.00 43.11 ATOM 5692 CG PRO 722 42.046 -3.509 18.715 1.-00 45.16 ATOM 5693 C PRO 722 39.772 -6.317 18.295 1.00 43.09 ATOM 5694 0 PRO 722 39.764- -6.888 19,385 1.00 41.32 ATOM 5695 N SER 723 39.382 -6.902 17.170 1.00 45.79 'ATOM 5697 CA SER '723 -39.044 -9.316 17.144 1.00 46.67 ATOM 5698 CB SER 723 38.303 -8.664 15.857 1.00 44.69 ATOM 5699 OG SER 723 39.131 -8.414 14.736 1.00 49.79 ATOM 5701 C SER 723 40.422 -9.961 17.148 .1.-00 46.90 ATOM 5702 0 SER 723 41.360 -8.411 1.6.581 1.00 48.81 ATOM 5703 N ASN 724 40.540 -1.131 17.760 1. f) 49.28 ATOM 5705 CA ASN 724 41.826 10.804.. 17.849 1.00 52.10 ATOM 5706 CB ASN 724 42.480 10 .947. 16.469 1.00 55.86 ATOM 5707 CG ASM 724 41.774 1.1.957 15.592 1.00o 58.72 ATOM 5708 ODi ASN 724 41.686 -13.140 15.941 1.00 62.28 ATOM 5709 ND2 ASN 724 41.258 -11.503 14.449 1.00 59.56 ATOM 5712 C ASN 724 42.665 -9.931 18.770 1.00 51.97 ATOM 5713 0 ASN 724 43.621 -9.274 18.369 1.00 53.85 ATOM 5714 N CYS 725 42.202 -9.859 20.004 1.00 51.02 ATOM 5716 CA CYS 725 42.853 -9.094 21.049 1.00 50.18 ATOM 5717 CB CYS 725 42.708 -7.583 20.811 1.00 47.75 ATOM 5718 SG CYS 725 43.424 -6.577 22.130 1.00 44.37 ATOM 5719 C CYS 725 42.131 -9.507 22.315 1.00 49.31 ATOM 5720 0 CYS 725 40.916 -9.371 22.417 1. 00 49.90 ATOM 5721 N THR 726 42.866 -10.088 23.249 1.00 48.52 ATOM 5723 CA THR 726' 42.262 -10.541 24.490 1.00 49.58 ATOM 5724 CE THR 726 43.251 -11.444 25.291 1.00 49.84 ATOM 5725 OGi TIIR 726 44.236 -10.648 25.976 1.00 49.05 ATOM 5727 CG2 THR 726 43.982 -12.363 24.352 1.00 47.96 ATOM 5728 C TUR 726 41.788 -9.369 25.356 1.00 49.93 ATOM 5729 0 THR 726 42.305 -8.256 25.244 1.00 51.55 ATOM 5730 N ASN 727 40.829 -9.622 26.242 1.00 50.48 ATOM 5732 CA ASN 727 40.335 -8.577 27.144 1.00 52 .17 ATOM 5733 CE ASN 727 -39.190 -9.099 28.016 1.00 57.57 ATOM 5734 CG ASN 727 '39.533 -10.409 28.714 1.00 66.49 ATOM 5735 ODi ASN 727 40.709 -10.786 28.833 1.00 70.43 145. vOl WO 98/07835 WO 9807835PCT/US97/14885 279 ATOM 5736 ND2 ASN 727 38.500 -11.122 29.175 1.00 68.43 ATOM 5739 C ASN 727 41.4921 -8.091 28.023 1.00 50.29 ATOM 5740 0 ASN 727 41.467 -6.976 28.540 1.00 49.88 ATOM 5741 N GLU 728 .42.518 -8.927 28.163 1.00 50.60 ATOM 5743 CA GLU 728 43'.700 -8.597 28.956 1.00 49.33 ATOM 5744 CB GLU 728 44.529 -9.859 29.220 1.00 50.44 ATOM 5745 CG GLU 728 45.802 -9.600 30.008 1.00 55.30 ATOM 5746 CD GLU 728 46..577 -10.862 30.354 1.00 57.40 ATOM 5747 OE1 GLU 728 46.716 -11.754 29.489 1.00 56.75 ATOM 5748 0E2 GLU 728 47.062 -10.950 31.502 1.00 59.85 ATOM 5749 C GLU 728 44.539 -7.552 28.212 1.00 47.08 ATOM 5750 0 GLU 728 44.888 -6.512 28.776 1.00 48.02 ATOM 5751 N LEU 729 44.846 -7.821 26.945 1.00 43.34 ATOM 5753 CA LEU 729 45.630 -6.891 26.129 1.00 42.01 ATOM 5754 CB LEU 729 45.899 -7.500 24.751 1.00 39.46 ATOM 5755 CG -LEU 729 46.911 -8.639 24.772 1.00 40.31 ATOM 5756 CD1 LEU 729 46.782 -9.482- 23.531 1.00 42.21 ATOM 5757 CD2 LEU 729 48.314 -8.068 24.900 1.00 42.49 ATOM 5758 C LEU 729 44.901' -5.E57 25.980 1.00. 40.61 ATOM 5759 0 LEU 729 45.510 -4.481 25.953 1.00 38.33 ATOM 5760 N TYR 730 43.580 -5.637. .25.909 1.00 39.0~7 ATOM 5762 CA TYR 730 42.761 -4.455 25.773 1.00 38.61 ATOM 5763 CB TYR 730 .41.341 -4.837 25.369 1.00 36.79 ATOM 5764 CG TYR 730 40.454 -3.64.6 25.125 1.00 37.08 ATOM 5765 CD1 TYR 730 40.760 -2.721 24.127 1.00 32.86 ATOM 5766 CEl TYR 730 39.961 -1.616 23.912 1.00 29.79 ATOM 5767 CD2 TYR 730 39.328 -3.420 25.916 1.00 36.99 ATOM 5768 CE2 TYR 730 38.522 -2.312 25.704 1.00 36.69 ATOM 5769 CZ TYR 730 38.853 -1.412 24.706 1.00 32.69 ATOM. 5770 OH TYR 730 38.044 -0.320 24.492 1.00 38.80 ATOM 5772 C TYR 730 42.767 -3.662 27.080 1.00 39.75 ATOM 5773 0 TYR 730 42.*781 -2,430 27.065 1.00 40.53 ATOM 5774 N MET 731 42-738 -4.360 28.210 1.00 41.88 ATOM 5776 CA MET 731 42.*778 -3.684 29.509 1.00 45.34 ATOM 5777 CB MET 731 42.658 -4.697 30.646 1.00 53.46 ATOM 5778 CG MET 731 41.253 -5.248 30.836 1.00 64.30 ATOM 5779 SD MET 731 40.134 -4.095 31.653 1.00 75.78 ATOM 5780 CE MET 731 40.657 -4.338 33.370 1.00 69.70 ATOM 5781 C MET 731 44.099 -2.927 29.614 1.00 41.53 ATOM 5782 0 MET 731 44.157 -1.814 30.138 1.00 37.91 ATOM 5783 N MET 732 45.156 -3.545 29.098 1.00 40.48 ATOM 5785 CA MET 732 46.478 -2.937 29.091 1.00 40.23 ATOM 5786 CB MET 732 47.508 -3.872 28.436 1.00 40.29 ATOM 5787 CG MET 732 48.929 -3.307 28.390 1.00 38.07 ATOM 5788 SD MET 732 50.171 -4.522 27.908 1.00 *37.65 ATOM 5789 CE MET 732 50.407 -5.343 29.431 1.00 37.90 ATOM 5790 C MET 732 46.378 -1.623 28.317 1.00 38.96 ATOM 5791 0 MET 732 46.843 -0.591 28.790 1.00 41.36 ATOM 5792 N MET 733 45.744 -1.663 27.148 1.00 36.94 ATOM 5794 CA MET 733 45.574 -0.463 26.340 1.00 35.19 ATOM 5795 CB MET 733 44.796 -0.769 25.070 1.00 36.07 ATOM 5796 CG MET 733 45.549 -1.577 24.048 1.00 35.99 ATOM 5797 SD MET 733 44.471 -1.851 22.641 1.00 40.05 ATOM 5798 CE MET 733 45.244 -3.351 21.909 1.00 33.13 SSSD/551 45. vOl WO 98/07835 PCTIUS97/14985 280

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5799 5800 5801.

5803 5804 5805 5806 5807 5809 5810 5813 5816 5817 5818 5820 5821 5822 5823 5824 5825 5826 5827 5829 5830 5831 5832 5833 5834 5836 5837 5838 5839 5840 5841 5842 5843 5845 5846 5847 5848 5849 5850 5852 5853 5854 5855 5856 5858 5859 5861 5862 5 863 5865 5866

C

0

N

CA

CB

CG

CD

NE

Cz

NH).

NH2

C

0

N

CA

CB

CG

OD1 0D2

C

0

N

CA

CB

SG

C

0

N

CA

CB

CG

CD2 CE2 CE3 CD1 NEl CZ2 CZ3 CH2

C

0

N

CA

CB

CG

CD2 ND1 CE 1 NE2 0

.N

CA

CB

MET

MET

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

AS P AS P AS P AS P AS P

ASP

AS P AS P

CYS

CYS

CYS

CYS

CYS

CYS

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ALA

ALA

ALA

733 733 734 734 734 734 734 734 734 734 734 734 734 735 735 735 735 735 735 735 735 736 736 736 736 736 736 737 737 737 737 737 737 737 737 737 737 737 737 737 737 738 738 738 738 738 738 738 738 738 738 739 739 739 44.800 45.207 43 .690 42 .849 41.577 40.699 40.256 39.443 38 .120 37.435 37.477 43.627 43.445 44.530 45.379 46.325 45.622 46.048 44.657 46.215 46. 235 46.890 47. 730 48.379 49. 453 46.938 47. 516 45.620 44 .772 43. 791 44.453 43.893 44.852 42.672 45.695 45. 941 44.627 42.452 43.426 44.028 42. 979 44.575 43. 932 44.454 43.742 43.473 43.220 42.659 42.798 44..174 45.314 43.099 43.155 41.823 0.560 1.719 0 .125 1. 014 0.297 -0.225 0.877 1 .898 1.838 0 .811 2 .804 1.587 2.757 0.782 1.208 087 1.022 -2.194 -0.713 2.385 3.446 2 .182 3 .196 2 .652.

1.261 4.429 5 .491 4 .290 5 .423 5 .028 4 .586 3 .718 3 .583 3 .040 4.932 4 .336 2 .795 2 .261 2 .145 6.029 6 .658 5.873 6.423 5 .735 6 .154 7.379 5 .244 5 .899 7 .194 7.921 8 .356 8.686 10.150 10.681 27.141 27.245 27.735 28 .532 28.993 27 .856 26 .909 27 .567 27.700 27.222 28 .338 29.715 30.068 30.276 31.399 31.825 32 .574 32.428 33.313 30.938 31.585 29.805 29..181 27.916 28 .198 28 .814 28 .606 28.713 28 .370 27.271 26 .011 25.020 23 .992 24 .900 25 .556 24.343 22.859 23 .778 22 .772 29.563 29.398 30 .763 31 .948 33.205 34.458 34 .963 35.355 36.357 36.146 32 .037 32.021 32.224 32 .322 32 .790 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00o 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 37.29 39.14 38 .76 -39.49 40.33 38.02 42.72 48.85 52 54 .79 54.69 38.70 40.92 38.76 38.60 41.34 44 .66 43.15 44.46 37 .76 36.35 35.39 34.77 30.62 30.96 35.98 37.38 38.50 40.16 38.41 39.33 39.64 39.97 37.06 39.56 38.61 38.78 38.90 38.18 41.30 41.45 43.01 44.64 46.20 50.35 49.09 49.94 52 .92 46.91 45.26 45.31 46.61 48.49 49.69 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97I1488 281

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5867 5868 5869 5871 5872 5873 5874 5875 5876 5877 5878 5879 5880 5881 5882 5883 5884 5886 5887 5888 5890 5891 5892 5894 5895 5896 5897 5898 5899 5902 5903 5904 5906 5907 5908 5909 5910 5912 5913 5916 5919 5920 5921 5922 5923 5924 5925 5926 5927 5928 5930 5931 5932 5934

C

0

N

CA

CB

CGl CG2

C

0

N

CD

CA

CB

CG

c 0

N

CA

CB

OG

C

0

N

CA

CG

CD

OE1 NE2

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

001 CG2

ALA

ALA

VAL

VAL

VAL

VAL

VAL

VAL

VAL

PRO

PRO

PRO

PRO

PRO

PRO

PRO

SER

SER

SER

SER

SER

SER

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

A.RG

ARG

PRO

PRO

PRO

PRO

PRO

PRO

PRO

THR

THR

THR

THR

THR

739 739 740 740 740 740 740 740 740 741 741 741 741 741 742 741 742 742 742 742 742 742 743 743 743.

743 743 743 743 743 743 744 744 744 744 744 744 744 744 744 744 744 745 745 745 745 745 745 745 746 746 746 746 746 44 .272 45. 004 44 .336 45.352 44.897 45.847 43 .485 46 .649 46.773 47.646 47 .603 48.949 49.762 48 .714 49.641 50.449 49.327 49. 928 49. 760 48.403 49.339 49.926 48.164 47.529 46.022 45.519 46.178 46.905 45.922 47 .874 47. 548 48.497* 48.914 49.349 48.296 48 .906 47.948 48.258 49.524 47.307 50.110 50.906 50.223 49.345 51. 38f* 51.063 50.255 52.664 52.631 53.783 55.066 56.108 56.286 55.666 10.682 11. 601 10.138 10.485 10.075 10.624 9.727 8.534 10. 421 11.861 9.852 11.087 12.000 9.016 8.139 9.290 8.557 9.326 9.638 7.159 6.284 6.959 5.658 5.791 5.305 6.030 5.425 7.338 4.768 578 5.339 4.559 5.469 6.406 7.383 8.437 9.658 10.001 10. 569 3.712 4.124 2.489 1.749 1.685 0.311 0.642 2.269 3.009 2.001 2.462 2.571 1.285 3.567 33 .224 32.846 34.439 35.439 36.850 37.878 37.105 35.130 35.440 34.565 34.253 34 .197 33 .828 33 .255 35.275 34 .955 36.541 37.651 38. 963 39.209 37.787 38.427 37.203 37.273 37.432 38.784 39.947 40.748 40.052 36.095 36 .114 35. 059 33.880 32 .724 32.190 31.216 30.922 30.493 30.278 30.360 34.295 35.145 33 .754 32 .831 34.157 33 .558 32.344 33 .573 32.595 34.224 33 .728 34.869 35.487 35. 899 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00- 1.00 1.00 50. 77 51. 77 51.47 51. 09 52.40 53.38 55.18 48. 99 47. 72 48.31 47.84 48.51 46.83 46.21 49. 12 46.57 49.47 49.50 51 .06 53.81 48.81 49.45 47.82 46. 34 49.74 55.41 59. 59. 02 60.03 44.34 44 .64 42.83 40.34 35.84 28.25 22.56 28.09 32.83 34.44 32.00 41.58 45.48 40.97 39.90 39.77 39.31 40. 98 38.44 39.64 37.50 37.56 38.58 43.28 34 .64 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 282 ATOM 5935 C THR 746 55.546 1.393 ~32.739 1.00 36.49 ATOM 5936 0 THR 746 55.118 0.234 32.817 1.00 34.18 ATOM 5937 N PHE 747 56.453 1.768 31.839 1.00 35.27 ATOM 5939 CA PEE 747 56.995 0.814 30.880 1.00 33.48 ATOM 5940 CB PHE 747 58.025 1.475. 29.970 1.00 34.35 ATOM 5941 CG PHE 747 57.419 2.369 28.920 1.00 32.49 ATOM 5942 CD1 PEE 747 56.715 1.825 27.856 1.00 -30.69 ATOM 5943 CD2 PHE 747 57.519 3.749 29.018 1.00 32.81 ATOM 5944 CEl PEE 747 56.122 2.639 26.907 1.00 29.41 ATOM 5945 CE2 PEE 747 56.926 4.573 28.072 1.00 32.93 ATOM 5946 CZ PEE 747 56.223 4.014 27.015 1.00 31.50 ATOM 5947 C PEE 747 57.621 -0.363 31.606 1.00 34.65 ATOM 5948 0 PEE 747 57.616 -1.474 31.099 1.00 36.34 ATOM 5949 N LYS 748 58.142 -0.128 32.808 1.00 37.75 ATOM 5951 CA LYS 748 58.748 -1.205 33.583 1.00 39.67 ATOM 5952 CE LYS 748 59.382 -0.664 34.873 1.00 43.06 ATOM 5953 CG LYS 748 59.958 -1.757 35.774 1.00 48.96 ATOM 5954 CD LYS 748 60.750 -1.207 36.966 1.00 52.20 ATOM 5955 CE LYS 748 61.183 -2.344 37.907 1.00 53.62 ATOM 5956 NZ LYS 748 62.057 -1.893 39.031 1.00 54.82 ATOM 5960 C LYS 748 57.680 -2.263 33.882 1.00 39.65 ATOM 5961 0 LYS 748 57.902 -3.454 33.652 1.00 38.91 ATOM 5962 N GLN .749 56.503 -1.818 34.331 1.00 39.39 ATOM 5964 CA GLN 749 55.402 -2.742 34.623 1.00 40.70 ATOM 5965 CB GLN 749 54.177 -1.991 35.14G 1.00 43.82 ATOM 5966 CG GLN 74.9 54,395 -1.149 36.373 1-.00 50.97 ATOM 5967 CD GLN 749 53.175 -0.304 3 6. 715 1.00 55.53 ATOM 5 968 OE1- GLN 749 53.272 0.914 36.895 3..00 55.80 ATOM 5969 NE2 GLN 749 52.012 -0.940 36.773 1.00 60.05 ATOM 5972 C GLN 749 55.009 -3.455 33.334 1.00 40.03 ATOM 5973 0 GLN 749 54.903 -4.679 33.298 1.00 40.26 ATOM 5974 N LEU 750 54.802 2.666 32.278 1.00 39.18 ATOM 5976 CA LEU 750 54.400 -3.171 30.964 1.00 36.65 ATOM 5977 CE LEU 750 54.369 -2.039 29.927 1.00 34.58 ATOM 5978 CG LEt) 750 53.355 -0.910 30.116 1.00 32.52 ATOM 5979 CD1 LEt) 750 53.644 0.210 29.125 1.00 31.67 ATOM 5980 CD2 LET) 750 51.947 -1.435 29.935 1.00 31.37 ATOM 5981 C LET) 750 55.321 4.255 30.477 1.00 35.81 ATOM 5982 0 LEt) 750 54.856 -5.267 29.963 1.00 35.81 ATOM 5983 N VAL 751 56.626 -4.035 30.620 1.00 37.38 ATOM 5985 CA VAL 751 57.607 -5.029 30.193 1.00 38.66 ATOM 5986 CE VAL 751 59.077 -4.545 30.411 1.00 35.42 ATOM 5987 CG1 VAL 751 60.075 -5.646 30.041 1.00 29.83 ATOM 5988. CG2 VAL 751 5 9.342 -3.324 29.559 1.00 29.95 ATOM 5989 C VAL 751 57.337 -6.314 30.974 1.00 41.63- ATOM 5990 0 VAL 751 57.312 -7.401 30.396 1.00 42.43 ATOM 5991 N GLU 752 57.051 -6.174 32.267 1.00 43.35 ATOM 5993 CA GLU 752 56.766 -7.329 33.111 1.00 47.39 ATOM 5994 CE GLU 752 56.674 -6.914 34.587 1.00 50.66 ATOM 5995 'CG GLU. 75 '2 57.950 -6.243 35.101 1.00 54.77 ATOM 5996 CD GLU .752 58.006 -6.101 36.612 1.00 55.14 ATOM 5997 OE1 GLU. 752 58.246 -4.972 37.102 1.00 54.14 ATOM 5998 0E2 GLt) 752 57.844 -7.131 37.308 1.00 57.73 ATOM 5999 C GLU 752 55.496 -8.068 32.655 1.00 46.00 145. vOl WO 98/07835 WO 9807835PCT1US97/14885 283 ATOM 6000 0 GLU 752 55.548 -9.261 32.328 1.00 46.25 ATOM 6001 N ASP 753 54.380 -7.346 32.601 1.00 44.35 ATOM 6003 CA ASP 753 53.099 -7.912 32.180 1.00 44.19 ATOM 6004 CB ASP 753 52.059 -6.814 31.985 1.00 46.22 ATOM 6005 CG ASP 753 51.512 -6.279 33.278 1.00 50.48 ATOM 6006 OD1 ASP 753 51.396 -7.062 34.248 1.00 52.15 ATOM 6007 0D2 ASP 753 51.170 -5.069 33.306 1.00 52.20 ATOM 6008 C ASP 753 53.244 -8.608 30.849 1.00 44.54 ATOM 6009 0 ASP 753 52.770 -9.724 30.674 1.00 46.03 ATOM 6010 N LEU 754 53.880 -7.918 29.906 1.00 44.43 ATOM 6012 CA LEU 754 54.079 -8.438 28.563 1.00 43.70 ATOM 6013 CB LEU 754 54.570 -7.339 27.618 1.00 43.48 ATOM 6014 CG LEU 754 53.481 -6 .350 27.201 1.00 44.67 ATOM 6015 CD1 LEU 754 54.095 -5.218 26.399 1.00 44.51 ATOM 6016 CD2 LEU 754 52.384 -7.069 26.408 1.00 42.07 ATOM 6017 C LEU 754 54.993 -9.642 28.512 1.00 43.14 ATOM 6018 0 LEU 754 .54.795 -10.536 27.697 1.00 41.32 ATOM 6019 N ASP 755 55.990 -9.671 29.383 1.00 44.74 ATOM 6021 CA ASP 755 56.897 -10.800 29.426 1.00 47.24 ATOM 6022 CB ASP 755 57.942 -10.575 30.517 1.00 51.26 ATOM 6023 .CG ASP 755 59.121 -11.518 30.407 1.00 55.39 ATOM 6024 ODi ASP 755 59.739 -11.793 31.455 1.00 60.61 ATOM 6025 0D2 ASP 755 59.443 -11.970 29.283 1.00 57.16 ATOM 6026 C0 ASP 755. 56.023 -12.005 29.771 1.00 47.67 ATOM 6027 0 ASP 755 56.041 -13.032 29.081 1.00 45.99 ATOM 6028 N ARG 756 55.186 -11.816 30.789 1.0.0 46.72 ATOM 6030 CA ARG 756 54.272 -12.851 31.256 1.30 46.25 ATOM 6031 CB ARG 756 53.519 -12.368 32.499 1.00 46.31.

ATOM 6032 CG ARG '756 52.391 -13.287 32.953 1.00 46.99 ATOM 6033 CD ARG 756 51.733 -12.776 34.227 1.00 48.10 ATOM 6034 NE ARG 756 51.320 -11.379 34.118 1.00 53.67 ATOM 6036 CZ ARG 756 50.294 -10.951 33.385 1.00 55.35 ATOM 6037 NH1 ARG 756 49.562 -11.812 32.684 1.00 54.10 ATOM 6040 NH2 ARG 756 50.008 -9.654 33.344 1.00 56.02 ATOM 6043 C ARG 756 53.282 -13.261 30.175 1.00 45.05 ATOM 6044 0 ARG 756 53.213 -14.429 29.806 1.00 47.19 ATOM 6045 N ILE 757 52.550 -12.289 29.647 1.00 43.47 ATOM 6047 CA ILE 757 51.552 -12.553 28.617 1.00 43.80 ATOM 6048 CB ILE 757 50.842 -11.241 28.161 1.00 42.02 ATOM 6049 CG2 ILE 757 49.811 -11.536 27.086 1.00 39.63 ATOM 6050 CG1 ILE 757 50.154 -10.578 29.361 1.00 40.00 ATOM 6051 CD1 ILE 757 49.600 -9.212 29.086 1.00 42.68 ATOM 6052 C ILE 757 52.148 -13.296 27.428 1.00 46.03 ATOM 6053 0 ILE 757 51.549 -14.250 26.947 1.00 47.78 ATOM 6054- N VAL 758 53.359 -12.925 27.015 1.00 49.03 ATOM 6056 CA VAL 758 54.015 -13.584 25.884 1.00 51.51 ATOM 6057 CB VAL 758 55.412 -12.971 25.556 1.00 50.75 ATOM 6058 CG1 VAL 758 56.105 -13.780 24.470 1.00 50.31 ATOM 6059 CG2 VAL 758 55.269 -11.541 25.081 1.00 52.52 ATOM 6060 C VAL 758 54.209 -15.050 26.212 1.00 54.30 ATOM 6061 0 VAL 758 53.991 -15.915 25.369 1.00 54.80 ATOM 6062 N ALA 759 54.617 -15.311 27.450 1.00 57.65 ATOM 6064 CA ALA 759 54.858 -16.667 27.919 1.00 60.62 ATOM 6065 CB ALA 759 55.423 -16.637 29.327 1.00 60.32 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 284

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

6066 6067 6068 6070 6071 6072 6073 6074 6075 6076 6077 6079 6080 6081 6083 6084 6085 6086 6087 6088 6089 6090 2682 2685 2688 2691 2694 2697 2700 2703 2706 2709 2712 2715 2718 2721 2724 2727 2730 2733 2736 2739 2742 2745 2748 2751 2754 2757 2760 2763 2766 2769 2772 2775 c 0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

OG1 CG2

C

0

SG

CG

SD

CE

SG

OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 ALA 759 ALA 759 LEU 760 LEU 760 LEU 760 LEU 760 LEU 760 LEU 760 LEU 760 LEU 760 THR 761 THR 761 THR 761 THR 761 THR 761 THR 761 THR 761 CYS 1603 MET 534 MET 534 MET 534 CYS 603 TIP3 1 TIP3 2 TIP3 3 TIP3 4 TIP3 5 TIP3 6 TIP3 7 TIP3 8 TIP3 9 TIP3 10 TIP3 11 TIP3 12 TIP3 13 TIP3 14 TIP3 15 TIP3 16 TIP3 17 TIP3 18 TIP3 19 TIP3 20 TIP3 21 TIP3 22 TIP3 23 TIP3 24 TIP3 25 TIP3 26 TIP3 27 TIP3 28 TIP3 29 TIP3 30 TIP3 31 TIP3 32 53.571 53.568 52.475 51.191 50.302 50.894 49.988 51.109 50.483 49.390 51.103 50.516 50.829 50.247 50.249 51.003 52.202 18.536 69.178 68.892 70.060 56.041 71.788 40.022 83.745 83 420 75.022 86-.308 51.888 55..125 57.087 52.142 41.312 45.083 64.608 77.192 79.201 82.988 14.096 38.325 26.939 34.305 20.300 50.996 17.261 27.724 31.558 26.907 28.705 88.639 -2.328 34.919 80.124 5.417 -17.478 -18.638 -16.856 -17.533 -16.912 16.962 -16.246 -18.410 -17.535 -18.088 -16.933 -16.882 -15.539 14.463 -15.525 -18.044 -18.201 -8.818 12.159 13.138 12.456 -7.885 25.340 4.089 19.577 20.163 16.439 19.567 11.346 9.616 4.825 4.824 5.600 9.130 -2.335 13.199 17.296 11.608 -9.819 0.249 6.001 -1.615 2.328 -11.607 -6.167 8.124 0.294 -12.815 -17.192 13.953 -3.576 -4.069 17.865 3.492 27.889 27.478 28.305 28.333 29.407 30.820 31.809 31.227 26.984 26.860 25.973 24.634 23.925 24.669 22.521 23.769 23.533 20.295 22.968 24.442 25.568 16.319 2.479 16.127 10.S10 7.482 6.505 9.284 24.141 22.499 32.412 13.180 22.910 21.671 28.803 23.753 17.997 15.745 0.333 5.313 5.100 16.992 27.798 38.052 -1.444 14.996 6.872 28.161 13.269 7.692 11.086 19.070 9.324 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 0.50 0.50 0.50 0.50 0.50 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 63.25 65.81 63.56 64.25 65.66 65.62 64.75- 66.65 64.89 66.37 65.24 64.44 62.95 62.70 60.59 64.71 64.70 33.97 PRT2 31.30 PRT2 33.06 PRT2 34.22 PRT2 37.82 PRT2 24.18 43.09 27.38 30.85 33.15 33.55 34.30 21.44 28.79 21.14 49.23 37.09 44.31 32.96 38.51 27.56 23.53 43.17 30.00 44.82 45.23 43.49 27.13 31.20 34.54 49.20 30.16 41.04 44.89 53.72 28.96 10.771 1.00 34.07 SSSD/55145. v01 WO 98/07835 PCT/US97/14885 285 ATOM 2778 OH2 TIP3 33 -10.718 4.889 11.542 1.00 30.81 ATOM 2781 OH2 TIP3 34 29.486 -8.823 20.599 1.00 51.35 ATOM 2784 OH2 TIP3 35 6.151 3.065 13.821 1.00 34.56 ATOM 2787 OH2 TIP3 36 31.907 2.919 0.361 1.00 48.13 ATOM 2790 OH2 TIP3 37 19.974 1.928 -3.873 1.00 30.12 ATOM 2793 OH2 TIP3 38 61.976 2.660 32.604 1.00 36.01 ATOM 2796 OH2 TIP3 39 21.084 -7.119 -3.759 1.00 20.12 ATOM 2799 OH2 TIP3 40 -15.729 8.693 22.468 1.00 54.88 ATOM 2802 OH2 TIP3 41 40.160 2.461 8.734 1.00 37.95 ATOM 2805 OH2 TIP3 42 19.248 11.349 0.190 1.00 37.63 ATOM 2808 OH2 TIP3 43 66.856 9.143 17.185 1.00 27.91 ATOM 2811 OH2 TIP3 44 87.262 19.150 18.734 1.00 57.83 ATOM 2814 OH2 TIP3 45 74.597 17.144 3.987 1.00 42.19 ATOM 2817 OH2 TIP3 46 29.192 16.988 10.582 1.00 37.28 ATOM 2820 OH2 TIP3 47 66.415 7.073 14.829 1.00 34.86 ATOM 2823 OH2 TIP3 48 85.063 21.453 5.510 1.00 27.42 ATOM 2826 OH2 TIP3 49 -4.716 2.835 2.998 1.00 40.54 ATOM 2829 OH2 TIP3 50 19.369 5.069 4.888 1.00 38.40 ATOM 2832 OH2 TIP3 51 34.750 5.517 24.999 1.00 29.11 ATOM 2835 OH2 TIP3 52 34.740 -16.765 14.093 1.00 32.68 ATOM 2838 OH2 TIP3 53 59.994 7.555 27.844 1.00 32.60 ATOM 2841 OH2 TIP3 54 -7.401 -1.595 6.080 1.00 43.73 ATOM 2844 OH2 TIP3 55 55.257 12.084 25.108 1.00 44.32 ATOM 2847 OH2 TIP3 56 68.239 6.953 16.647 1.00 44.46 ATOM 2850 OH2 TIP3 57 73.621 20.852 18.820 1.00 29.47 ATOM 2853 OH2 TIP3 58 3.399 -83..294 -8.210 1.00 22.31 ATOM 2856 OH2 TIP3 59 37:999 10.824 5.505 1.00 31.62 ATOM 2859 OH2 TIP3 60 29.779 -9.515 -1.395 1.00 40.76 ATOM 2862 OH2 TIP3 61 49.114 1.432 12.261 1.00 29.92 ATOM 2865 OH2 TIP3 62 41.257 4.012 29.005 1.00 39.24 ATOM 2868 OH2 TIP3 63 11.113 -12.848 1.296 1.00 34:36 ATOM 2871 OH2 TIP3 64 -1.221 -4.593 21.504 1.00 34.24 ATOM 2874 OH2 TIP3 65 30.002 16.453 13.258 1.00 49..66 ATOM 2877 OH2 TIP3 66 8.212 4.106 3.434 1.00 36.54 ATOM 2880 OH2 TIP3 67 72.868 18.807 22.589 1.00 38.26 ATOM 2883 OH2 TIP3 68 -8.056 -3.666 25.021 1.00 39..81 ATOM 2886 OH2 TIP3 69 66.436 -4.683 28.008 1.00 60.97 ATOM 2889 OH2 TIP3 70 22.063 -20.641 4.804 1.00 42.25 ATOM 2892 OH2 TIP3 71 59.860 -7.407 4.859 1.00 56.78 ATOM 2895 OH2 TIP3 72 16.887 -13.832 -2.611 1.00 59.32 ATOM 2898 OH2 TIP3 73 -15.108 7.351 4.303 1.00 31.87 ATOM 2901 OH2 TIP3 74 32.901 2.922 13.663 1.00 37.89 ATOM 2904 OH2 TIP3 75 0.173 -2.666 11.035 1.00 39.12 ATOM 2907 OH2 TIP3 76 17.533 2.317 5.808 1.00 18.66 ATOM 2910 OH2 TIP3 77 27.183 3.730 6.349 1.00 29.04 ATOM 2913 OH2 TIP3 78 -8.812 5.887 9.703 1.00 30.53 ATOM 2916 OH2 TIP3 79 1.614 -2.195 8.694 1.00 30.79 ATOM 2919 OH2 TIP3 80 -5.304 -3.157 6.846 1.00 47.38 ATOM 2922 OH2 TIP3 81 17.401 2.918 1.973 1.00 20.47 ATOM 2925 OH2 TIP3 82 20.333 3.188 3.159 1.00 24.44 ATOM 2928 OH2 TIP3 83 0.408 -2.516 22.276 1.00 31.11 ATOM 2931 OH2 TIP3 84 20.095 -6.123 -1.372 1.00 17.62 ATOM 2934 OH2 TIP3 85 11.018 -15.627 7.421 1.00 60.29 ATOM 2937 OH2 TIP3 86 4.089 -12.037 11.797 1.00 39.47 SSSD/55145. v01 WO 98/07835 PCT/US97/14885 286 ATOM 2940 OH2 TIP3 87 6.459 0.908 -3.278 1.00 30.31 ATOM 2943 OH2 TIP3 88 -13.493 1.004 5.319 1.00 41.13 ATOM 2946 OH2 TIP3 89 15.418 -7.532 0.022 1.00 21.29 ATOM 2949 OH2 TIP3 90 -2.128 -5.834 4.052 1.00 57.55 ATOM 2952 OH2 TIP3 91 12.731 4.833 -4.212 1.00 44.52 ATOM 2955 OH2 TIP3 92 69.320 27.812 2.191 1.00 37.47 ATOM 2958 OH2 TIP3 93 24.851 -12.871 0.285 1.00 44.73 ATOM 2961 OH2 TIP3 94 60.301 -4.459 33.927 1.00 40.13 ATOM 2964 OH2 TIP3 95 10.488 5.951 3.205 1.00 41.53 ATOM 2967 OH2 TIP3 96. -9.708 -4.233 4.439 1.00 29.77 ATOM 2970 OH2 TIP3 97 72.950 -1.768 10.144 1.00 39.69 ATOM 2973 OH2 TIP3 98 -3.287 5.612 30.618 1.00 34.65 ATOM 2976 OH2 TIP3 99 36.658 1.007 11.717 1.00 35.43 ATOM 2979 OH2 TIP3 100 21.221 6.459 16.863 1.00 20.70 ATOM 2982 OH2 TIP3 101 5.833 -8.726 22:274 1.00 47.13 ATOM 2985 OH2 TIP3 102 -13.529 7.868 17.445 1.00 31.95 ATOM 2988 OH2 TIP3 103 26.795 -10.682 -0.807 1.00 28.65 ATOM 2991 OH2 TIP3 104 23.711 1.909 18.309 1.00 28.29 ATOM 2994 OH2 TIP3 105 -2.187 12.232 3.920 1.00 44.98 ATOM 2997 OH2 TIP3 106 59.483 12.398 33.535 1.00 39.58 ATOM 3000 OH2 TIP3 107 4.439 -10.915 1.996 1.00 43.77 ATOM 3003 OH2 TIP3 108 8.041 2.687 6.648 1.00 45.32 ATOM 3006 OH2 TIP3 109 75.836 1.477 25.476 1.00 41.65 ATOM 3009 OH2 TIP3 110 48.604 i5.594 14.349 1.00 36.36 ATOM 3012 OH2 TIP3 111 2.396 -11.387 9.259 1.00 34.21 ATOM 3015 OH2 TIP3 112 82.927 26.453 12.907 1.00 36.54 ATOM 3018 OH2 TIP3 113 8.983 -6.631 -3.299 1.00 47.01 ATOM 3021 OH2 TIP3 114 -8.690 4.367 4.504 1.00 41.25 ATOM 3024 OH2 TIP3 115 7.941 -13.921 8.777 1.00 36.12 ATOM 3027 OH2 TIP3 116 51.295 6.440 10.632 1.00 28.37 ATOM 3030 OH2 TIP3 117 20.432 3.771 15.637 1.00 21.22 ATOM 3033 OH2 TIP3 118 72.882 3.887 20.227 1.00 30.22 ATOM 3036 OH2 TIP3 119 5.187 -11.863 22.711 1.00 47.49 ATOM 3039 OH2 TIP3 120 33.889 2.571 16.293 1.00 40.04 ATOM 3042 OH2 TIP3 121 9.504 -12.183 7.160 1.00 31.48 ATOM 3045 OH2 TIP3 122 8.397 3.827 -1.647 1.00 46.92 ATOM 3048 OH2 TIP3 123 7 281 7 321 2.391 1.00 62.46 ATOM 3051 OH2 TIP3 124 35.682 -1.725 0.534 1.00 36.75 ATOM .3054 OH2 TIP3 125 44.465 10.095 11.089 1.00 44.72 ATOM 3057 OH2 TIP3 126 45.247 11.893 21.405 1.00 33.51 ATOM 3060 OH2 TIP3 127 57.386 -10.506 14.020 1.00 45.72 ATOM 3063 OH2 TIP3 128 -3.033 15.103 16.644 1.00 38.48 ATOM 3066 OH2 TIP3 129 85.621 11.111 8.814 1.00 38.13 ATOM 3069 OH2 TIP3 130 13.040 -2.760 2.176 1.00 31.26 ATOM 3072 OH2 TIP3 131 75.607 3.932 20.836 1.00 55.09 ATOM 3075 OH2 TIP3 132 13.080 7.467 -2.358 1.00 35.05 ATOM 3078 OH2 TIP3 133 11.308 -9.967 0.995 1.00 28.96 ATOM 3081 OH2 TIP3 134 13.716 -16.170 3.848 1.00 44.64 ATOM 3084 OH2 TIP3 135 -6.498 -3.706 16.178 1.00 43.17 ATOM 3087 OH2 TIP3 136 25.841 -12.949 3.950 1.00 41.14 ATOM 3090 OH2 TIP3 137 -16.285 10.803 6.585 1.00 45.75 ATOM 3093 OH2 TIP3 138 86.457 12.585 6.477 1.00 36.37 ATOM 3096 OH2 TIP3 139 32.097 -4.644 2.224 1.00 28.35 ATOM 3099 OH2 TIP3 140 44.936 7.528 11.961 1.00 46.60 SSSD/55145. v01 WO 98/07835 PCT/US97/14885 287 ATOM 3102 OH2 TIP3 141 80.781 12.162 16.353 1.00 41.46 ATOM 3105 OH2 TIP3 142 2.547 -7.532 -1.453 1.00 41.42 ATOM 3108 OH2 TIP3 143 31.850 -5.907 21.194 1.00 54.70 ATOM 3111 OH2 TIP3 144 74.524 -2.663 12.264 1.00 40.35 ATOM 3114 OH2 TIP3 145 7.592 6.769 -0.931 1.00 58.34 ATOM 3117 OH2 TIP3 146 71.168 5.735 21.648 1.00 27.86 ATOM 3120 OH2 TIP3 147 67.876 -4.900 8.725 1.00 33.58 ATOM 3123 OH2 TIP3 148 0.554 -10.181 6.605 1.00 75.65 ATOM 3126 OH2 TIP3 149 67.965 18.266 10.874 1.00 30.42 ATOM 3129 OH2 TIP3 150 3.509 8.125 4.021 1.00 40.77 ATOM 3132 OH2 TIP3 151 52.216 12.175 18.131 1.00 47.63 ATOM 3135 OH2 TIP3 152 -10.336 6.394 5.014 1.00 48.53 ATOM 3138 OH2 TIP3 153 76.427 1.384 -1.196 1.00 47.21 ATOM 3141 OH2 TIP3 154 10.116 12.199 17.089 1.00 70.16 ATOM 3144 OH2 TIP3 155 34.043 14.595 18.314 1.00 40.56 ATOM 3147 OH2 TIP3 156 2.488 -8.304 16.835 1.00 64.47 ATOM 3150 OH2 TIP3 157 29.610 1.954 6.685 1.00 48.74 ATOM 3153 OH2 TIP3 158 32.578 -17.270 12.109 1.00 37.35 ATOM 3156 OH2 TIP3 159 42.013 18.106 11.196 1.00 68.33 ATOM 3159 OH2 TIP3 160 87.646 10.346 5.465 1.00 75.39 ATOM 3162 OH2 TIP3 161 69.931. -3.739 24.921 1.00 70.42 ATOM 3165 OH2 TIP3 162 77.277 5.700 23.531 1.00 53.26 ATOM 3168 OH2 TIP3 163 34.172 15.704 1.865 1.00 44.88 ATOM 3171 OH2 TIP3 164 -9.871 7.514 7.751 1.00 39.18 ATOM 3174 OH2 TIP3 165 11.814 5.604 7.443 1.00 46.70 ATOM 3177 OH2 TIP3 166 -8.801 13.912 13.532 1.00 52.89 ATOM 3180 OH2 TIP3 167 32.195 3.409 18.336 1.00 32.33 ATOM 3183 OH2 TIP3 168 -8.858 9.696 24.279 1.00 38.90 ATOM 3186 OH2 TIP3 169 -1.135 -6.924 15.691 1.00 43.05 ATOM 3189 OH2 TIP3 170. 79.806 0.323 15.371 1.00 36..91 ATOM 3192 OH2 TIP3 171 67.181 20.622 -1.545 1.00 44.72 ATOM 3195 OH2 TIP3 172 -0.823 3.732 1.065 1.00 52.11 ATOM 3198 OH2 TIP3 173 -0.130 6.021 2.491 1.00 40.87 ATOM 3201 OH2 TIP3 174 -1.027 8.941 1.064 1.00 60.72 ATOM 3204 OH2 TIP3 175 -5.566 8.867 2.163 1.00 47.25 ATOM 3207 OH2 TIP3 176 -7.259 10.294 4.033 1.00 53.61 ATOM 3210 OH2 TIP3 177 2.664 7.247 1.058 1.00 46.41 ATOM 3213 OH2 TIP3 178 5.295 10.728 8.257 1.00 39.84 ATOM 3216 OH2 TIP3 179 63.743 12.726 22.713 1.00 49.55 ATOM 3219 OH2 TIP3 180 79.165 1.016 17.948 1.00 51.41 ATOM 3222 OH2 TIP3 181 13.823 -1.538 -3.942 1.00 39.85 ATOM 3225 OH2 TIP3 182 59.255 3.213 32.873 1.00 76.77 ATOM 3228 OH2 TIP3 183 32.210 13.612 20.027 1.00 60.41 ATOM 3231 OH2 TIP3 184 72.606 16.267 22.574 1.00 60.78 ATOM 3234 OH2 TIP3 185 -0.147 5.713 30.877 1.00 50.19 ATOM 3237 OH2 TIP3 186 -1.207 -4.507 27.969 1.00 65.19 ATOM 3240 OH2 TIP3 187 81.340 15.584 16.808 1.00 64.48 ATOM 3243 OH2 TIP3 188 -17.535 3.884 23.785 1.00 57.17 ATOM 3246 OH2 TIP3 189 27.503 10.697 14.669 1.00 36.11 ATOM 3249 OH2 TIP3 190 34.585 4.535 27.618 1.00 61.68 ATOM 3252 OH2 TIP3 191 -3.701 -4.982 9.069 1.00 43.66 ATOM 3255 OH2 TIP3 192 42.524 7.811 22.390 1.00 34.53 ATOM 3258 OH2 TIP3 193 52.937 11.764 21.790 1.00 36.19 ATOM 3261 OH2 TIP3 194 -7.665 8.600 6.358 1.00 59.08 SSSD/55145. v01 WO 98/07835 PCT/US97/14885 288

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3264 3267 3270 3273 3276 3279 3282 3285 3288 3291 3294 3297 3300 3303 3306 3309 3312 3315 3318 3321 3324 3327 3330 3333 3336 3339 3342 3345 3348 3351 3354 3357 3360 3363 3366 3369 3372 3375 3378 3381 3384 3387 3390 3393 3396 3399 3402 3405 3408 3411 3414 3417 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 TIP3 195 TIP3 196 TIP3 197 TIP3 198 TIP3 199 TIP3 200 TIP3 201 TIP3 202 TIP3 203 TIP3 204 TIP3 205 TIP3 206 TIP3 207 TIP3 208 TIP3 209 TIP3 210 TIP3 211 TIP3 212 TIP3 213 TIP3 214 TIP3 215 TIP3 216 TIP3 217 TIP3 218 TIP3 219 TIP3 220 TIP3 221 TIP3 222 TIP3 223 TIP3 224 TIP3 225 TIP3 226 TIP3 227 TIP3 228 TIP3 229 TIP3 230 TIP3 231 TIP3 232.

TIP3 233 TIP3 234 TIP3 235 TIP3 236 TIP3 237 TIP3 238 TIP3 239 TIP3 240 TIP3 241 TIP3 242 TIP3 243 TIP3 244 TIP3 245 TIP3 246 86.880 55.377 51.394 20.021 28.959 26.533 36.739 16.968 28.177 31.488 10.665 6.916 -12.659 11.274 11.491 34.037 31.162 36.937 64.024 36.528 90.599 50.139 66.523 74.880 -3.095 5.601 35.616 -5.381 46.509 -3.791 1.622 86.244 11.011 64.610 11.446 72.056 57.359 43.344 66.723 88.036 12.085 64.898 72.114 25.792 -18.262 30.336 22.712 29.700 63.297 61.458 -0.217 66.196 5.187 16.579 16.147 20.540 19.664 22.988 '7.087 7.226 1.819 -3.219 2.812 -4.295 3.003 18.397 -20.752 14.318 -14.418 6.134 1.501 -1.796 -16.494 15.732 -12.200 6.160 14.357 10.908 9.662 -1.588 12.484 -1.531 13.520 -1.011 18.259 7.980 11.633 -1.971 13.599 26.505 5.933 .4.857 4.042 6.342 -11.645 10.526 -1.024 30.536 18.976 20.591 9.744 3.142 -3.682 25.022 6.407 12.455 16.006 14.081 -11.503 26.814 -5.481 20.929 -3.876 -0.402 11.220 23.133 7.959 5.659 -8.031 20.406 -17.829 13.438 1.258 -1.830 9.732 11.744 20.728 30.066 16.772 15.661 22.036 4.257 2.346 27.862 -0.425 3.209 28.348 7.731 -8.081 27.181 10.614 12.607 11.280 16.201 -15.818 -2.226 9.496 18.074 -0.480 5.497 7.093 11.497 2.232 32.172 6.250 12.159 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00.

1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 L. 00 1.00 1.00 1.00 1.00 1.00

I.OO

1. 00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 55.88 48.25 46.81 52.98 40.50 54.24 42.13 54.54 61.36 47.49 41.42 61.94 52.96 48.45 44.51 48.43 44.86 49.85 37.53 57.04 54.08 54.64 39.41 41.84 52.35 29.30 44.48 44.23 53.82 61.42 58.60 59.84 63.07 48.11 51.35 43.88 65.45 61.52 43.79 61.83 46.29 50.06 53.01 55.19 51.54 46.53 47.29 40.10 49.90 45.71 46.12 34.47 SSSD/55145. v01 WO 98/07835 PCT/US97/14885 289 TABLE 3 x y Atom No.

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

Atom A.A A.A Z OCC Type 1 N 3 CA 4 CB 5 C 6 0 7 N 9 CA 10 CB 11 CG 12 CD1 ]33 CD2 14 C 15 0 16 N 17 CD 18 CA 3.9 CB 20 CG 21 C 22 0 23 N 25 CA 26 CB 27 CG 28 CD 29 OE1 30 OE2 31 C 32 0 33 N 35 CA 36 CB 37 CG 38 ODI 39 OD2 40 C 41 0 42 N 43 CD 44 CA 45 CB 46 CG 47 C 48 0 49 N 51 CA Type

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PRO

PRO

PRO

PRO

PRO

PRO

PRO

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ARG

No.

1464 1464 1464 1464 1464 1465 1465 1465 1465 1465 1465 1465 1465 1466 1466 1466 1466 1466 1466 1466 1467 1467 1467 1467 1467 1467 1467 1467 1467 1468 1468 1468 1468 1468 1468 1468 1468 1469 1469 1469 1469 1469 1469 1469 1470 -13 .712 -12 .478 -11 465 11.865 -11.765 -11 .466 -10.899 -10 .097 -8.571 -8.175 -7.926 12.009 -13 .070 11.821 -10.682 -12.781 -12.176 -10.681 -12.859 1i.834 -14.064 -14 .247 -15.725 -16 .334 -17 .823 -18 .294 -18 .529 -13 .794 -13 .885 -13.291 -12.869 -11.362 -10.942 -11.689 -9.836 -13.244 -12.462 -14.446 -15.401 -14.981 -16.235 -16.690 -14.029 -14.136 n13.128 16.996 17.133 18.020 15.766 15.402 15.003 13.691 13.171 13.277 14.728 12.722 12.706 12.719 11.919 12. 019 10.902 10.426 10.667 9.756 9.283 9.278 8.213 8.123 9.410 9.280 8.135 10.315 6.865 6.632 5.991 4.649 4.567 3.223 2.225 3.165 3.672 3.404 3.089 3.311 2.124 1.615 2.811 0.974 0.364 0.666 8.424 7.646 8.378 7.319 6.145 8.333 8.067 9.258 9.169 8 .977 10 .426 7.748 8.375 6.682 5 .751 6 .232 4 .910 5 .109 7 .246 7 .748 7.513 8 .482 8.863 9.417 9 .694 9.854 9.756 7.939 6 .740 8 .813 8.409 8 .120 7.507 7 .592 6 .935 9 .512 10.437 9.403 8 .298 10.365 9.659 8.879 10.687 11.748 9.758 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 61.15 60.03 62.43 57.36 60.80 50.25 42.73 41.34 39.78 45.14 34.20 39.42 36 .63 38.54 37.04 38. 39.49 40.64 39.08 41.23 37.11 35.96 39.90 46.64 51.50 54 .17 53.39 33.77 36.27 29.80 28.19 27.83 27.78 25.64 27.59 28.05 25.89 29.07 29.93 28.65 30.89 28.99 27.63 26.94 26.37 ARG 1470 -12.161 -0.414 9.947 1.00 26.64 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 290 ATOM 52 CB ARG 1470 -11.363 -0.661 8.666 1.00 27.12 ATOM 53 CG ARG 1470 -12.150 -1.014 7.424 1.00 29.72 ATOM 54 CD ARG 1470 -11.189 -1.184 6.236 1.00 30.37 ATOM 55 NE ARG 1470 -10.450 0.044 5.971 1.00 32.56 ATOM 57 CZ ARG 1470 -9.624 0.211 4.948 1.00 37.69 ATOM 58 NHI ARG 1470 -9.428 -0.784 4.091 1.00 44.25 ATOM 61 NH2 ARG 1470 -8.997 1.370 4.778 1.00 34.12 ATOM 64 C ARG 1470 -11.129 -0.176 11.051 1.00 27.58 ATOM 65 0 ARG 1470 -10.504 -1.123 11.522 1.00 28.12 ATOM 66 N TRP 1471 -10.900 1.079 11.421 1.00 27.62 ATOM 68 CA TRP 1471 -9.870 1.362 12.408 1.00 26.66 ATOM 69 CB TRP 1471 8.661 1.938 11.686 1.00 24.95 ATOM 70 CG TRP 1471 -8.010 0.951 10.790 1.00 25.65 ATOM 71 CD2 TRP 1471 -7.100 -0.083 11.186 1.00 23.19 ATOM 72 CE2 TRP 1471 -6.734 -0.776 10.022 1.00 21.80 ATOM 73 CE3 TRP 1471 -6.567 0.489 12.414 1.00 21.84 ATOM 74 CDI TRP 1471 -8.155 0.843 9.435 1.00 23.15 ATOM 75 NEI TRP 1471 -7.388 -0.192 8.970 1.00 23.32 ATOM 77 CZ2 TRP 1471 -5.855 -1.857 20.052 1.00 22.54 ATOM 78 CZ3 TRP 1471 -5.6.98 -1.564 12.439 1.00 21.72 ATOM 79 CH2 TRP 1471 -5.352 -2.235 11.269 1.00 21.90 ATOM 80 C TRP 1471 -10.224 2.278 13.558 1.00 28.44 ATOM 81 0 TRP 1471 -9.497 2.334 14.546 1.00 29.29 ATOM 82 N GLU 1472 -11.317 3.015 13.424 1.00 29.49 ATOM 84 CA GLU 1472. -11.719 3.962 14.453 1.00 29.97 ATOM 85 CB GLU 1472 -12.920 4.769 13.961 1.00 33.80 ATOM 86 CG GLU 1472 -13.218- 6.050 14.731 1.00 33.27 ATOM 87 CD GLU 1472 -12.475 7.249 14.195 1.00 34.26 ATOM 88 OE1 GLU 1472 11.9*70 7.191 13.055 1.00 38.00 ATOM 89 OE2 GLU 1472 -12.413 8.265 14.910 1.00 34.01 ATOM 90 C GLU 1472 12.034 3.366 15.826 1.00 27.30 ATOM 91 0 GLU 1472 -12.640 2.309 15.945 1.00 28.36 ATOM 92 N LEU 1473 -11.619 4.069 16.866 1.00 25.91 ATOM 94 CA LEU 1473 -11.896 3.652 18.229 1.00 24.89 ATOM 95 CB LEU 1473 -10.625 3.210 18.948 1.00 24.70 ATOM 96 CG LEU 1473 -10.766 2.923 20.454 1.00 24.56 ATOM 97 CD1 LEU 1473 -11.498 1.613 20.701 1.00 21.89 ATOM 98 CD2 LEU 1473 -9.385 2.872 21.095 1.00 23.90 ATOM 99 C LEU 1473 -12.426 4.907 18.882 1.00 27.05 ATOM 100 0 LEU 1473. -11.968 6.016 18.567 1.00 25.17 ATOM 101 N' PRO 1474 -13.479 4.766 19.706 1.00 28.20 ATOM 102 CD PRO 1474 -14.290 3.551 19.886 1.00 29.92 ATOM 103 CA PRO 1474 -14.088 5.897 20.411 1.00 30.61 ATOM 104 CB PRO 1474 -15.197 5.224 21.226 1.00 28.15 ATOM 105 CG PRO 1474 -15.613 4.110 20.357 1.00 24.28 ATOM 106 C PRO 1474 -13.036 6.545 21.312 1.00 32.98 ATOM 107 0 PRO 1474 -12.253 5.838 21.968 1.00 34.79 ATOM 108 N ARG 1475 -13.035 7.875 21.366 1.00 32.75 ATOM 110 CA ARG 1475 -12.060 8.606 22.168 1.00 34.22 ATOM 111 CB ARG 1475 -12.250 10.116 .21.997 1.00 34.21 ATOM 112 CG ARG 1475 -12.153 10.549 20.559 1.00 42.48 ATOM 113 CD ARG 1475 -11.956 12.056 20.364 1.00 45.16 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 291 ATOM 114 NE ARG 1475 -11.655 12.317 18.954 1.00 45.65 ATOM 116 CZ ARG 1475 -10.447 12.599 18.484 1.00 41.31 ATOM 117 NHI ARG 1475 -9.420 12.686 19.318 1.00 35.94 ATOM 120 NH2 ARG 1475 -10.253 12.673 17.172 1.00 42.37 ATOM 123 C ARG 1475 -12.114 8.232 23.641 1.00 35.29 ATOM 124 0 ARG 1475 -11.094 8.178 24.318 1.00 37.28 ATOM 125 N ASP 1476 -13.304 7.931 24.129 1.00 35.37 ATOM 127 CA ASP 1476 -13.468 7.570 25.526 1.00 36.97 ATOM 128 CB ASP 1476 -14.952 7.586 25.896 1.00 39.47 ATOM 129 CG ASP 1476 -15.748 6.501 25.205 1.00 40.02 ATOM 130 ODI ASP 1476 -15.221 5.809 24.320 1.00 41.08 ATOM 131 OD2 ASP 1476 -16.9.26 6.327 25.571 1.00 47.00 ATOM 132 C ASP 1476 -12.850 6.225 25.894 1.00 36.07 ATOM 133 0 ASP 1476 12 830 5.842 27.066 1.00 36.26 ATOM 134 N ARG 1477 -12.382 5.495 24.888 1.00 36.94 ATOM 136 CA ARG 1477 -11.766 4.189 25.104 1.00 35.22 ATOM 137, CB ARG 1477 -12.081 3.268 23.925 1.00 34.29 ATOM 138 CG ARG 1477 -13.5.46 3.056 23.675 1.00 32.23 ATOM 139 CD ARG 1477 -14.206 2.434 24.879 1.00 30.56 ATOM 140 NE ARG 1477 -14.426 3.419 25.925 1.00 31.86 ATOM 142 CZ ARG 1477 -14.730 3.126 27.182 1.00 33.09 ATOM 143 NH1 ARG 1477 -14.855 1.858 27.563 1.00 35.00 ATOM 146 NH2 ARG 1477 -14.904 4.101 28.053 1.00 29.62 ATOM 149 C ARG 1477 -10.262 4.270 25.2'71 1.00 35.51 ATOM 150 0 ARG 2477 -9.621 3.290 25.637 1.00 36.44 ATOM 151 N LEU 1478 -9.'704 5.444 25.023 1.00 34.59 ATOM i53 CA LEU 1478 -8.270 5.630 25.129 1.00 36.35 ATOM 154 CB LEU 1478 -7.750 6.254 23.840 1. 00 36.41 ATOM 155 CG LEU 1478 -6.250 6.185 23.556 1.00 37.1.9 ATOM 156 CDI LEU 1478 -5.791 4.728 23.479 1.00 34.63 ATOM 157 CD2 LEU 1478 -5.'959 6.914 22.251 1 00 34.88 ATOM 158 C LEU 1478 -7.901 6.517 26.325 1.00 38.74 ATOM 159 0 LEU 1478 -8.146 7.733 26.309 1.00 41.20 ATOM 160 N VAL 1479 -7.311 5.907 27.355 1.00 36.92 ATOM 162 CA VAL 1479 -6.885 6.622 28.560 1.00 35.79 ATOM 163 CB VAL 1479 -6.929 5.693 29.780 1. G0 35.81 ATOM 164 CG1 VAL 1479 -6.579 6.453 31.032 1.00 40.11 ATOM 165 CG2 VAL 1479 -8.302 5.056 29.907 1.00 35.59 ATOM 166 C VAL 1479 -5.438 7.118 28.362 1.00 36.60 ATOM 167 0 VAL 1479 -4.479 6.369 28.583 1.00 33.48 ATOM 168 N LEU 1480 -5.282 8.372 27.938 1.00 39.09 ATOM 170 CA LEU 1480 -3.949 8.932 27.675 1.00 42.05 ATOM 171 CB LEU 1480 -4.040 10.277 26.952 1.00 41.08 ATOM 172 CG LEU 1480 -4.633 10.286 25.529 1.00 39.28 ATOM 173 CD1 LEU 1480 -4.766 11.720 25.051 1.00 40.04 ATOM 174 CD2 LEU 1480 -3.758 9.489 24.582 1.00 39.66 ATOM 175 C LEU 1480 -3.001 9.027 28.867 1.00 41.51 ATOM 176 0 LEU 1480 -3.312 9.637 29.886 1.00 41.73 ATOM 177 N GLY 1481 -1.817 8.444 28.697 1.00 40.68 ATOM 179 CA GLY 1481 -0.849 8.439 29.775 1.00.41.28 ATOM 180 C GLY 1481 0.412 9.225 29.529- 1.00 43.08 ATOM 181 0 GLY 1481 0.474 10.147 28.701 1.00 45.65 SSSD/55145. vOl WO 98/07835 -PCT/US97/14885 292 ATOM 182 N LYS 1482 1.481 8.825 30.219 1.00 42.54 ATOM 184 CA LYS 1482 2.781 9.453 30.128 1.00 43.74 ATOM 185 CB LYS 1482 3.670 8.842 31.229 1.00 46.34 ATOM 186 CG LYS 1482 5.155 8.979 30.954 1.00 52.23 ATOM 187 CD LYS 1482 5.867 7.716 31.382 1.00 56.63 ATOM 188 CE LYS 1482 5.373 6.518 30.607 1.00 54.20 ATOM 189 NZ LYS 1482 6.199 5.320 30.955 1.00 59.97 ATOM 193 C LYS 1482 3.552 9.422 28.806 1.00 43.96 ATOM 194 0 LYS 1482 3.557 8.422 28.111 1.00 44.68 ATOM 195 N PRO 1483 4.259 10.521 28.481 1.00 44.06 ATOM 196 CD PRO 1483. 4.339 11.798 29.208 1.00 43.53 ATOM 197 CA PRO 1483 5.005 10.573 27.208 1.00 44.07 ATOM 198 CB PRO 1483 5.590 12.004 27.281 1.00 43.17 ATOM 199 CG PRO 1483 .4.630 12.738 28.114 1.00 43.75 ATOM 200 C PRO 1483 6.172 9.543 27.116 1.00 43.47 ATOM 201 0 PRO 1483 6.853 9.308 28.120 1.00 43.76 ATOM 202 N LEU 1484. 6.408 9.001 25.932 1.00 41.71 ATOM 204 CA LEU 1484 7.512 8.045 25.663 1.00 38.05 ATOM 205 CB LEU 1484 6.964 6.803 24.927 1.00 33.38 ATOM 206 CG LEU 1484 6.001 5.992 25.770 1.00 31.95 ATOM 207 CD1 LEU 1484 5.2-58' 4.914 24.975 1.00 27.4 1 ATOM 208 CD2 LIEU 1484 6.750. 5.396 26.953 1. 00 29.64 ATOM 209 C LIEU 1484 8.603 8.710 24.855 1.00 40.09 ATOM 210 0 LEU 1484 8.334 9.499 23.960 1.00 41.74 ATOM 211 N GLY 1485 9.843 8.387 25.197 1.00 43.19 ATOM 213 CA GLY 1485 10.*976 8.923 24 .512 1.0.0 50.32 ATOM 214 -C GLY 1485' 11.261 10.408 24.697 1.01) 54.65 ATOM 215 0 GLY 148 5 11.036 10.973 25.770 1.00 54.73 ATOM 216 N GLU 1486 .11.741 11.072 23.647 1.00 59.07 ATOM 218 CA GLU 1486 12.081 12.483 23.666 1.00 61.01 ATOM 219 CB GLU 1486 13.489 12.646 24.275 1.00 62.51 ATOM 220 C GLU 1486 .12.014 13'.183 22.295 1.00 62.48 ATOM 221 0 GLU 1486 12.901 13.970 21.949 1.00 64.10 ATOM 222 N GLY 1487 10.975 12.892 21.519 1.00 62.29 ATOM 224 C.A GLY 1487 10.792 13.522 20.236 1.00 59.87 ATOM 225 C GLY 1487 11.469 12.881 19.044 1.00 58.88 ATOM 226 0 GLY 1487 11.447 13.426 17.950 1.00 60.19 ATOM 227 N ALA 1488 12.073 11.714 19.239 1.00 57.19 ATOM 229 CA ALA 1488 12.721 11.016 18.140 1.00 55.59 ATOM 230 CB ALA 1488 13.477 9.804 18.663 1.00 56.35 ATOM 231 C ALA 1488 11.690 10.601 17.112 1.00 54.96 ATOM 232 0 ALA 1488 11.927 10.626. 15.913 1.00 56.42 ATOM 233 N PEE 1489 10.509 10.241 17.598 1.00 54.99 ATOM 235 CA PEE 1489 9.401 9.807 16.721 1.00 54:' 07 ATOM 236 CB PHE 1489 8.857 8.454 17.162 1.00 51.18 ATOM 237 CG PEE 1489 9.880 7.373 17.137 1.00 46.81 ATOM 238 CD. PEE 1489 10.641 -7.093 18.271 1.00 46.81 ATOM 239 CD2 PEE 1489 10.096 6.612 15.984 1.00 48.30 ATOM 240 CEl PHE 1489 11.585 6.090 18.262 1.00 47.41 ATOM 241 CE2 PEE 1489 11.040 5.601 15.963 1.00 48.23 ATOM 242 CZ PEE 1489 11.794 5.336 17.111 1.00 47.94 ATOM 243 C PEE 1489 8.261 10.814 16.748 1.00 54.90 SSSD/55145. vOl WO 98/07835 PCT/US97/1488 293 ATOM 244 0. PHE 1489 7.199. 10.5 65 16.184 1.00 59.10 ATOM 245 N GLY 1490 8.431 11.908 17.504 1.00 53.55 ATOM 247 CA GLY 1490 7.432 12.958 17.611 1.00 50.20 ATOM 248 C GLY 1490 6.745 12.844 18.942 1.00 49.82 ATOM 249 0 GLY 1490 7.266 12.161 19.837 1.00 50.95 ATOM 250 N GLN 1491 5.614 13.514 19.124 1.00 49.53 ATOM 252 CA GLN 1491 4.922 13.441 20.395 1.00 49.16 ATOM 253 CB GLN 1491 3.927 14.590 20.564 1.00 51.74 ATOM 254 CG GLN 1491 3.439 14.796 21.994 1.00 64.00 ATOM 255 CD GLN 1491 2.545 16.039 22.180 1.00 71.35 ATOM 256 OE1 GLN 1491 2.534 16.922 21.352 1.00 77.94 ATOM 257 NE2 GLN 1491 1.824 16.083 23.289 1.00 76.51 ATOM 260 C GLN 1491 4.207 12.083 20.505 1.00 45.94 ATOM 261 0 GLN 1491 3.151. 11.869 19.919 1.00 48.02 ATOM 262 N VAL 1492 4.848 11.129 21.184 1.0.0 41.00 ATOM 264 CA VAL 1492 4.293 9.810 21.421 1.00 37.44 ATOM 265 CB VAL 1492 5.235 8.665 21.025 1.00 34.74 ATOM 266 CG1 VAL 1492 4.593 7.325 21.285 1.00 28.97 ATOM 267 CG2 VAL 1492 5.632 8.769 19.553 .1.00 35.78 ATOM 268 C VAL 1492 4.014 9.621 22.901 1.00 38.67 ATOM 269 0 VAL 1492 4.907 9.769 23.735 1.00 38.62 ATOM 270 N VAL 1493 2.776 9.276 23.250 1.00 39.98 ATOM 272 CA VAL 1493 2.423 9.062 24.653 1.00 37.79 ATOM 273 CB VAL 1493 1.257 9.970 25.093 1.00 37.36 ATOM 274 CG1 VAL 1493 1.489 1.1.403 24.689 1.00 39.11 ATOM 275 CG2 VAL 1493. 074: 9.480 24.555 1t.00 38.99 ATOM 276 C VAL 1493 2.052 7.603 24.877 1.00 36.38 ATOM 277 0 'VAL 1493 1.759' 6.874 23.945 1.00 37.73 -ATOM 278 N LEU 1494 2.094 7.176 26.123 1.00 35.42 ATOM 280 CA LEll 1494 1.718 5.817 26.483 1.00 33.65 ATOM 281 CB LEU 1494 2.536 5:291 27.670 1.00 29.88 ATOM 282 CG LEU 1494 2.117 3.945 28.279 1.00 30.31 ATOM 283 CDI. LEl 1494 2.103 2.844 27.244 1.00 30.83 ATOM 284 CD2 LEt) 1494 3.049 3.574 29.400 1.00 32.12 ATOM 285 C LEt) 1494 0.260 5.934 26.870 1.00 34.27 ATOM 286 0 LEU 1494 -0.168 6.994 27.348 1.00 34.85 ATOM 287 N ALA 1495 -0.527 4.898 26.608 1.00 32.20 ATOM 289 CA ALA 1495 -1.930 4.954 26.980 1.00 29.71 ATOM 290 CB ALA 1495 -2.724 5.722 25.930 1.00 25.48 ATOM 292. C ALA 1495 -2.499 3.567 27.183 1.00 28.85 ATOM 292 0 ALA 1495 -1.826 2.563 26.998 1.00 27.28 ATOM 293 N GLU 1496 -3.743 3.519 27.615 1.00 32.20 ATOM 295 CA GLU 1496 -4'.413 2.250 27.824 1.00 33.34 ATOM 296 CB GLU 1496 7-4.735 2.063 29.301 1.00 35.65 ATOM 297 CG GLU 1496 -3.521 1.962 30.198 1.00 39.14 ATOM 298 CD GLU 1496 -3.899 2.045 31.663 1.00 42.57 ATOM 299 OE1 GLU 1496 -4.469 3.083 32.061 1.00 42.59 ATOM 300 0E2 GLU 1496 -3.646 1.069 32.407 1.00 42.76 ATOM 301 C GLU 1496 -5.692 2.274 26.994 1.00 33.40 ATOM 302 0 GLU 1496 -6..439 3.261 27.017 1.00 34.36 ATOM 303 N ALA 1497 -5.875 1.247 26.177 1.00 31.67 ATOM 305 CA ALA 1497 -7.051 1.168 25.351 1.00 31.23 SSSD/55145. vOl WO 98/07835 PCT/US97/14886 294 ATOM 306 CB ALA 1497

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307 308 309 311 312 313 314 31L5 316 317 318 320 321 322 323 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 341 342 343 344 345 348 349 350 352 353 354 355 356 358 359 362 365 366 367 369 370 C ALA 0 ALA N ILE CA ILE CB ILE CG2 ILE CGl ILE CD1 ILE C ILE O ILE N GLY CA GLY C GLY 0 GLY N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU 0 LEU N PRO CD PRO CA PRO CB PRO C-G PRO C PRO 0 PRO N ASN CA ASN CB ASN CG ASN ODi ASN ND2 ASN C ASN 0 ASN N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NH1 ARG NH2 ARG C ARG 0 ARG N VAL CA VAL CB VAL 1497 1497 1498 1498 1498 1498 1498 1498 1498 .14 98 1499 1499 1499 1499 1500 1500 1500 1500 1500 1500 1500 1500 1505 1505 1505 1505 1505 1505 1505 1506 1506 1506 1506 1506 1506 1506 1506 1507 1507 1507 1507 1507 1507 1507 1507 1507 1507 1507 1508 1508 1508 -6.671 0.750 -8.000 0.168 -7.599 -0.954 -9.218 0.602 -10.222 -0.294 -11.294 0.453 -12.267 -0.551 -10.663 1.316 -11.656 2.262 -10.953 -0.929 -11.571 -0.227 -10.859 -2.245 -11.544 -2.918 -10.673 -3.299 -9.921 -4.269 -10.739 -2-508 -10.003 -2.765 -8.478 -2.898 -7.504 -1.703 -6.069 -2.217 -7.638 -0.883 -10.535 -4.027 -10.480 -5.145 -13.253 -5.837 13.877. -7.173 -14.197 4.82 5 -15.548 -5.521 -15.216 -6.944 -13.904 -4.396 -13.883' -3,202 -13.640 5.363 -13.337 -5.053 -14.202 -5.893 -15.657 -5.493 -15.999 -4.309 -16.529 -6.478 -11.863 -5.251 -11.487 -5.343 -11.029 -5.284 -9.594 -5.466 -9.111 -6.650 -9.327 -7.993 -8.402 -8.180 -8.592 -9.494 -8.030 -9.898 -7.219 -9.096 -8.340 -11.093 -8.871 -4.234 -9.227 -3.695 -7.912 3749 -7.143 -2.598 -6.786 -1.604 23.953 25.974 26.261 26.282 26.854 27. 679 28.300 28.770 29. 419 25.680 24.877 25.559 24.477 23.298 23.387 22.223 20. 973 21.185 21.167 21.284 19.899 20. 275 20. 806 25.284 25.239 25.779 25. 627 25.940 27.227 27.531 28. 102 29. 497 30.434 30. 395 3 0.487 30.260, 29. 836 31.008 28.606 28.976 28.142 28.781 29. 963 30.556 31. 689 32.375 32.174 28.485 27.440 29.265 28.830 29.961 1.00 28.13 1.00 32.02 1.00 33.45 1.00 34.15 1.00 35.89 1.00 35.30 1.00 32.95 1.00 35.29 1.00 31.69 1.00 38.79 1.00 37.46 1.00 43.14 1.00 46.90 1.00 49.69 1.00 51.47 1.00 49.92 1.00 49.62 1.00 49.96 1.00 49.26 1.00 47.17 1.00 47.80 1.00 49.49 1.00 47.99 1.00 50.58 1.00 51.43 1.00 48.08 1.00 48.59 1.00 51.66 1.00 44.58 1.00 42.73 1.00 42.10 1.00 45.05 1.00 47.04 1.0.0 48.72 1.00 50.48 1.00 51.15 1.00 46.50 1.00 46.50 1.00 46.99 1.00 47.52 1.00 54.20 1.00 64.52 1.00 71.17 1.00 76.52 1.00 81.64 1.00 83.30 1.00 84.44 1.00 43.46 1.00 42.73 1.00 40.84 1.00 38.27 1.00 34.90 SSSD/551 45. vOl WO 98/07835 PCTIUS97/14885 295 ATOM 371 CG1 VAL 1508 -8.038 -1.124 30.646 1.00 41.81 ATOM 372 CG2 VAL 1508 -5.850 -2.226 30.944 1.00 35.89 ATOM 373 C VAL 1508 -5.874 -3.147 28.211 1.00 36.81 ATOM 374 0 VAL 1508 -5.371 -4.191 28.637 1.00 35.13 ATOM 375 N THR 1509 -5.393 -2.465 27.180 1.00 36.04 ATOM 377 CA THR 1509 -4.184 -2.854 26.485 1.00 33.31 ATOM 378 CB THR 1509 -4.503 -3.254 25.025 1.00 33.79 ATOM 379 OGi THR 1509 -5.511 -4.275 25.014 1.00 33.98 ATOM 381 CG2 THR 1509 -3.259 -3.774 24.321 1.00 32.78 ATOM 382 C TER 1509 -3.268 -1.627 26.453 1.00 32.37 ATOM 383 0 THR 1509 -3.718 -0.533 26.113 1.00 31.97 ATOM 384 N LYS 1510 -2.015 -1.786 26.884 1.00 32.96 ATOM 386 CA LYS 1510 -1.071 -0.673 26.828 1.00 33.25 ATOM 387 CB LYS 1510 0.157 -0.902 27.699 1.00 34.65 ATOM 388 CG LYS 1510 -0.093 -0.909 29.197 1.00 39.64 ATOM 389 CD LYS 1510 1.237 1.105 29.91.3 1.00 43.51 ATOM 390 CE LYS 1510 1.110 -1.949 31.173 1.00 48.42 ATOM 391 NZ LYS 1510 0.399 -1.256 32.287 1.00 53.03 ATOM 395 C LYS 1510 -0.646 -0.550 25.370 1.00 32.26 ATOM 396 0 LYS 1510 -0.240 l533. 24.736 1.0.0 30.20 ATOM 397 N VALJ 1511 0.760 0.665 24.849 1.00 32.28 ATOM 399 CA VAL 1511 .0.436 0.980 23.472 1.00 30.73 ATOM 400 CB VAL 3~.511 -1.738 1.140 22.666 1.00 32.25 ATOM 401 CG1 VAL 1511 -2.566 (.14'7 22.723 1.00 29.00 ATOM 402 CG2 VAL 1511. -2.549 2.3471 23.193 1.00 29.17 ATOM 403 C VAL 1511 0.329 2.30.7 23.423 1.00 30.91 ATOM 404 0 VAL 1511 0.445 3.008 24.433 1.00 31.94 ATOM 405 N ALA 1512 0.842 .2.658 22.250 1.00 27.30 ATOM 407 CA ALA 1512 1.550 -3.914 22.094 1.00 24.22 A.TOM 408 CB ALA 1512 2.921 3.694 21.493 1.00 .23.39 ATOM 409 C ALA 152.2 0.698 4.769 21.181 1.00 23.62 ATOM 410 0 ALA 1512 0.116 4.271 20.228 1.00 22.69 ATOM 413 N VAL 1513 0.605 6.054 21.484 1.00 27.51 ATOM 413 CA VAL 1513 -0.192 6.984 20.688 1.00 30.03 ATOM 414 CB VAL 1513 -1.359 7.613 21.522 1.00 28.31 ATOM 415 CG1 VAL 1513 -2.218 8.522 20.650 1.00 28.93 ATOM 416 CG2 VAL 1513 -2.214 6.542 22.159 1.00 26.00 ATOM 417 C VAL 1513 0.674 8.108 20.107 1.00 31.21 ATOM 418 0 VAL 1513 1.370 8.816 20.834 1.00 29.73 ATOM 419 N LYS 1514 0.631 8.225 18.784 1.00 33.99 ATOM 421 CA LYS 1514 1.342 9.258 18.037 1.00 35.44 ATOM 422 CB LYS 1514 1.831 8.692 16.707 1.00 34.55 ATOM 423 CG LYS 1514 2.835 7.586 16.872 1.00 35.38 ATOM 424 CD LYS 1514 3.025 6.807 15.599 1.00 36.87 ATOM 425 CE LYS 1514 3.457 7.710 14.438 1.00 45.19 ATOM 426 NZ LYS 1514 4.598 8.622 14.755 1.00 44.31 ATOM 430 C LYS 1514 0.304 10.345 17.761 1.00 35.97 ATOM 431 0 LYS 1514 -0.806 10.037 17.299 1.00 34.39 ATOM 432 N MET 1515 0.673 11.596 18.028 1.00 38.17 ATOM -434 CA MET 1515 -0.207 12.747 17.835 1.00 41.17 ATOM 435 CB MET 1515 -0.901 13.098 19.145 1.00 39.54 ATOM 436 CG MET 1515 0.075 13.428 20.255 1.00 39.11 145. vOl WO 98/07835 PCTIUS97/14885 296 ATOM 437 SD MET 1515 -0.766 13.612 21.799 1.00 43.85 ATOM 438 CE MET 1515 -1.212 11.937 22.087 1.00 46.18 ATOM 439 C MET 1515 0.612 13.939 17.391 1.00 43.65 ATOM 440 0 MET 1515 1-834 13.905 17.445 1.00 45.72 ATOM 441 N LEU 1516 -0.053 14.962 16.872 1.00 48.7 3 ATOM 443 CA LEU 1516 0.640 16.175 16.448 1.00 52.23 ATOM 444 CB LEU 1516 -0.152 16.917 15.374 1.00 49.77 ATOM 445 CG LEtJ 1516 -0.413 16.254 14-036 1.00 48.04 ATOM 446 CD1 LEU 1516 -1.418 17.104 13.285 1.00 48.16 ATOM 447 CD2 LEU 1516 0.884 16.102 13.265 1.00 42.80 ATOM 448 C LEU 1516 0.810 17.119 17.631 1.00 55.67 ATOM 449 0 LEU 1516 0.217 16.927 18.703 1.00 53.99 ATOM 450 N LYS 1517 1.580 18.174 17.402 1.00 60.97 ATOM 452 CA LYS 1517 1.823 19.193 18.416 1.00 65.19 ATOM 453 CB LYS 1517 3.274 19.668 18.344 1.00 69.34 ATOM 454 CG LYS 1517 4.294 18.559 18.529 1.00 72.86 ATOM 455 CD LYS 1517 5.646 18.935 17.929 1.00.74.91 ATOM 456 CE LYS 1517 6.686 17.852 18.197 1.00 74.38 ATOM 457 NZ LYS 1517 8.010 18.241. 17. 64 9 1.00 75.45 ATOM 461 C LYS 1517 0.879 20.357 18.139 1.00 65.97 ATOM 462 0 LYS 1517 0.303 20.451 17. 053 1.00 64.59 ATOM 463 N SER 1518 0.776 21.270 19.098 1.00 68.20 ATOM 465 CA SER 1518 -0.107 22.422 18.972 1.00 71.92 ATOM 466 CB SER 1518 -0.002 23.322 20.202 1.00 69.89 ATOM 467 C SER 1518 0.144 .23.247 17.718 1.0.0 74.68 ATOM 468 0 SER 1518 -0.798 23.604 17.006 1.00 77.44 ATOM 469 N ASP 1519 1.417 23.493 17.422 1L. 00 76.04 ATOM 471 CA ASP 1519 1.799 24.299 16.264 1.00 76.42 ATOM 472 CB ASP 1519 3.126 25.011 16.539 1.00 77.59 ATOM 473 C ASP 1519 1.912 23.525 14.958 1.00 75.88 ATOM 474 0 ASP 1519 2.374 24.075 13.959 1.00 77.52 ATOM 475 N ALA 1520 1.486 22.265 14.956 1.00 74.39 ATOM 477 CA ALA 1520 1.574 21.439 13.758 1.00 72.83 ATOM 478 CB ALA 1520 0.930 20.079 14.010 1.00 73.06 ATOM 479 C ALA 1520 0.889 22.153 12.598 1.00 71.47 ATOM 480 0 ALA 1520 -0.096 22.858 12.797 1.00 73.48 ATOM 481 N THR 1521 1.440 22.015 11.401 1.00 69.15 ATOM 483 CA THR 1521 0.858 22.653 10.234 1.00 70.05 ATOM 484 CB THR 1521 1.950 23.110 9.272 1.00 70.21 ATOM 485 OGi TRR 1521 2.505 21.969 8.6.07 1.00 72.71 ATOM 487 CG2 TER 1521 3.053 23.815 10.043 1.00 71.01 ATOM 488 C THR 1521 -0.015 21.616 9.550 1.00 70.64 ATOM 489 0 THR 1521 0.015 20.443 9.932 1.00 72.38 ATOM 490 N GLU 1522 -0.782 2-2.026 8.542 1.00 69.70 ATOM 492 CA GLU 1522 -1.623 21.081 7.815 1.00 67.41 ATOM 493 CB GLU 1522 -2.478 21.800 6.761 1.00 70.01 ATOM 494 C GLU 1522 -0.718 20.024 7.168 1.00 64.50 ATOM 495 0 GLU 1522 -1.125 18.878 7.006 1.00 63.76 ATOM 496 N LYS 1523 0.512 20.419 6.827 1.00 60.75 ATOM 498 CA LYS 1523 1.483 19.502 6.240 1.00 58.57 ATOM 499 CB LYS 1523 2.782 20.230 5.883 1.00 60.63 ATOM 500 CG LYS 1523 3.909 19.318 5.361 1.00 62.47 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 297

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501 502 503 507 508 509 511 512 52.3 514 515 516 517 518 520 521 522 523 524 525 526 527 529 530 531 533 534 535 537 538 539 540 541 542 543 544 546 547 548 549 550 551 552 553 555 556 557 558 559 560 561 562 CD LYS CE LYS NZ LYS C LYS 0 LYS N ASP CA ASP CB ASP CG ASP ODi ASP 0D2 ASP C ASP O ASP N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU o LEU N 'SER CA SER CB SER OG SER C SER O SER N ASP CA ASP CB ASP CG ASP ODi ASP 0D2 ASP C ASP 0 ASP N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE .C ILE O ILE

SER

1.523 1523 1523 1523 1523 1524 1524 1524 1524 1524 1524 1524 1524 1525 1525 1525 1525 1525 1525 1525 1525 1526 1526 1526 1526 2.52 6 1526 1527 1527 1527 1527 1527 1527 1527 1527 1528 1528 1528 1528 1528 1528 1528 1528 1529 1529 1529 1529 1529 1529 1529 1529 1530 3.459 4 .633 4.210 1 .763 1.790 1. 960 2 .211 2.487 3 .865 4 .004.

4.816 1. 032 1.221 -0.176 -1.368 -2.624 -4 .020 -4 .245 -5.058 -1.340 -1.509 -1.062 0.998 -0.541 .398 -0.015 0 .346 1.203 244 3.531 4.22.8 3.861 5.132 1.788 1.867 1.224 0.728 0.185 -0.146 1.009 -0.435 0.351 -0.342 -1.236 -2.306 -3 .304 -4.388 -3.953 -4 .877 -1.684 -2 .058 -0,703 18.461 17.700 16 .733 18.441 17.251 18.885 17 .980 18.762 19.401 20.511 18.785 17.031 15.858 17.530 16.715 17 .588 16.937 15 .945 18 026 15 .699 14 .506 16 .172 15.320 16 .105 17.190 14 .201 13 .038 14 .553 13 .552 14 .208 15.069 14 .972 15.840 12 .443 11.259 12.535 11.874 12 .606 11.789 10.845 12 .711 10 .9.77 9 .756 11.575 10.829 11.757 10.926 12.723 13.736 9.856 8.683 10.331 4 .168 3 .559 2 .498 7 .281 6 .972 8.517 9.630 10 .915 10.928 11.489 9 .831 10. 176 9.593 -9.711 9.633 9 .585 10. 727 9 .644 8 .575 8 .813 7 .362 6 .181 4 .947 4 .656 6 .383 6 .198 6 .769 6 .969 7 47: 6.404 5 .198 6 .788 7 .903 7 .557 9 .036 10.009 11. 242 12 .491 12 .820 13.642 9.374 9 .552 8 .585 7 .924 7 .178 S .521 8.169 7.526 6 .947 6 .912 6 .191 1.00 63.35 1.00 66.57 1.00 69.56 1.00 55.98 1.00 56.37 1.00 52.16 1.00 48.91 1.00 50.87 1.00 53.00 1.00 53.77 1.00 56.30 1.00 45.34 1.00 45.63 1.00 40.15 1.00 39.38 1.00 41.66 1.00 42.75 1.00 42.97 1.00 42.24 1.00 39.77 1.00 39.11 1.00 39.64 1.00 40.65 1.00 43.32 1.00 52.41 1.00 39.12 1.00 41.75 1.00 38.30 1.00 39.28 1.00 41.16 1.00 45.20 1.00 43.25 1.00 45.93 1.00 37.34 1.00 37.24 1.00 35.88 1. 00 35.07 1.00 34.38 1.00 35.86 1.0.0 34.83 1.00 29.98 1.00 33.31 1.00 34.55 1.00 32.16 1.00 30.94 1.00 27.07 1.00 26.06 1. 00 23.67 1.00 22.34 1.00 31.34 1.00 33.57 1.00 30.74 145. vOl WO 98/07835 PCT/US97/14888 298 ATOM 564 CA SER 1530

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

565 566 568 569 570 572 573 574 575 576 577 578 579 580 582 583 584 585 586 587 588 589 591 592 593 594 595 596 597 598 599 601 602 603 604 605 606 607 608 610 611 612 613 614 615 616 617 619 620 621 622 CB SER OG SER C SER O SER N GLU CA GLU CE GLU CG GLU CD GLU 0E1 GLU 0E2 GLU C GLU O GLU N MET CA MET CE MET CG MET SD MET CE MET C MET 0 MET N GLU CA GLU CE GLU CG GLU CD GLU 0EI GLU 0E2 GLU C GLU O GLU N MET CA MET CE MET CG MET SD MET CE MET C MET 0 MET N MET CA MET CE MET CG MET SD MET CE MET C MET O MET N LYS CA LYS CE LYS CG LYS CD LYS 1530 1530 1530 1530 1531 1531 1531 1531 1531 1531 1531 1531 1531 1532 1532 1532 1532 1532 1532 1532 1532 1533 1533 1533 1533 1533.

1533 1533 1533 1533 1534 1534 1534 1534 1534 1534 1534 1534 1535 1535 1535 1535 1535 1535 1535 1535 1536 1536 1536 1536 1536 0.007 9.496 1.109 10.302 0.596 11.501 0.620 8.262 0.478 7.140 1.287 8.464 1.918 7.367 2.729 7.893 3.501 6.803 4.341 7.319 4.927 6.473 4.435. 8.549 0.906 6. ,325 1.200 5.126 -0.285 6.788 -1.365. 5.898 -2.473 6.720 -3.645 5.889 -4.969 6.899 -5.178 8.102 1.923 5.076 -2.048 3.850 -2.221 5;*760 -2.732' 5.111 -2.983 6.143 -4.064 7.1.27 -5.402 6.461 -5.913 5.745 -5.964 6.6E2 -1.723 4.089- -2.080 2.983 -0.455 4.472 0.664 3.618 1.957 4.390 3.159 3.559 3.577 3.513 5.153. 4.319 0.670 2.373 0.816 1.250 0.509 2.571 0.469 1.453 0.419 1.946 1.717 2.540 1.722 2.764 1.681 4.534 -0.725 0.540 -0.636 -0.694 -1.823 1.135 -3.011 0.364 -4.176 1.289 -4.689 2.080 -5.810 2.979 5.230 4.548 4.002 5.895 5.377 7.034 7.759 8.944 9.701 10.868 11.572 11.094 8.222 8.228 8.600 9. 048 9.714 10.191 30.860 9.576 7.861 7.933 6.762 5.565 4.476 4.852 5.119 4.240 6.209 5.093 4 .706 5 .166 4 .793 5 .003 4.851 3 .164 3.204 5.681 5.198 6.982 7 .902 9.352 9.850 11.628 11.727 7 .572 7.706 7.104 6 .732 6.413 7.579 7 .127 1.00 32.04 1.00 35.20 1.00 41.97 1.00 29.06 1.00 26.64 1.00 23.86 1.00 23.86 1.00 25.69 1.00 23.65 1.00 26.03 1.00 25.92 1.00 26.55 1.00 25.44 1.00 23.67 1.00. 26.39 1.00 26.57 1.00 24.81 1.00 27.47 1.00 28.43 1.00 24.45 1.00 28.30 1.00 27.95 1.00 28.95 1.00 30.32 1.00 25.40 1.00 26.09 1.00 25.89 1.00 27.24 1.00 30.00 1.00 31.64 1.00 33.57 1.00 33.57 1.00 32.86 1.00 32.89 1.00 39.27 1.00 51.24 1.00 44.97 1.00 31.84 1.00 33.78 1.00 30.36 1.00 28.83 1.00 24.75 1.00 21.50 1.00 22.97 1.00 23.90 1.00 30.33 1.00 33.31 1.00 28.91 1.00 28.07 1.00 25.52 1.00 21.46 1.00 19.89 145. vOl WO 98/07935 WO 9807835PCTIUS97/14885 299 ATOM 623 CE LYS 1536 -6.414 3.717 8 .288 1.00 23.50 ATOM 624 NZ LYS 1536 -7.469 4.668 7.850 1.00 23.53 ATOM 628 C LYS 1536 -2.765 -0.542 5.530 1.00 29.09 ATOM 629 0 LYS 1536 -3.127 -1.708 5.550 1.00 34.02 ATOM 630 N MET 1537 -2.141 -0.009 4.488 1.00 29.03 ATOM 632 CA MET 1537 -1.869 792 3 .288 1.00 30.13 ATOM 633 CB MET 1537 -1.315 0.111 2.177 1.00 31.96 ATOM 634 CG MET 1537 -2.304 1.114 1.589 1.00 35.15 ATOM 635 SD MET 1537 -3.757 0.380 0.787 1.00 41.18 ATOM 636 CE MET 1537 -3.026 -0.360 -0.666 1.00 43.05 ATOM 637 C MET 1537 -0.905 -1.946 3 .531 1.00 30.22 ATOM 638 0 MET 1537 -1.118 -3.051 3 .045 1.00 30.88 ATOM 639 N ILE 1538 0.164 -1.686 4 .275 1.00 30.91 ATOM 641 CA ILE 1538 1.192 -2.701 4.536 1.00 30.29 ATOM 642 CB ILE 1538 2.429 -2.082. 5 .221 1.00 28.64 ATOM 643 CG2 ILE 1538 3.493 -3.142 5.453 1.00 29.84 ATOM 644 CG1 ILE 1538 3.025 -1.030 4.287 1.00 32.82 ATOM 645 CD1 ILE 1538 4.358 -0.446 4.763 1.00 38.38 ATOM 646 C ILE 1538 0.759 -4.000 5.237 1.00 29.07 ATOM 647 0 ILE 1538 1.229 -5.078 4.876 1.00 28.30 ATOM 648 N GLY 1539 -0.178 -3 .925 6.174 1.00 27.61 ATOM 650 CA GLY 1539 -0.592 -5.147 6.849 1.00 26.22 ATOM 651 C GLY 1539 0.273 -5.484 8.055 1.00 25.67 ATOM 652 0 GLY 1539 1.345 -4.906 8.241 1.00 28.05 ATOM 653 N LYS 1540 -0.150 -6.483 8.819 1.00 23.80 ATOM- 655 CA LYS 1540 0.532 -6.876 10.046 1.00 21.77 ATOM 656 CB LYS 1540 -0.491 -7.436 11.045 1.00 20.04 ATOM 657 Cr, LYS 1540 -1.505 -6.435 11.480 1.00 24.45 ATOM 658 CD LYS 1540 -2.472 -6.997 12.488 1.00 32.57 ATOM 659 CE LYS 1540 -3.516 -5.946 12.882 1.00 35.05 ATOM 660 NZ LYS 1540 -2.959 -4.850 13.733 1.00 39.81 ATOM 664 C LYS 1540 1.669 -7.862 9.958 1.00 20.19 ATOM 665 0 LYS 1.540 1.671 -8.738 9.099 1.00 21.80 ATOM 666 N HIS 1541 2.626 -7.722 10.876 1.00 19.98 ATOM 668 CA HIS 1541 3.770 -8.626 11.000 1.00 22.43 ATOM 669 CB HIS 1541 4.854 -8.374 9.965 1.00 22.34 ATOM 670 CG HIS 1541 5.892 -9.455 9.923 1.00 20.68 ATOM 671 CD2 HIS 1541 5.906 -10.654 9.295 1.00 20.60 ATOM 672 ND1 HIS 1541 7.074 -9.382 10.633 1.00 23.67 ATOM 674 CEl HIS 1541 7.771 -10.490 10.444 1.00 23.35 ATOM 675 NE2 HIS 1541 7.087 -11.278 9.634 1.00 22.04 ATOM 677 C HIS 1541 4.385 -8.477 12.376 1.00 27.21 ATOM 678 0 HIS 1541 4.538 -7.367 12.885 1.00 31.33 ATOM 679 N LYS 1542 4.726 -9.619 12.958 1.00 29.25 ATOM 681 CA LYS 1542 5.319 -9.698 14.285 1.00 30.39 ATOM 682 CB LYS 1542 5.660 -11.151 14.610 1.00 33.76 ATOM 683 CG LYS 1542 6.232 -11.370 15.994 1.00 42.16 ATOM 684 CD LYS 1542 6.400 -12.833 16.230 1.00 49.69 ATOM 685 CE LYS 1542 7.040 -13.499 14.988 1.00-57.71 ATOM 686 NZ LYS 1542 7.499 -14.904 .15.237 1.00 62.05 ATOM 690 C LYS 1542 6.515 -8,.808 14.462 1.00 27.21 ATOM 691 0 LYS 1542 6.690 -8.232 15.522 1.00 29.68 145. vOl WO 98/07835 PCT/IUS97/14885 300

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

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ATOM

ATOM

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ATOM

ATOM

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ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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ATOM

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692 694 695 696 697 698 701 702 703 705 '706 707 708 709 710 711 712 714 715 716 717 718 719 720 "721 '72 3 724 725 726 72"1 730 "731 732 734 735 736 737 738 739 740 741 743 744 745 746 747 748 749 750 752 753 754 N ASN CA ASN CB ASN CG ASN ODI ASN ND2 ASN C ASN 0 ASN N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE 0 ILE N ILE CA ILE CB ILE CG2 ILE.

CG ILE CD1 ILE C ILE 0 ILE N ASN CA ASN CB ASN CG ASN ODI ASN ND2 ASN C ASN 0 ASN N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU 0 LEU N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU 0 LEU N GLY CA GLY C GLY 0 GLY 1543 1543 1543 1543 1543 1543 1543 1543 1544 1544 1544 1544 1544 1544 1544 1544 1545 1545 1545 1545 1545 1545 1545 1545 1546 1546 1546 1546 1546 1546 1546 1546 1547 1547 1547 1547 1547 1547 1547 1547 1548 1548 1548 1548 1548 1548 1548 1548 1549 1549 1549 1549 7.293 8.472 9.697 9. 914 9.734 10.255 8.444 9.469 7.276 7.121 6.626 7.549 5.182 4.639 6.122 5.399 6.167 5.214 5.641 4..473 6.1880 6.643 3.914 3.842 2. 909 1.602 0. 944 1.759 1.884 2.319 0.646 0 .739 -0.285 -1.336 -1.819 -3 .012 -2.630 -3.555 -2.469 -2 .835 2.998 -4.063 -3.717 -2.370 -2.282 -2.175 -5.401 -6.447 -5.367 -6.607 -6.319 -5.148 -8.619 -7 787 -8.550 -9.855 -10.942 -9.758 -6.326 -5.781 -5.692 -4.281 -4.095 -4.837 -4.580 342 -3.656 -4.377 -2.340 -±.687 -0.242 0. 500 -0.284 -0.808 -1.641 -1 001 -2.358 -2.424 -3.793 -4 .923 -5.059 -5.748 -1.368 -0.911 -1.014 -0.041 0.553 1.515 2.928 1.570 -0.826 -1.934 -0.260 -0.902 -0.951 -1.553 -1.656 -2.929 -0.198 -0.837 1 .115 1 .843 3..324 3. 716 13.410 13.537 13.031 13.793 13.239 15.078 13.032 12.623 13 .088 12.710 11.240 10.267 11.063 9.659 13.696 14.397 13.856 14.746 15.138 15.831 .16 .050 17.446 13.955 12.897 14.455 13.800 14.005 13.434 12.214 14.313 14.292 15.429 13.422 13 .692 12.360 12 .343 12 .842 10. 924 14 .384 13.956 15.460 16.222 17.721 18.117 19.616 17.492 16.017 16.036 15.823 15.616 15.490 15.405 1.00 23.81 1.00 24.70 1.00 24.68 1.00 24.82 1.00 27.33 1.00 16.75 1.00 24.93 1.00 26.76 1.00 24.21 1.00 21.87 1.00 23.23 1.00 23.87 1.00 22.57 1.00 17.59 1.00 21.64 1.00 21.00 1.00 21.59 1.00 24.05 1.00 23.68 1.00 21.90 1.00 21.94 1.00 9.18 1.00 25.08 1.00 26.68 1.00 25.88 1.00 24.61 1.00 23.18 1.00 21.54 1.00 21.52 1.00 18.83 1.00 23.02 1.00 25.66 1.00 24.45 1.00 24.27 1.00 18.04 1.00 19.96 1.00 10.60 1.00 16.44 1.00 26.95 1.00 27.38 1.00 26.61 1.00 26.25 1.00 22.48 1.00 20.24 1.00 19.27 1.00 19.23 1.00 26.75 1.00 25.56 1.00 25.78 1.00 25.80 1.00 27.76 1.00 28.05 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 301

ATOM

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755 757 758 759 760 761 763 764 765 766 767 768 770 771 772 774 775 776 777 779 780 781 782 783 784 787 788 789 791 "792 793 794 795 796 797 798 800 801 802 803 804 805 806 807 808 809 810 812 813 814 815 816

N

CA

CB

C

0

N

CA

CB

SG

C

0

N

CA

CB

OG1 CG2

C

0

N

CA

CB

CG

CD

OE1 NE2

C

0

N

CA

CB

CG

ODI

OD2

C

0

N

CA

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

CD1 CD2

ALA

ALA

ALA

ALA

ALA

CYS

CYS

CYS

CYS

CYS

CYS

THR

THR

THR

THR

THR

THR

THR

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

GLY

GLY

GLY

GLY

PRO

PRO

PRO

PRO

PRO

PRO

PRO

LEU

LEU

LEU

LEU

LEU

LEU

1550 1550 1550 1550 1550 1551 1551 1551 1551 1551 1551 1552 1552 1552 1552 1552 1552 1552.

1553 1553 1553 1553 1553 1553 1553 1553 1553 1554 1554 1554 1554 1554 1554 1554 1554 1555 1555 1555 1555 1556 1556 1556 1556 1556 1556 1556 1557 1557 1557 1557 1557 1557 -7.369 -7.212 -6.925 -8.430 -9.562 -8.182 -9.227 -8.966 -9.101 -9.092 -8.156 -9.966 -9.889 779 -10.978 -8.629 -11.045 -10.'918 -12.201 -13.374 -14.641 -14 .714 -14.584 -15.300 -13 .668 -13 .502 -13.030 14 .122 -14.369 -15.693 16.907 -17.686 -17.092 -13.249 -13.443 -12.077 -10.960 -9.605 -9.533 -8.511 -8.575 -7.123 -6.296 -7.254 -6.891 -7.378 -6.168 -5.859 -5.173 -4.674 -5.810 -4.085 4.143 5.582 5.947 6.353 5.866 7.551 8.471 8.952 7.681 9.646 10.436 9. 699 10. 736 10. 110 9.393 9.133 11.716 12.838 1.1.268 12. 124 11.279 10.530 11.453 12.449 11. 1.29 13.040 1.2. 714 14. 195 15.202 14. 913 15. 174 16.097 14.463 15.299 14. 955 15. 753 15. 864 15.674 15.478 15.693 15.755 15.533 15.748 16.353 14. 134 13.175 14. 031 12. 745 12.950 11.716 1-0. 730 12. 161 15.530 15.414 13.978 15.897' 15.797 16 .429 16 .899 18.342 19.630 15.934 16 .044 14 .933 13 .921 12.495 12.191 12.414 3 .905 13 .403 14 .369 14.329 14 .147 12.820 11.617 11.506 1.0.718 15.526 16 .613 25.290 16 .33 17. 028 16.153 16.488 15.146 17.336 18.501 16.902 17.823 17.167 15.953 17.961 19.429 17.500 18.773 19.770 16.990 17.568 15.884 15.300 13.944 13.183 12.943 11.880 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.90 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 0.0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 27.34 25.85 23.09 26.58 28.26 26.30 28.29 27.12 27.09 28.57 26.80 29.27 29.30 27.19 26.68 27.00 29.86 30.69 31 21 34.31 33.00 34. 68 39.26 43.55 37. 56 36.86 34.88 40.73 42.49 46.26 51.14 57.62 55.72 42.31 43.61 41.03 37.98 38.30 37.28 37.62 37.23 33.79 33.33 36.99 33.57 32.10 33.23 34.20 32.88 29.78 29.22 28.17 SSSD/55145. vOl WO 98/07835 PCTfUS97/14885- 302 ATOM 817 C LEU 1557 -4.950 11.927 16.225 1.00 36.29 ATOM 818 0 LEtJ 1557 -3.847 12.365 16.580 1.00 37.50 ATOM 819 N TYR 1558 -5.427 10.765 16.658 1.00 35.35 ATOM 821 CA TYR 1558 -4.619 9.890 17.495 1.00 33.09 ATOM 822 CB TYR 1558 -5.323 9.516 18.805 1.00 34.16 ATOM 823 CG TYR 1558 -5.363 10.629 19.806 1.00 24.40 ATOM 824 CD1 TYR 1558 -6.364 10.688 20.771 1.00 33.23 ATOM 825 CEl TYR 1558 -6.438 11.747 21.663 1.00 34.52 ATOM 826 CD2 TYR 1558 -4.426 11.655 19.757 1.00 37.30 ATOM 827 CE2 TYR 1558 -4.488 12.715 20.640 2.00 38.44 ATOM 828 CZ TYR 1558 -5.494 12. 762 21.587 1.00 36.17 ATOM 829 OH TYR 1558 -5.561 13.848 22.431 1.00 34.28 ATOM 831 C TYR 1558 -4.379 8.627 16.700 1.00 31.12 ATOM 832 0 TYR 1558 -5.329 7.980 16.255 1.00 29.83 ATOM 833 N VAL 1559 -3.109 8.321 16.468 1.00 29.60 ATOM 835 CA VAL 1559 -2.727 7.115 15.7-53 1.00 -27.08 ATOM 836 CB VAL 1559 -1.647 7.420 14.704 1.00 24.96 ATOM 837 CG1 VAL 1559 -1.281 6.149 13.926 1.00 24.36 ATOM 838 CG2 VAL 1559 -2.147 8.525 13.765 1.00 19.21 ATOM 839 C VAL 1559 -2.238 6.102 16.794 1.00 25.65 ATOM 840 0 VAL 1559 -1.169 6.257 17.389 1.00 24.97 ATOM 841 N ILE 1560 -3.067 5.095 17.046 1.00 25.91 ATOM 843 CA ILE 1560 -2.777 4.062 18.042 1.00 26.94 ATOM 844 CE ILE 1560 -4.081 3.53.0 18.637 1.00 24.89 ATOM 845 CG2 ILE 1560 -3.785 2.744 19. 900 1.00 17.89 ATOM 846 CG1 ILE 156.0 5.028 4.7071 18.907 1.00 22.84 A~TOM 847 CD1 ILE 1560 -6.450 4.304 -'9.163 1.0.0 22.51 ATOM 848 C ILE 156.0 -1.955 2.896 1.00 30.61 ATOM 849 0 ILE 1560 -2.445 2.2.11 16.636 1.00 31.41 ATOM 850 N VAL 1561 -0.698 2.811 17.890 1.00 30.26 ATOM 852 CA VAL 1561 0.222 1.779 17.429 1.00 29.39 ATOM 853 CB VAL 1561 1.466 2.437 16.730 1.00 30.18 ATOM 854 O-Gi VAL 3.561 1.030 3.188 15.475 1.00 20.60 ATOM 855 CG2 VAL 1561 2.148 3.415 17.675 1.00 32.91 ATOM 856 C VAL 1561 0.662 0.870 18.588 1.00 27.40 ATOM 857 0 VAL 1561 0.323 1.128 19.742 1.00 29.33 ATOM 858 N GLU 1562 1.381 -0.209 18.279 1.00 24.75 ATOM 860 CA GLIJ 1562 1.852 -1.142 19.308 1.00 22.64 ATOM 861 CB GLU 1562 2.426 -2.410 18.676 1.00 17.97 ATOM 862 CG GLU 1562 1.365 -3.282 18.029 1.00 24.33 ATOM 863 CD GLU 1562 1.909 -4.552 17.383 1.00 26.80 ATOM 864 OE1 GLU 1562 1.247 -5.592 17.507 1.00 33.32 ATOM 865 0E2 GLU 1562 2.974 -4.538 16 722 1.00 25.62 ATOM 866 C GLU 1562 2.885 -0.534 20-259 1.00 25.09 ATOM 867 0 GLU 1562 3.638 0.355 19.899 1.00 23.82 ATOM 868 N TYR 1563 2.897 -1.023 21.491 1.00 28.01 ATOM 870 CA TYR 1563 3.805 -0.539 22.512 1.00 26.93 ATOM 871 CB TYR 1563 3.045 -0.428 23.829 1.00 27.19 ATOM 872 CG TYR 1563 3.868 0.008 25.009 1.00 27.72 ATOM 873 CD1 TYR 1563 4.581 1.196 24.976 1.00 30.61 ATOM 874 CEl TYR 1563 5.303 1.620 26.069 1.00 33.05 ATOM 875 CD2 TYR 1563 3.908 -0.753 26.176 1.00 25.77 145. vOl WO 98/07835 WO 9807835PCTfUS97/14885 303

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

876 877 878 880 881 882 884 885 886 887 888 890 891 892 894 895 896 898 899 900 901 902 903 907 908 909 911 912 913 914 916 917 918 919 920 923 924 925 927 928 929 930 931 932 933 934 936 937 938 939 940 942 CE2 cz

OH

C

0

N

CA

CB

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

CD

C E

NZ

C

0

N

CA

C

N

CA

CB

CG

ODi ND2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CD

CZ

TYR

TYR

TYR

TYR

TYR

ALA

ALA

ALA

ALA

ALA

SER

SER

SER

SER

SER

SER

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

GLY

GLY

GL.Y

GLY

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

ARG

ARG

ARG

ARG

ARG

ARG

ARG

1563 1563 1563 1563 1563 1564 1564 1564 1564 1564 1565 1565 1565 1565 1565 1565 1566 1566 1566 1566 1566 1566 1566 1566 1566 1567 1567 1567 1567 1568 1568 1568 1568 1568 1568 1568 1568 1569 1569 1569 1569 1569 1569 1569 1569 1570 1570 1570 1570 .1570 1570 1570 .4.626 5.329 6.091 4.989 4.815 6 .189 7.453 8.392 8 .036 8 .790 7.650 8.062 7.501 8.108 9.530 9.897 10.368 11.798 12.452 12.037.

12 .605 12.345 12.651 12.526 13.755 11.753 12.319 13 .079 12.875 13.975 14 .'754 15.272 16 .342 17.305 16.212 15.892 16.371 16.346 17.417 17.511 18.508 18.431 18.244 18.805 19.530 19.179 20.485 20. 639 21.922 21.918 20.700 20.393 -0.344 0.845 1.271 -1.487 704 908 -1.634 -1.349 -1.092 -0.129 706 -1.251 -2.152 -3.419 -1.085 -0.330 801 -1.708 -3.082 943.

339 -6.024 -7.460 678 -0.567 0. 1.27' 1. 1B4 0:'742 -0364 1.601 1.308 2. 591 3.285 2.670 4.5-91 0.333 0.201 -0.300 -1.291 -2.022 173 -4.211 819 -0.779 -1.484 0.427 0.985 2.395 3.091 4.581 5.272 5.595 27.267 27.210 28.276 22 .675 22.735 22 .743 22 .916 21. 721 24.229 24.249 25.333 26.652 27.729 27.650 26 .915 27.810 26.178 26.410 26.335 27.507 27.457 28.784 28.722 25.573 25.640 24.851 24 .035 22.806 22.324 22.320 21.121 20.464 21. 281 21.730 21.420 21.352 22.472 20.274 20.323 18.972 18.797 19. 939 17.461 20.754 21. 447 20.341 20.703 20.115 20.543 20.212 20.649 21.912 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 0.0 1.00 1.00 1.00 1.00 1.00 1.00 1. 0.0 1.0~0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1,.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 26 .81 32 .81 40.16 28 .73 27.05 29.89 28 27.54 27. 31.20 27.11 28 .91 27.33 26 .58 30.19 33 .44 30 .99 30.50 30.38 27.83 32.36 30.57 34. 82 30.39 32 .53 29.45 29.17 28 .14 27.70 29.48 30.00 28 .53 30.13 31.50 30. 91 28.83 29.87 27.43 29.95 28.96 30.82 28 .31 25.70 29 .74 28.35 31.42 32 .81 31.01 35.33 38.30 47.77 53 .56 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 304 ATOM 943 NHI ARG 1570

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

946 949 950 951 953 954 955 956 957 958 959 960 961 963 964 965 966 967 968 969 970 971 973 974 975 977 978 979 980 981 982 983 984 986 987 988 989 990 991 994 995 996 998 999 1000 1001 1002 1004 1005 1006 1007 NH2 ARG C ARG 0 ARG N GLU CA GLU CB GLU CG GLU CD GLU OEI GLU OE2 GLU C GLU O GLU N TYR CA TYR CB TYR CG TYR CDI TYR CEI TYR CD2 TYR CE2 TYR CZ TYR OH TYR C TYR O TYR N LEU CA LEU CB LEU CG LEU CDI LEU CD2 LEU C LEU 0 LEU N GLN CA GLN CB GLN CG GLN CD GLN OE1 GLN NE2 GLN C GLN O GLN N ALA CA ALA CB ALA C ALA O ALA N ARG CA ARG CB ARG CG ARG CD ARG 1570 1570 1570 1571 1571 1571 1571 1571 1571 1571 1571 1571 1572 1572 1572 1572 1572 1572 1572 1572 1572 1572 1572 1572 1573 1573 1573 1573 1573 1573 1573.

1573 1574 1574 1574 1574 1574 1574 1574 1574 1574 1575 1575 1575 1575 1575 1576 1576 1576 1576 1576 21.212 19.245 20.620 21.548 19.677 19.637 18.403 18.407 17.048 15.991 17.043 19.593 20.327 18.750 18.591 17.571 17.376 16.392 3.6.180 18.151 17.948 16.954 16.732 19.904 20.186 20.692 21.970 22.487 21.833 22.339 22.129 22.997 23.752 23.003 23.942 23.844 24.526 24.289 23.697 24.736 23.687 24.600 22.422 22.021 20.551 22.304 22.006 22.857 23.148 22.234 20.794 19.838 5.304 6.223 1. 034 0.455 1. 724 1. 855 2.662 4.118 4.823 4.133 6. 081 0.459 0. 172 -0.405 -1.766 -2.499 -3.973 -4.378 711 941 -6.284 -6.659 -7.925 2. 525 -3.309 -2.338 -3.033 018 -3.888 -3.448 -5.354 -2.417 -3.134 -1.090 -0.399 1.110 1.582 3.054 3.796 3.480 -0.759 -1.144 -0.731 -1.044 -0.714 -2.484 -2.842 -3.317 -4.703 -5.669 -5.518 -6.352 22.931 22.161 22.230 22.814 22.863 24.311 24.725 24.267 24.459 24.595 24.446 24.948 25.892 24 .400 24.878 23.995 24.309 25.187 25.458 23.703 23.969 24.852 25.143 24.871 25.796 23.812 23 .712 22.273 21.198 19.840 21.426 24.655 25.311 24.735 25.608 25.394 24.113 23.801 24.595 22.625 27.073 27.801 27.469 28.831 29.024 29.275 30.417 28.395 28.768 28.019 28.472 27.687 1.00 51.30 1.00 51.34 1.00 35.61 1.00 34.40 1.00 36.79 1.00 37.35 1,00 41.36 1.00 49.97 1.00 59.14 1.00 59.21 1.00 59.41 1.00 37.09 1.00 37.70 1.00 35.08 1.00 32.72 1.00 31.62 1.00 25.69 1.00 27.87 1.00 28.57 1.00 22.18 1.00 25.06 1.00 25.65 1.00 25.29 1.00 34.57 1.00 35.05 1.00 33.34 1.00 33.00 1.00 28.86 1.00 23.37 1.00 16.57 1.00 20.31 1.00 36.57 1.00 39.00 1.00 37.26 1.00 37.50 1.00 36.96 1.00 39.10 1.00 40.63 1.00. 38.68 1.00 38.62 1.00 38.27 1.00 39.43 1.00 38.80 1.00 39.51 1.00 36.89 1.00 40.89 1.00 44.53 1.00 39.11 1.00 38.24 1.00 38.42 1.00 39.73 1.00 37.87 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14985 305

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

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ATOM

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ATOM

ATOM

1008 1010 1011 1014 1017 1018 1019 1021 1022 1023 1024 1025 1027 1028 1031 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1052 1053 1054 1055 1056 1058 1059 1060 1061 1062 1064 1065 1066 1067 1068 1069 1072 1073 1074 1076

NE

cz NHl NH2

C

0

N

CA

CB

CG

CD

NE

cz

NHI

NH2

C

0

N

CD

CA

CB

CG

C

0

N

CD

CA

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C

0

N

CA

CB

C

0

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CA

CB

C

0

N

CA

CB

CG

CD

OE1 NE2

C

0

N

CA

ARG

ARG

ARG

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ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

PRO

PRO

PRO

PRO

PRO

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PRO

PRO

PRO

PRO

PRO

PRO

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ALA

ALA

ALA

ALA

ALA

ALA

ALA

ALA

ALA

ALA

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

LEU

LEU

1576 1576 1576 1576 1576 1576 1577 1577 1577 1577 1577 1577 1577 1577 1577 1577 1577 1578 1578 1578 1578 1578 1578 1578 1579 1579 1579 15,79 1579 1579 1579 1592 1592 1592 1592 1592 1593 1593 1593 1593 1593 1594 1594 1594 1594 1594 1594 1594 1594 1594 1595 1595 18.489 17.830 18.399 16. 573 24.604 24.978 25.428 26. 866 27.485 27.247 27.857 27. 971 28.395 28.754 28.449 27.449 26.878 28. 564 29.270 29.159 30.225 30.600 29. 768 30.261 29.705 29.169 30. 251 30.088.

28.865 31.711 32 .620 19.075 20.500 20.*954 21.412 22.621 20. 849 21.638 20.773 22.258 21.664 23.465 24.186 25. 576, 26.523 27.751 28.264 .28. 209- 23.474 22.780 23.684 23.084 -6.260 -5.123 -3.961 -5.152 -5.076 -6.256 -4.042 -4.194 -2.871 -2.477 113 -0.797 0.369 1.352 0.562 4.548 -4.180 -5.296 -5.985 -5.648 -6.676 -6.300 -4.373 -3.525 -4.205 143 -3.017 -3.356 -4.224 -2.767 3.257 -5.384 -5.078 -4.184 -6.308 -6.166 -7.505 -8.735 -9.953 -8.840 -8.426 -9.388 -9.553 -10.118 166 -9.877 -10.847 -9.408 -10.432 -11.393 -10.104 -10.828 28.235 28.436 28.143 28.877 28.612 28.623 28.501 28.388 27. 952 26.526 26.287 24.866 24.384 25.205 23.074 29. 760 30.801 29.797 28.692 31.082 30.709 29.331 31. 666 .30.922 32.993 33.994 33.654 35.134 35.14 2 33.289 33.953 32.475 32.354 33.503 32.251 32.044 32.409 32.2 94 32.579 30. 891 29. 894 30. 830 29. 569 29. 837 30.542 31. 111 30.537 32. 265 28. 539 28.876 27. 273 26. 169 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00.

1 .00 i .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .0.0 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 41 .03 43.27 42.64 46 .13 39.77 40.25 40.39 40.42 37.67 36.22 35. 38 .72 37. 57 37.49 39.58 42 42 .57 43 .36 42 .43 43 .08 40.33 40.71 42 .44 41.24 44. .57 46 .68 44 .89 45.31 44.45 45.17 47.72 49.23 50.33 51.83 50.65 51.55 49.06 48.07 47.87 47.59 49.09 47.30 45.32 44.82 49.34 52.40 51.16 54 .00 45.00 45.28 45.08 44.65 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 306

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1077 1078 1079 1080 1081 1082 1083 1085 1086 1087 1089 1090 1091 1093 1094 1095 1097 1098 1099 1101 1102 .1103 1104 1105 1106 1110 lll 1112 1114 1115 1116 1117 1118 1119 1120 1121 1123 1124 1125 1126 1127 1128 1129 1130 1132 1133 1134 1135 1136 1137 1138 1140 CB LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N SER CA SER CB SER OG SER C SER O SER N SER CA SER CB SER OG SER C SER 0 SER N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS O LYS N ASP CA ASP CB ASP CG ASP ODI ASP OD2 ASP C ASP O ASP N LEU CA LEU CB LEU CG LEU CDI LEU CD2 LEU C LEU O LEU N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL O VAL N SER CA SER 1595 1595 1595 1595 1595 1 595 1596 1596 1596 1596 1596 1596 1597 1597 1597 1597 1597 1597 1598 "1598 1598 1598 1598 1598 1598 1598 1598 1599 1599 1.599 1599 1599 1599 1599 1599 1600 1600 1600 1600 1600 1600 1600 1600 1601 1601 1601 1601 1601 1601 1601 1-602 1602 22.758 -9.864 21.619 -8.877 21.855 -7.563 20.276 -9.510 24.044 -11.885 25.252 -11.661 23.511 -13.058 24.325 -14.151 23.633 -15.495 22.401 -15.605 24.557 -13.968 23.891 -13.156 25.475 -14.756 25.782 -14.690 26.921 -15.643 27.976 -15.516 24.526 -15.076 24.233 -14.498 23.767 -16.025 22.551 -16.454 21.978 -17.715 21.374 -18.643 20.450 -19.665 2C 054 -20.709 21.219 -21.551 21.521 -15-336 20.840 -15.099 21.447 -14.624 20.520 -13.508 20.635 -12.898 20.143 -13.838 20.659 -13.'717 19.256 -14.691 20.777 -12.430 19.846 -11.945 22.046 -12.070 22.439 -11.050 23.921 -10.695 24.341 -10.072 25.857 -9.923 23.666 -8.731 22.136 -11.478 21.620 -10.686 22.439 -12.729 22.161 -13.231 22.827 -14.600 22.467 -15.108 24.326 -14.474 20.642 -13.340 20.152 -13.151 19.904 -13.635 18.450 -13.726 25.023 25.295 24.564 24.918 25.685 25.632 25.376 24. 868 25.124 24.432 23.366 22 .707 22.823 21.407 21.065 22.007 20.633 19.577 21.178 20.519 21.147 20.101 20.706 19.702 19.334 20.552 19.548 21. 681 21.841 23 .238 24.339 25.475 24.072 20.802 20.153 20.636 19.666 19.845 21.190 21.226 21.404 18.212 17.418 17.863 16.5.8 16.261 14.885 16.362 16.310 15.191 17.382 17.318 1.00 43.08 1.00 43.22 1.00 41.25 1.00 41.96 1.00 44.58 1.00 44.62 1.00 45.71 1.00 45.30 1.00 46.19 1.00 44.03 1.00 45.09 1.00 45.03 1.00 44.55 1.00 45.00 1.00 45.'60 1.00 54.80 1.00 43.92 1.00 45.51 1.00 39.36 1.00 36.56 1.00 34.93 1.0) 37.52 1.00 34.85 1.00 30.95 1.00 30.59 1.00 36.21 1.00 36.39 1.00 33.57 1.00 31.94 1.00 33.82 1.00 38.08 1.00 37.52 1.00 36.17 1.00 30.89 1.00 30.88 1.00 31.39 1.00 31.55 1.00 30.47 1.00 29.24 1.00 29.75 1.00 24.50 1.00 31.39 1.00 31.23 1.00 30.00 1.00 27.94 1.00 27.68 1.00 24.69 1.00 25.87 1.00 28.98 1.0 0 28.55 1. 00 27.64 1.00 27.07 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 307

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1141 1142 1144 1145 1146 1148 1149 1150 1151 1152 1153 1155 1156 1157 1158 1159 1161 1162 1163 1164 1165 1166 1167 1168 1169 1171 1172 1173 1175 1176 1177 1178 1179 1180 1183 1184 1185 1187 1188 1189 1190 1191 1192 1193 1195 1196 1197 1198 1199 1201 1202 1203 CB SER OG SER C SER

SER

CYS

CA CYS CB CYS SG CYS C CYS 0 CYS N ALA CA ALA CB ALA C ALA 0 ALA N TYR CA TYR CB TYR CG TYR CD1 TYR CEl TYR CD2 TYR CE2 TYR CZ TYR OH TYR C TYR O TYR N GLN CA GLN CB GLN CG GLN CD GLN OE1 GLN NE2 GLN C GLN 0 GLN N VAL CA VAL CB VAL CGI VAL CG2 VAL C VAL O VAL N ALA CA ALA CB ALA C ALA 0 ALA N ARG CA ARG CE ARG CG ARG 1602 1602 1602 1602 1603 1603 1603 1603 1603 1603 1604 1604 1604 1604 1604 1605 1605 1605 1605 1605 1605 1605 1605 1605 1605 1605 1605 1606 1606 1606 1606 1606 1606 1606 1606 1606 1607 1607 1607 1607 1607 1607 1607 1608 1608 1608 1608 1608 16-09 1609 1609 1609 17.899 -14 .362 16.488 -14 .202 17.864 -12.327 16.826 -12.181 18.504 -11.306 18.087 -9 .909 19.074 -8.965 18.716 -7.213 18.155 -9.628 17.175 -9.238 19.340 -9.833 19.573 -9.611 20.970 10.098 18.517 -10.295 17.892 -9.646 18.270 -11.577 17.286 -12 .384 17.209 -13 .771 16.132 -14 .663 16.281 -15 .298 15.270 -16 .097 14.949 14.859 13.935 -15 .650 14.091 -16 .266 13.037 -17.023 15.885 -11.750 15.327 -11..587 15.337 -11.366 14.018 -10 .737 13:662 -10 .424 13.642 -11.636 13.237 -11.279 12.227 -10.603 14.033 -11.705 13.953 -9.449 12.936 -9.136 15.030 -8.674 15.120 -7.430 16.408 -6.667 16.556 -5.433 16.382 -6.282 15.121 -7.743 14.406 -7.093 15.902 -8 .749 15.965 -9.135 16.971 -10.227 14.579 -9.589 14.201 -9.372 13.819 -10.191 12.453 -10.648 .11.998 -11.660 12.451 -13 .050 18.584 18.673 17.093 16.438 17.663 17.461 18.143 18.030 15.961 15.329 15.398 13.979 13.588 13.132 12.310 13.399 12.666 13.300 12. 742 11.510 10.989 13.441 12.934 11.713 11.225 12.572 11 .475 13 .717 13. 776 15.227 16.127 17.540 17.758 18.507 12.949 12.319 13.000 12.255 12.625 11.752 14.094 10.757 9.979 10.355 8.950 8.750 8 .492 7.337 9.409 9.124 10.160 9. 863 1.00 29.97 1.00 38.86 1.00 27.45 1.00 29.38 1.00 25.31 1.00 24.49 1.00 21.15 0.50 11.83 PRT1 1.00 26.92 1.00 30.04 1.00 28.35 1.00 28.00 1.00 25.49 1.00 26.69 1.00 31.40 1.00 26.33 1.00 24.79 1.00 23.42 1.00 29.93 1.00 30.00 1.00 32.29 1.00 32.69 1.00 33.02 1.00 34.40 1.00 34.18 1.00 26.08 1.00 25.43 1,00 25.38 1.00 25.47 1.00 24.21 1.00 24.37 1.00 27.16 1.00 29.64 1.00 30.69 1.00 26.89 1.00 26.40 1.00 27.79 1.00 26.35 1.00 24.87 1.00 25.90 1.00 17.95 1.00 27.69 1.00 30.85 1.006 24.59 1.00 23.22 1.00 17.65 1.00 24.58 1.00 26.22 1.00 25.65 1.00 24.86 1.00 28.15 1.00 30.10 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 308

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1204 1205 1207 1208 1211 1214 1215 1216 1218 1219 1220 1221 1223 1224 1225 1226 1227 1228 1229 1230 1232 1233 1234 1235 1236 1237 1238 1239 1240 1242 1243 1244 1245 1246 1247 1248 1249 1250 1252 1253 1254 1256 1257 1258 1259 1260 1261 1262 1263 1265 1266 1267 CD ARG 1609 NE ARG CZ ARG NHI1 ARG NH2 ARG C ARG O ARG N GLY CA GLY C GLY O GLY N MET CA MET CB MET CG MET SD MET CE MET C MET O MET N GLU CA GLU CB GLU CG GLU CD GLU OE1 GLU OE2 GLU C GLU 0 GLU N TYR CA TYR CB TYR CG TYR CD1 TYR CEI TYR CD2 TYR CE2 TYR CZ TYR OH TYR C TYR 0 TYR N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU 0 LEU N ALA CA ALA CB ALA C ALA 1609 1609 1609 1609 1609 1609 1610 1610 1610 1610 1611 1611 1611 1611 1611 1611 1611 1611 1612 1612 1612 .1612 1612 1612 1612 1612 1612 1613 1613 1613 1613 1613 1613 1613 1613 1613 1613 1613 1613 1614 1614 1614 1614 1614 1614 1614 1614 1615 1615 1615 1615 11.683 -13.980 10.942 -14.941 10.058 -15.792 9.800 -15.790 -9.468 -16.678 11.421 -9.518 10.522 -9.582 11.501 -8.522 10.591 -7.398 10.822 -6.741 9.872 -6.452 12.097 -6.558 12.488 -5.955 13.991 -5.686 14.391 ""-4.4.78 13.362 -3.000 13.665 -2.715 12.090 -6;791 11.700 -6.251 12.213 8.108 11.836 -9.002 12.120 -1.0.446 11.602 -11.443 11.796 -12.872 11.658 -13.143 12.085 -13.733 10.354 -8.812 9.974 -8.697 9.518 -8.752 8.092 -8.545 7.341 -8.625 5.867 -8.318 4.969 -9.307 3.610 -9.049 5.373 -7.041 4.017 -6.761 3.137 -7.776 1.779 -7.542 7.870 -7.170 7.125 -7.034 8.541 -6.154 8.400 -4.794 9.219 -3.830 8.548 -3.413 9.509 -2.571 7.255 -2.647 8.793 -4.671 .8.156 -3.939 9.840 -5.397 10.333 -5.408 11.685 -6.088 9.334 -6.107 10.723 9.927 10.437 11.740 9.645 9.008 8.155 9.888 9.789 8.432 7.688 8.088 6.809 6.801 7.652 7.330 5.612 5.590 4.553 5.710 4.632 5. 024 4.026 4.477 5.692 3.617 4.305 3.130 5.337 5.133 6.462 6.335 5.968 5.872 6.600 6.502 6.135 6.009 4.504 3.540 5.045 4.536 5.392 6.707 7.518 6.436 3.066 2.294 2.684 1.317 1.254 0.404 1.00 32.49 1.00 34.58 1.00 35.69 1.00 32.47 1.00 36.67 1.00 22.96 1.00 23.65 1.00 20.88 1.00 21.47 1.00 23.55 1.00 23.53 1.00 24.37 1.00 25.10 1.00 25.4"7 1.00 27.09 1.00 22.57 1.00 21.91 1.00 26.57 1.00 24.98 1.00 27.89 1.00 26.91 1.00 26.70 1.00 29.25 1.00 31.24 1.00 33.39 1.00 31.91 1.00 27.55 1.0.0 30.04 1.00 25.13 1.00 21.91 1.00 21.00 1.00 17.47 1.00 18.34 1.00 18.83 1.00 14.48.

1.00 19.67 1.00 22.67 1.00 21.91 1.00 22.06 1.00 22.01 1.00 22.04 1.00 20.56 1.00 18.43 1.00 15.96 1.00 15.70 1.00 11.06 1.00 22.69 1.00 24.91 1.00 24.55 1.00 21.18 1.00 18.35 1.00 21.97 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97I14889 309 ATOM 1268 0 ALA 1615

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1269 1271 1272 1273 1275 1276 1277 1279 1280 1281 1282 1283 1284 1288 1289 1290 1292 1293 1294 1295 1296 1297 1301 1302 1.303 1305 1306 1307 1308 1309 1310 1312 1313 1314 1315 1316 1317 1318 1319 1321 1322 1323 1324 1325 1327 1328 1330 1331 1332 1334 1335 N SER CA SER CB SER OG SER C SER O SER N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS o LYS N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS O LYS N CYS CA' CYS CB CYS SG CYS C CYS O CYS N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE O ILE N HIS CA HISA CB HIS CG HIS CD2 HIS NDl HIS CEl HIS NE2 HIS C HIS 0 HIS N ARG CA ARG CB ARG 1616 1616 1616 1616 1616 1616 1617 1617 1617 1617 1617 1617 1617 1617 1617 1618 1618 1618 1618 1618 1618 1618 1618 1618 1619 1619 1619 1619 1619 1619 1620 1620 1620 1620 1620 1620 1620 1620 1621 1621 1621 1621 1621 1621 1621 1621 1621 1621 1622 1622 1622 9.089 -5.642 8.704 -7.173 7.722 -7.919 7.305 -9.179 6.382 -8.862 6.475 -7.071 5.733 -7.277 6.217 -6.169 5.078 -5.280 4.555 -4.951 3.843 -6.124 2.509 -6.395 1.714 -7.442 2.339 -8.767 5.409 -4.019 4.640 -3.053 6.557 -4.028 7.014 -2.904 5.906 -2.507 5.735 -3.411 5.506. -4.864 5.533 -5.752 4'.231 -5.707 7.466 -1.658 7.537 -0.576 7.827 -1L.821 8.21.3 -0.693 7.535 -0..814 8.019 0.405 9.717 -0.529 10.419 -1.487 10.197 0.690 11.610 1.039 12.151 1.823 13.607 2.215 11.966 0.997 12.127 1.803 11.631 1.926 10.912 2.932 12.398 1.526 12.463 2.254 13.214 1.425 13.024 1.897 12.4'85 1.280 13.449 3.134 13.182 3.253 12.596 2.144 13.110 3.616 12.561 4.597 14.327 3.639 15.129 4.853 14.289 6.018 705 0.893 0 .097 0.831 1. 851 -0.149 -1.117 0.789 0.705 2.099 2 .750 2. 081 2. 809 2.616 -0.061 -0.022 -0.748 -1.582 -2 .571 -3.790 432 663 -5.369 -0.816 -1.385 0.449 1.276 2.647 3.894 1.451 1.790 1.211 1.388 0 .172 0.393 -1.111l -2.401 2 .652 2 .715 3 .665 4.931 5. 980 7.398 8.475 7.842 9.131 9.543 4.831 5.306 4.291 4.130 3 .581 1.00 23.80 1.00 22.49 1.00 21.81 1.00 19.78 1.00 23.88 1.00 23.60 1.00 21.74 1.00 25.84 1.00 23.96 1.00 20.74 1.00 23.40 1.00 28.70 1.00 31.16 1.00 41.91 1.00 24.25 1.00 25.22 1.00 24.20 1.00 25.15 1.00 27.00 1.00 29.09.

1 .060 31. 82 1.00 30.21 1.00 26.34 1.00 23.50o 1.00 22.10* 1.00 23. 72:.

1.0.0 20.89 1.00 18.41 1.00 26.34 1.00 22.94 1.00 23'.2 0 1.00 21.17 1.00 22.35 1.00 17.30 1.00 8.27 1.00 18.27 1.00 17.57 1.00 25.20 1.00 29.69 1.00 22.66 1.00 22.78 1.00 22.65 1.00 22.07 1.00 20.50 1.00 23.11 1.00 23.92 1.00 24.44 1.00 24.07 1.00 24.37 1.00 26.42 1.00 24.59 1.00 17.58 SSSD/55145. vol WO 98/07835 PCTIUS97/14885- 310

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1336 1337 1338 1340 1341 1344 1347 13 48 1349 1351 1352 13.53 1354 1355 1356 1357 1358 1360 1361 1362 1363 1364 1365 1366 1367 1369 1370 1371 1372 1373 1375 1376 1377 1378 1379 1381 1382 1383 1384 1385 1387 1388 1391 1394 1395 1396 1398 1399 1400 1401 14 02 1405 CG ARG 1622 CD ARG NE ARG CZ ARG NHl ARG NH2 ARG C ARG 0 ARG N ASP CA ASP CB ASP CG ASP ODi ASP 0D2 ASP C ASP O ASP N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N ALA CA ALA CB ALA C ALA O ALA N ALA CA ALA CB ALA C ALA 0 ALA N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NHl ARG NH2 ARG C ARG 0 ARG N ASN CA ASN CB ASN CG ASN ODi ASN ND2 ASN C ASN 1622 1622 1622 1622 1622 1622 1622 1623 1623 1623 1623 1623 1623 1623 1623 1624 1624 1624 1624 1624 1624 1624 1624 1625 1625 1625 1625 1625 1626 1626 1626 1626 1626 1627 1627 1627 1627 1627 1627 1627 1627 1627 1627 1627 1628 1628 1628 1628 1628 1628 1628 13.810 5.7G7 12.925 6.860 12.574 6.5.90 11.537 5.852 10.719 5.308 11.356 5.611 15.918 5.257 16.767 6.138 15.685 4.585 16.437 4.927 15.922 6.213 16.891 6.772 16.428 7.338 18.121 6.645 16.498 3.797 16.148 3.959 16.956 2.642 17.087 1.480 17.149 0.220 17.118 -1.150 15.8.50 -1.348 17.228 -2.175 18.340 1.628 39.464 .1.773 18.116 1.598 19.164 1.750 19.520 3.233 18.575 1.214 17.352 1.077 19.429 0.942 18.969 0. 40D8 20.139 -0.048 18.111 1.397 17.333 1.006 18.303 2.685 17.503 3.722 18.017 5.107 18.086 5.287 18.255 6.756 18.548 6.928 19.779 6.904 20.826 6.721 19.976 7.059 16.029 3.567 15.092 3.897 15.850 3.039 14.534 2.849 14.569 3.308 14.709 4.823 14.018 5.567 15.599 5.277 13.945 1.440 2 .163 1.634 0 .243 -0.145 0.753 1.433 5.388 5.337 6 .505 7.703 8.349 9.373 10.382 9.167 8.713 9.887 8.246 9.107 8.242 8.916 9.756 7.805 10.002 9.514 11. 313 12.314 .12.473 13.613 13.716 14.605 15.900 16. 764 16.664 17.523 16.407 17.048 16.627 15.104 14.688 13.261 12.749 13.539 11. 450 16.591 17.333 15.375 14.758 13.301 13.167 13 .844 12.297 14.862 1.00 13.88 0.50 4.97 0.50 6.49 0.50 3.84 0.50 2.25 0.50 2.48 1.00 24.72 1.00 26.90 1.00 25.61 1.00 28.41' 1.00 30.38 1.00 33.47 1.00 43.35 1.00 31.88 1.00 28.86 1.00 28.31 1.00 27.81 1.00 27.28 1.00 27.53 1.00 27.69 1.00 23.77 1.00 29.15 1.00 26.27 1.00 25.89 1.00 23.29 1.00 19.68 1.00 18.85 1.00 20.79 1.00 20.75 1.00 22.03 1.00 23.43 1.00 22.46 1.00 25.86 1.00 29.51 1.00 26.92 1.00 27.30 1.00 28.29 1.00 36.26 1.00 41.19 1.00 39.94 1.00 42.33 1.00 44.75 1.00 41.50 1.00 27.42 1.00 26.53 1.00 26.82 1.00 24.08 1.00 26.30 1.00 25.19 1.00 28.59 1.00 22.32 1.00 24.35 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 31.1

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1406 1407 1409 1410 1411 1412 1413 1414 1415 1417 1418 1419 1420 1421 1422 1423 1424 1426 1427 1428 1429 1430 1431 1432 1434 1435 1436 1438 1439 1440 1441 1443 1444 1.4 45 1446 1447 1448 1449 1450 1451 1453 1454 1455 1456 1457 1458 1459 1460 1462 1463 1464 1465 0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

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CD1 CD2 c 0

N

CA

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C

0

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0

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CA

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0

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ASN

VAL

VAL

VAL

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LEU

LEU

LEU

LEU

LEU

LEU

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VAL

VAL

VAL

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VAL

THR

'rHR

THR

THR

'rMR

THR

THR

GLU

GLU

GLU

GLU

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GLU

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GLU

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ASP

ASP

ASP

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AS P

ASP

AS P

ASN

ASN

ASN

ASN

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1628 1629 1629 1629 1629 1629 1629 1629 1630 1630 1630 1630 1630 1630 1630 1630 1631 1631 1631 1631 1631 1631 1631 1632 1632 1632 1632 1632 1632 1632 1633 1633 1633 1633 1633 1633 1633 1633 1633 1634 1634 1634 1634 1634 1634 1634 1634 1635 1635 1635 1635 1635 13.026 14.473 13.988 15.077 14.612 15.378 13 .625 14.427 12.393 11.936 10.609 10.634 9.240 11.409 11.833 11.666 11.933 11.883 13.222 11.210 14 .376 10.730 10.630 9.866 8 .728 7.674 8.169 7.330 9.157 10.256 8.260 8.513 7.259 7.386 8.463 8.519 9.249 8 .914 9.632 8.456 8.768 7.588 6.258 6.064 5.412 10.035 10.395 10.730 11.974 13 .042 13 .576 13.795 1.084 0.637 -0.718 -1.813 -3.142 -1.977 -0.670 -0.237 -1.031 010 -0.252 1.179 1.680 2.100 -2.434 -3.412 -2.542 -3.831 -4.105 -5.477 -3.976 3.918 -3.102 911 i 1.49 6. 061 -7.406 5.554 -5.810 6.320 -5.823 -6.424 310 -6.881 -6.192 -4.939 -6.916 -7.889 -8.435 -8.526 -9.941 -10.639 -10.420 -11.042 -9.622 -10. 109 11. 225 -8.998 -8.948 891 -9.426 -8.236 14.105 15 .785 16.055 15.822 16.398 14.346 17.536 18 .361 17.866 1.9.247 19.339 18.789 18.654 19.668 19.829 19.092 21 .150 21.833 22. 553 23.233 21.576 22 .853 23.787 22.659 23 .540 22 .874 22. 792 21.480 24 .842 24 .947 25.822 27.122 27.991 29.399 30.260 30.297 30.918 26.986 27.826 25.910 25.677 24.990 25.725 26.799 25.236 24 .849 24.495 24.589 23.792 24.361 25.6.77 25.880 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00J 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00.

1.00.

1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 24 .66 22.35 20.65 18.07 11.84 12 24 .27 25.94 24 .99 25. 22.79 17.86 18.49 17.63 28 .29 28.56 29.46 29.40 27.48 24.53 22.55 31.94 33 .13 32.21 31.77 32.38 32.38 28. 30.39 30.28 32 .43 32.84 35. 28 46.57 54.03 58 .68 56. 84 35 .14 33 .92 38.25 39.22 44 .88 54 .17 56.33 54.47 37.53 36.33 39.12 37.21 37.83 38.65 43 .82 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 312 ATOM 1466 ND2 ASN 1635 13.768 -10.353 26.596 1.00 39.49 ATOM 1469 C ASH 1635 11.807 -9.193 22.287 1.00 35.03 ATOM 1470 0 ASN 1635 12.649 -9.834 21.648 1.00 32.37 ATOM 1471 N VAL 1636 10.705 -8.700 21.736 1.00 33.30 ATOM 1473 CA VAL 1636 10.418 -8.846 20.320 1.00 30.50 ATOM 1474 CB VAL 1636 8.895 -9.014 20.075 1.00 31.54 ATOM 1475 CG1 VAL 1636 8.600 -9.178 18.584 1.00 29.16 ATOM 1476 CG2 VAL 1636 8.384 -10.214 20.838 1.00 34.29 ATOM 1477 C VAL 1636 10.908 -7.577 19.629 1.00 29.28 ATOM 1478 0 VAL 1636 10.553 -6.463 20.037 1.00 27.08 ATOM 1479 N MET 1637 11.760 -7.755 18.623 1.00 27.82 ATOM 1481 CA MET 1637 12.318 -6.634 17.874 1.00 27.09 ATOM 1482 CB MET 1637 13.578 -7.070 17.127 1.00 27.47 ATOM 1483 CG MET 1637 14.648 -7.697 18.010 1.00 28.35.

ATOM 1484 'SD MET 1637 15.243 -6.594 19.297 1.00 30.41 ATOM 1485 CE MET 1637 15.104 -7.640 20.728 1.00 26.00 ATOM 1486 C MET 1637 11-272 -6.200 16.868 1.00 26.01 ATOM .1487 0 MET 1637 10.751 -7.034 16.131 1.00 26.05 ATOM 1488 N LYS 1638 10.983 .4.900 16.823 1.00 25.44 ATOM 1490 CA LYS 1638 9.984 -4;349 15-9061 1.00 22.01 ATOM 1491 CB LYS 1638 8.693 -4.028 16.658 1.00 19.65 ATOM 1492 CG LYS 1638 7.887 -5.254 17.034 1.00 21.22 ATOM 1493 CD LYS 1638 6.666 -4.904 17.869 1.00 21.73 ATOM 1494 CE LYS 1638 5.7.76 -6.133 18.076 1.00 19.32 ATOM 1495 NZ LYS 1638 4.970 -6.522 16.869 .1.00 23.14 A~TOM 1499 C LYS 1638 10.477 -3.106 15.191 1.00 21.85 ATOM i500 0 LYS 1638 1.0.896 -2.147 15.808 1.00 24.35 ATOM 1501 N ILE 1639 10.371 -3.110 13.878 1.00 24.47 ATOM 1503 CA ILE 1639 10.803 -1 '983 13.073 1.00 24.90 ATOM 1504 CB ILE 1639 11.090 -2.443 11.625 1.00 22.12 ATOM 1505 CG2 ILE 1639 11.413 -1.275 10.720 1.00 17.41 ATOM 1506 CG1 ILE 1639 12-.256 -3.423 11.664 1.00 18.67 ATOM 1507 CD1 ILE 1639 12.309 -4.308 10.492 1.00 26.15 ATOM 1508 C ILE 1639 9.772 -0.856 13.117 1.00 28.52 ATOM 1509 0 ILE 1639 8.557 -1.094 12.964 .1.00 27.86 ATOM 1510 N ALA 1640 10.267 0.363 13.358 1.00 30.06 ATOM 1512 CA ALA 1640 9.444 1.564 13.445 1.00 29.37 ATOM 1513 CB ALA 1640 9.627 2.211 14.812 1.00 28.25 ATOM 1514 C ALA 1640 9.782 2.566 12.344 1.00 29.68 ATOM 1515 0 ALA 1640 10.808 2.453 11.660 1.00 30.81 ATOM 1-516 N ASP 1641 8.892 3.536 12.154 1.00 30.35 ATOM 1518 CA ASP 1641 9.067 4.608 11.154 1.00 30.40 ATOM 1519 CB ASP 1641 10.309 5.454 11.454 1.00 32.89 ATOM 1520 CG ASP 1641 10.018 -6.678 12.321 1.00 34.68 ATOM 1521 ODi ASP 1641 10.952 7.497 12.469 1.00 35.84 ATOM 1522 0D2 ASP 1641 8.897 6.824 12.856 1.00 38.22 ATOM 1523 C ASP 1641 9.102 4.162 9.705 1.00 28.91 ATOM 1524 .0 ASP 1641 9.484 4.941 8.826 1.00 29.26 ATOM 1525 N PILE 1642 8.650 2.941 9.440 1.00 27.21 ATOM 1527 CA PHE 1642 8.648 2.435 8.072 1.00 25.07 ATOM 1528 CB PILE 1642 8.432 0.909 8.043 1.00 19.6-4 ATOM 1529 CG PILE 1642 7.135 0.451 8.639 1.00 16.47 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885

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ATOM

1530 1531 1532 1533 1534 1535 1536 1537 1539 1540 1541 1542 1544 1545 1546 1547 1548 1549 1550 1551 1553 1554 1555 1556 1557 1559 1560 1561 1562 1563 1565 1566 1567 1568 1569 1570 1571 1572 1574 1575 1576 1577 1578 1579 1580 1581 1583 1584 1585 1586 1587 1589 CD1 PHE CD2 PE CE1 PE CE2 PHE CZ PHE C PHE 0 PHE N GLY CA GLY C GLY O GLY N LEU CA LEU CE LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N ALA CA ALA CE ALA C ALA O ALA N ALA CA ALA CB ALA C ALA O ALA N ASP CA ASP CB ASP CG ASP ODI ASP 0D2 ASP C ASP 0 ASP N ILE CA ILE CE ILE CG2 ILE CG1 ILE CD1 ILE C ILE 0 ILE N HIS CA HIS CE HIS CG HIS CD2 HIS NDl HIS CEl HIS 1642 1642 1642 1642 1642 1642 1642 1643 1643 1643 1643 1644 1644 1644 1644 1644 1644 1644 1644 1645 1645 1645 1645 1645 1646 1646 1646 1646 1646 1647 1647 1647 1647 1647 1647 1647 1647 1648 1648 1648 1648 1648 1648 1648 1648 1649 1649 1649 1649 1649 1649 1649 5. 974 7.080 4.781 5.892 4.743 7.667 7.910 6.585 5.631 5.786 4.922 6.930 7.189 8.498 8.473 7.520 9.854 7.213 7.759 6.577 6. 524 5.309 7.819 8.105 8.622 9. 871 10. 971 10.338 10. 319 10. 7 55' 11. 253 10. 868 11. 084 12.070 10.265 12.770 13.487 13.235 14.652 14.890 14.133 14.454 15.198 15. 439 16.591 14.8 05 15. 450 14.793 15.123 16.2 57 14. 239 14.798 0.400 0.018 -0.082 -0.463 -0.515 3.174 3.292 3.718 4.427 5.935 6.684 6.387 7.808 8.037 9.371 9.212 9.773 8.578 8.123 9.744 10. 652 11.563* 11.475.

12 .082 11.462 12 *.222 11.405 12.661 11.880 13.919 14.419 15.887 16.342 15.928 17.150 14.264 15.075 13.198 12.877 11. 624 10.443 11.886 11.083 14.044 14.271 14.791 15.941 16.285 15.332 14.628 15.006 14.148 7.878 9. 945 8.422 10.496 9.739 157 5. 971 7.707 6.866 6.893 6.436 7. 376 7.491 8.242 8.962 10. 127 9.442 6.179 5 .176 6.203 5. 067 5.202 5.141 6. 176 4.082 4.094 4. 778 2 *712 1.759 2.598 1.322 1. 092 -0.352 003 -0.837 1.332 1.926 0.684 0.595 -0.271 0.326 -1.718 -2.751 0. 014 0.380 -0.884 -1.500 84'4 -3.944 -4.208 -4.946 -5.779 1.00 21.72 1.00 17.01 1.00 20.97 1.00 18.72 1.00 20.32 1.00 25.57 1.00 28.40 1.00 25.69 1.00 24.81 1.00 24.84 1.00 19.20 1.00 29.50 1.00 34.24 1.00 33.10 1.00 36.00 1.00 41. 52 1.00 35.23 1.00 37.54 1.00 37.48' 1.00 41.66 1.00 43.66 1.00 36.13 1.00 44.67 1.00 47.17 1.00 45.69 1.00 48.62 1.00 49,50 1.00 50. 98 1.00 52.84 1.00 53.09 1.00 55.06 1.00 56.05 1.00 59.31 1.00 59.51 1.00 63.48 1.00 55.26 1.00 53.18 1.00 56.66 1.00 57.79 1.00 53.86 1.00 52.14 1.00 48.24 1.00 43.97 1.00 62.32 1.00 64.72 1.00 65.72 1.00 69.00 1.00 70.35 1.00 73.90 1..00 75.13 1.00 75.30 1.00 76.83 145. vOl WO 98/07835 PCTIUS97/14885 314

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1590 1592 1593 1594 1596 1597 1598 1599 1600 1602 1603 1605 1606 1607 1609 1610 1611 1612 1613 1614 1615 1616 1618 1619 1620 1621 1622 1623 1624 1625 1627 1628 1629 1630 1631 1632 1633 1634 1635 1637 1638 1639 1641 1642 1643 1644 1645 1646 1647 1648 1649 1651 NE2

C

0

N

CA

CB

CG

CD2 ND1 CEl NE2

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2 Cz

OH

C 0

N

CA CB CG CD1 CEl CD2 CE2 CZ OH C

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ASP

ASP

ASP

ASP

ASP

ASP

AS P

ASP

T'YR

TYR

TYR

TYR

TYR

rYR rYR rYR rYR rYR nY

[YR

[YR

[YR

[YR

[YR

rYR

[YR

[YR

[YR

[YR

7YR 1649 1649 1649 1650 1650 1650 1650 1650 1650 1650 1650 1650 1650 1651 1651 1651 1651 1651 1651 1651 1651 1652 1652 1652 1652 1652 1652 1652 1652 1653 1653 1653 1653 1653 1653 1653 1653 1653 1653 1653 1653 1654 1654 1654 1654 1654 1654 1654 1654 1654 1654 16.025 13.905 -5.34 8 15.419 17.150 -0.576 15.517 18.284 -1.041 15.218 16.912 0.718 15.199 17.987 1. 710 13.778 18.488 1.956 13.272 19.401 0.882 13.451 20.734 0.691 12.529 18.955 -0.185 12.262 19.972 -0.993 12.814 21.058 -0.481 15.856 17.593 3.029 15.783 18.334 4.010 16.543 16.451 3.033 17.221 .15.939 4.222 17.622 14.*462 4.031 18.499 13.978 5.19,9 16.359 13.604 3.890 16.643 1.2.143 3.593 18.472 16.734 4.569 19.375 .16.882 3.745.

18.543 17.222 5.802 19.707 17.987 6.240 19.344 18.923 7.398 20.512 19.790 7.843 21.306 20.248 6.985 20.646 20.034 9.060 20.802 17.023 65.673 20.746 16.457 7.762 21.802 16.856 5.814 22.926 15.968 6.089 23.852 15.906 4.875 23.362 14.971 3.795 24.153 14.679 2.684 23.725 13.773 1.717 22.121 14.335 3.910 21.685 13.429 2.953 22.487 13.148 1.859 22. 044 12.239 0.921 23.733 16.313 7.345 24.403 15.453 7.912 23.644 17.564 7.789 24.379 18.013 8.963 24.947 19.417 8.741 26.038 19.467 7.691 25.736 3-9.698 6.353 26.734 19.708 5.383 27.364 19.252 8.035 28.366 19.261 7.079 28.047 .19.488 5.754 29*.048 19.485 4.806 23.560 17.980 10.239 1.00 76.74 1.00 70.22 1.00 72.83 1.00 71.28 1.00 72.52 1.00 75.67 1.00 82.16 1.00 86.17 1.00 86.37 1.00 89.04 1.00 89.37 1.00 71.11 1.00 69.56 1.00 70.84 1.00 70.50 1.00 71.73 1.00 71.65 1.00 73.10 1.00 75.18 1.00 69.85 1.00 70.30 1.00 68.99 1.00 68.06 1.00 70.53 i. 00 72.86 1.00 73.36 1L.00 76.01 1.00 66.08 1.00 64.92 1.00 64.14 1.00 63.02 1.00 61.29 1.00 62.37 1.00 61.11 1.00 62.89 1.00 64.11 1.00 66.09 1.00 65.03 1.00 65.78 1.00 63.49 1.00 63.39 1.00 64.37 1.00 63.95 1.00 60.86 1.00 57.70 1.00 58.03 1.00 60.65 1.00 56.79 1.00 58.85 1.00 60.88 1.00 64.23 1.00 65.89 TYR 1654 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 315 ATOM 1652 0 TYR 1654

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1653 1655 1656 1657 1658 1659 1660 1664 1665 1666 1668 1669 1670 1671 1672 1673 1677 1678 1679 1681 1682 1683 1685 1686 1687 1688 1690 1691 1692 1693 1694 1696 1697 1698 1699 1700 1703 1704 1705 1707 1708 1709 1710 1712 1713 1714 1715 1716 1718 1719 1722 N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS 0 LYS N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS O LYS N THR CA THR CB THR OGi THR CG2 THR C THR 0 THR N ALA CA A.LA CB A.LA C A.LA O ALA N ASN CA ASN CB ASN CG ASN ODi ASN Nfl2 ASN C ASN 0 ASN N GLY CA GLY C GLY 0 GLY N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NHl ARG NH2 ARG 1655 1655 1655 1655 1655 1655 1655 1655 1655 1656 1656 1656 1656 -1656 1656 1656 1656 1656 1657 1657 1657 1657 1657 1657 1657 1658 1658 1658 1658 1658 1659 1659 1659 1659 1659 1659 1659 1659 1660 1660 1660 1660 1661 1661 1661 1661 1661 1661 1661 1661 1661 24.074 18.283 22.297 17-586 21.443 17.527 19.972 17.611 19.019 17.651 17.607 17-867 16.595 17.393 15.204 17.553 21.714 16.242 21.872 15.169 21.766 16.358 22.035 15.212 22.983 15.618 24.395 15. 895 25.280 16.221 26.764 16.031 27. 592 16-186 20.777 14.560 19.695 15.1.48 20.928 13.337 19.821 12.607 20.109 11.078 21..295 10.823 20.289 10.S500 19.682 13.131 20.424 14.022 18.. 753 12 569 18.580 12.-992 17.391 12.254 19.880 12. 709 20.394 13.566 20.440 11. 526 21.663 11.092 21.835 9.583 22.632 8.937 22.525 9.331 23.402 7.907 22.910 11.816 24.004 11.585 22.744 12.678 23.867 13.421 24.604 12.750 25.726 13.132 23.980 11.758 24.626 11.062 24.387 9.549 24.977 8.874 24.776 7.376 25.178 6.665 24.952 5.369 24.319 4-643 25.375 4.792 11.316 10. 135 11.315 10. 915 12.090 11.603 12.627 12.110 12.093 11. 497 13 .419 14.275 15.403 14 .946 16.138 15.832 17. 062 14.855 14.837 15.359 15.960 16. 021 16.787 14.637 17.383 17.790 18 .148 19. 537 20. 173 20. 313 21.042 20.080 24D. 746 20.557 21.679 22.840 21.342 20.249 20.762 19.246 18 .689 17.536 17.196 16.914 15.808 15. 883 17.111 17.045 18.260 18.471 17.550 19.591 1.00 67.56 1.00 67.36 1.00 69.11 1.00 69.86 1.00 71.45 1.00 75.40 1.00 78.22 1.00 80.61 1.00 69.65 1.00 70.67 1.00 68.19 1.00 68.00 1.00 65-53 1.00 62.71 1.00 64.38 1.00 63.23 1.00 61.72 1.00 68.73 1.00 69.20 1.00 68.48 1.00 67.93 1.00 68.93 1.00 6-8.72 1.00 68.83 1.00 67.80' 1.00 .67.87 1.,00 68.95 1.00 70.64 1.00 71.19 1.00 69.64 1.00 70.13 1.00 68.02 1.00 66. 1.00 70.23 1.00 74.09 1.00 75.21 1.00 75.03 1.00 63.30 1.00 61.12 1.00 61.61 1.00 59.06 1.00 56.84 1.00 55.69 1.00 55.73 1.00 52.76 1.00 52.39 1.00 54.08 1.00 58.37 1.00 59.27 1.00 59.83 1.00 57.04 1.00 59.47 SSSD/55145. vOl WO 98/07835 PCTIUS97/14889 316

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1725 1726 1727 1729 1730 173 1 1732 1733 1734 1735 1736 1737 1738 1739 1740 1741 1742 1743 1745 1746 1747 1748 1749 1750 1751 1753 1754 1755 1756 1757 2758 1762 1.763 1764 1766 1767 1768 1769 1770 1771 1772 1773 1775 1776 1777 1778 1779 1780 1782 1783 1784- 1785 C ARG O ARG N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N PRO CD PRO CA PRO (CB PRO CG~ PRO C PRO O PRO N VAL CA VAL CE VAL CG1 VAL CG2 VAL C VAL O VAL N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS O LYS N TRP CA TRP CB TRP CG TRP CD2 TRP CE2 TRP CE3 TRP CD). TRP NEI TRP CZ2 TRP CZ3 TRP CR2 TRP C TRP 0 TRP N MET CA MET CB MET CG MET SD MET 1661 1661 1662 1662 1662 1662 1662 1662 1662 1662 1663 1663 1663 1663 1663 1663 1663 1664 1664 1664 1664 1664 1664 1664 1665 1665 1665 1665 1665.

1665 1665 1665 1665.

1666 1666 16.66 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1667 1667 1667 1667 1667 24.167 23.169 24 .911 24 .600 25.871 26.430 27.918 25.644 23 .999 24 .704 22 .680 21. 723 21.981 20. 595 20.375 22 .640 22.442 23 .427 24 .095 24 .887 23 947 25.894 25. 044 25.461 25 .353 26 .242; 26. 915 27 .910 28 .3631 29.430 29. 794 25 .595 26 .261 24 .289 23 .543 22 .282 22 .563 23 .065 23 .230 23.406 22.436 22 .834 23 .719 23 .894 24 .048 23 .176 22 .745 23 .439 23 .098 22 .972 21.830 21 .846 11.609 14.468 1.00 49.58 12.321 11.266 11.717 12 .261 13 .561 13.705 14 .760 10.570 9.628 10.631 11 .629 9 .603 10.214 10.937 9.266 8 .161 10. 3.88 9.91.5 11.125 12 .!199 11.654 8.728 8. 1",8 8.326 7 .200 7 .334 8 .452 8 .776 9.871 10.283 5.823 4.798 5.815 4.588 4 .529 4.067 4.857 3 .988 6.208 2.793 2 .737 4.430 6.647 5 .756 4 .499 3.451 5 .572 5 .642 7.095 7.836 9.559 14 .375 13.430 12.092 11.425 12.020 11.727 11.507 11 .276 10.892 11.010 11.521 10.237 10. 035 11.314 8 .907 8.402 8.343 7.058 6.466 6 .040 7.464 7.163 6.153 8.389 8.612 9.979 10. 001 11.400 11.385 12.. 7 77 8.413 8. 512 8. 156 7.884 8.760 10. 197 11.283 12.393 11. 430 10.690 11.997 13 .636 12.670 13.749 6.385 5. 900 5. 64t 4.232 3. 792 4.391 3.877 1.00 47.38 1.00 46.26 1.00 44.75 1.00 43.49 1.00 43.01 1.00 42.40 1.00 40.19 1.00 43.58 1.-00 43.68 1.00 40.72 1.00 40.27 1.00 36.86 1.00 36.67 1.00 36.84 1.00 33.34 1.00 33.65 1.00 31.26 1.00 30.43 1.00 27.09 1.00 23.98 1.00 26.06 1.00 28.18 1.00 28.30 1.00 25.52 1.00 25.42 2.0.0 23.52 1.00 23.14 1.00 29.84 1.00 28.33 1.00 30.88.

1.00 25.26 1.00 23.05 1.00 27.05 1.00 27.17.

1.00 26.98 1.00 29.62 1.00 29.64 1.00 28.25 1.00 29.15 1.00 26.48 1.00 24.81 1.00 28.40 1.00 29.38 1.00 29.83 1.00 27.71 1.00 29.42 1.00 25.52 1.00 25.24 1.00 26.58 1.00 32.35 1.00 40.32 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 317

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1786 1787 1788 1789 1791 1792 1793 1794 1795 1796 1797 1798 1799 1800 1801 1802 1804 1805 1806 1807 1808 1809 3810 1811 1812 1814 1815 1816 1817 1818 1820 1821 1822 1823 1824 1825 1826 1827 1829 1830 1831 1832 1833 1834 1835 1836 1837 1838 1839 .1841 1842 1843

CE

C

0

N

CA

CB

C

0

N

CD

CA

CB

CG

C

0

N

CA

CE

CG

CD

OE1 0E2

C

0

N

CA

CB

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CE

CG

CD1 CD2 CE 1 CE2

CZ

C

0

N

CA

CE

CG

MET

MET

MET

ALA

ALA

ALA

ALA

ALA

PRO

PRO

PRO

PRO

PRO

PRO

PRO

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ALA

ALA

ALA

ALA

ALA

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

ASP

AS P AS P

ASP

1667 1667 1667 1668 1668 1668 1668 1668 1669 166.9 1669 1669 1669 3669 1669 1670 1670 1670 3670 1670 1670 1670 1670 1670 167.1 1671 1671 1671 1671 1672 1672 1672 1672 1672 1672 1672 1672 1673 1673 1673 1673 1673 1673 1673 1673 1673 1673 1673 1674 .1674 1674 1674 21. 033 24. 042 25.256 23.473 24.272 23.397 24.866 24.254 26.050 26. 912 26. 662 27. 868 28.249 25. 734 25.685 24. 992 24'.095 23.600 22.1504 23.223 22.444 24.474 22 9.24 22.410 22. 512 21.423 20.813 21. 984 21.400 23.138 23.807 25. 030 25.870 25.081 27.123 24 .248 23. 958 24. 924 25.414 26.699 27.826 28.524 28.205 29.580 29.265 29.954 24.413 24.364 23.651 22. 716 22. 934 24.359 9.447 4.960 5. 037 4.302 3.647 2.720 4.759 5.817 4.530 3.339 5.561 4.835 3.893 6.078 7.281 5.179 5.584 4.369 3.486 2.266 1.393 2.175 6.440 7 .236 6.265 7.040 6.292 8.365 9.414 8.300 -9.481.

9. 064 10.157 10.853 9.530 10.431 11.625 9.901 10.725 10.110 9.928 8.724 10.960 8. 54G 10.786 9.568 10.957 12.046 9.928 10.027 8.858 8.765 2 .341 3. 276 3 .411 2.282 1 .271 0.425 0.410 0.242 -0.170 -0.107 -1.005 -1 .593 -0.498 -2.108 -2.371 746 -3 .826 4.620 -3.889 -3.229 -2.794 -3.130 -3 .356 -4.123 -2.101 -1.490 -0.312 006 1.229 -0.358 0. 172 0. 986 1. 648 2. 740 2.243 -0.942 -0.898 -1.956 -3 .053 -3 .639 -2.637 -2.580 -1.779 -1.692 70.880 -0.838 -4.194 -4.760 -4.554 -5.666 -6.625 -7.121 1.00 1. 00 1. 00 1.00 1.00.

1. 00 1.00 1.00 1.00 1. 00 1.00 1.00 1. 0.0 1.00 1 .0.0 1. 00 1.00 1 .00 1. 00 1. 00 1 .00) 1. 00 1 .00 1.00 1.00 1. 00 1 .00 1.00 1. 00 1.00 1.00 1. 0.0 1.00 1. 0 1 .00 1 .00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 38.17 25.07 27.61 24.92 26-.92 25.09.

27.82 27.06 27.84 27.12 28. 04 26.71 27.49 28 .51 30.64 28.25 26.82 29.32 30.38 32.52 28.06 28.67 24.79.

22.31 26 25.67 18 .88 26. 28 .14 29.03 34.07 34.45 39.50 41.71 40.16 38.47 42 39.07 38.00 36.48 33.36 29.55 31.85 26.33 30. 28. 99 39.64 37.72 41.35 43.38 47.84 53.24 145. vOl WO 98/07835 PCTIIJS97/14885 318 -ATOM 1844 ODi ASP 1674 25.049 9.808 -7.172 1.00 56.20 ATOM .1845 0D2 ASP 1674 24.786 7.640 -7.460 1.00 55.73 ATOM 1846 C ASP 1674 21.239 10.083 -5.321 1.00 45.94 ATOM 1847 0 ASP 1674 20-.402 10.200 -6.222 1.00 47.80 ATOM 1848 N ARG 1675 20.903 9.953 -4.040 1.00 45.98 ATOM 1850 CA ARG 1675 19.503 9.981 -3.608 1.00 43.76 ATOM 1851 CB ARG 1675 18.872 11.346 -3.887 1.00 48.61 ATOM 1852 CG ARG 1675 19.519 12.478 -3.142 1.00 58.37 ATOM 1853 CD ARG 1675 19.468 13:715 -3.992 1.00 70.39 ATOM 1854 NE ARG 1675 20.035 14.867 -3.306 1.00 79.14 ATOM 1856 CZ ARG 1675 19.612 16.116 -3.472 1.00 82.95 ATOM 1857 NH1 ARG 1675 18.610 16.386 -4.308 1.00 82.00 ATOM 1860 NH2 ARG 1675 20.194 17.097 -2.793 1.00 87.42 ATOM 1863 C ARG 1675 18.647 8.882 -4.236 1.00 39.26 ATOM 1864 0 ARG 167-5 17.461 9.074 -4.488 1.00 37.29 ATOM 1865 N ILE 1676 -19.270 7.746 -4.526 1.00 35.86 ATOM 1867 CA ILE 1676 18.544 6.614 -5.081 1.00 32.76 ATOM 1868 CB ILE 1676 19.324 5.927 -6.192 1.00 31.73.

ATOM 1869 CG2 ILE 1676 18.450 4.902 -6.868 1.00 30.02 ATOM 1870 CG1 ILE 1676 19.767 6.955 7.219 1.00 32.68 ATOM 1871 CD1 ILE 1676 20.658 6.371 -8.272 1.00 35.75 ATOM 1872 C ILE 1676 18.329 5.625 -3.946 1.00 31.08 ATOM 1873 0 ILE 1676 19.264 4.962 -3.505 1.00 28.77 ATOM 1874 N TYR 1677 17.1.02 5.558 -3.444 1.00 30.32 ATOM 1876 CA TYR 1677 .16.779. 4.653 -2.348 1LOO 29.68 ATOM 1877 CB TYR 1677 15.846 5.329 -1.354 1.00 31.14 ATOM 1878 CG TYR 1677 16.523 6.395 -0.514 1 00 32.95 ATOM 1879 CD1 TYR 1677 16.616 7.721 0.958 1.00 30.40 ATOM 1880 CEl TYR 1677 17.208 8.707 -0.171 1.00 27.57 ATOM 1881 CD2 TYR 1677 17.048 6.082 0.743 1.00 32.13 ATOM 1882 CE2 TYR 1677 17.642 7.059 1.543 1.00 31.50 ATOM 1883 CZ TYR 1677 17.711 8.366 1.081 1.00 31.12 ATOM 1884 OH TYR 1677 18.235 9.326 1.912 1.00 32.18 ATOM 1886 C TYR 1677 16.123 3.424 -2.933 1.00 28.88 ATOM 1887 0 TYR 1677 15.268 3.537 -3.811 1.00 32.20 ATOM 1888 N THR 1678 16.556 2.253 -2.481 1.00 26.34 ATOM 1890 CA THR 1678 16.023 0.988 -2.971 1.00 25.55 ATOM 1891 CB THR 1678 16.917 0.394 -4.043 1.00 28.81 ATOM 1892 OGi THR 1678 18.221 0.179 -3.483 1.00 34.06 ATOM 1894 CG2 THR 1678 17.010 1.320 -5.267 1.00 27.25 ATOM 1895 C THR 1678 16.037 0.007 -1.827 1.00 21.78 ATOM 1896 0 THR 1678 16.505 0.312 -0.744 1.00 25.57 ATOM 1897 N HIS 1679 15.559 -1.198 -2.071 1.00 20.86 ATOM, 1899 CA HIS 1679 15.580 -2.216 -1.030 1.00 20.30 ATOM 1900 CB HIS 1679 14.816 -3.453 -1.499 1.00 17.22 ATOM 1901 CG HIS 1679 13.367 -3.196 -1.797 1.00 19.02 ATOM 1902 CD2 HIS 1679 12.662 -3.275 -2.958 1.00 14.89 ATOM 1903 ND1 HIS 1679 12.459 -2.830 -0.826 1.00 18.98 ATOM 1905 CEl HIS 1679 11.260 -2.697 -1.370 1.00 16.10 ATOM 1906 NE2 HIS 1679 11.359 -2.961 -2.663 1.00 15.18 ATOM 1908 C HIS 1679 17.050 -2.535 -0.761 1.00 20.44 ATOM 1909 0 HIS 1679 17.428 -2.901 0.356 1.00 22.58 145. vOl WO 98/07835 PCT/US97/14885 319

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

1910 1912 1913 1914 1915 1916 1917 1920 1921 1922 1924 1925 1926 1928 1929 1930 1932 1933 1934 1935 1936 1937 1.938 1939 1941 1942 1943 1944 1945 1946 1947 1949 1950 1951 1952 1953 1954 1955 1956 1958 1959 1960 1961 1962 1963 1965 1966 1967 1969 1970 1971 1973 N GLN CA GLN CB GLN CG GLN CD GLN OE1 GLN NE2 GLN C GLN 0 GLN N SER CA SER CB SER OG SER C SER 0 SER N ASP CA ASP CB ASP CG ASP ODI ASP OD2 ASP C ASP 0 ASP N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL D VAL N TRP CA TRP CB TRP CG TRP CD2 TRP CE2 TRP CE3 TRP CD1 TRP NEl TRP CZ2 TRP CZ3 TRP CH2 TRP C TRP O TRP N SER CA SER CB SER OG SER C SER O SER N PHE CA PHE 1680 1680 1680 1680 168.0 1680 1680 1680 1680 1681 1681 1681 1681 1681 1681 1682 1682 1682 1682 1682 1682 1682 1682 1683 1683 1683 1683 1683 1683 1683 1684 1684 1684 1684 1684 1684 1684 1684 1684 1684 1684 1684 1684 1684 1685 1685 1685 1685 1685 1685 1686 1686 17.874 19.303 19.935 19. 934 18.949 17. 931 19.256 19.985 20.875 19.605 20.239 19. 923 18. 544 19.852 20.645 18.659 18.180 16.730 15.678 14.500 15.992 19.076 19.385 19.474 20.354 20. 543 21.770 19.320 21.674 22. 161 22.207 23.424 23.711 24.859 26.182 26.929 26.813 24.857 26.097 28.275 28.165 28.872 23.201 23.931 22.150 21.787 20.429 20. 318 21.747 22.145 21.260 21.174 -2.310 -2.539 -2.427 -3.711 -3.687 -3.000 -4.409 -1.559 -1.943 -0.286 0.678 2.128 2.326 0.364 0.609 -0.210 -0.604 -1.111 0.004 0.245 1.102 1.736 -1.799 -2.635 -3.737 -4.741 -5.613 -5.618 153 -3.570 -2.143 -1.482 -0.224 0.609 0.686 1.559 0.102 1.430 1.994 1.859 0.409 1.274 -1.112 -1.560 -0.342 0.086 0.768 1.626 -1.068 -0.902 -2.22-8 -3.424 -1.781 -1.721 -3.106 -3.889 -5.026 -4.961 6.091 -0.797 -0.039 -0.867 0.030 -0.346 -0.545 1.464 2.366 1.670 3.003 2.963 3.132 2.786 3.639 3.517 4.709 2.620 3.003 1.837 2.039 1. 736 3.523 4.573 2.837 3.295 2.463 2.970 2.421 3.249 1.315 4.075 4.246 3.000 1. 072 1.908 4.771 5.652 5.032 6.386 6.356 5.220 7.389 8.545 6.946 7.800 1.00 .20.58 1.00 22.70 1.00 26.26 1.00 31.86 1.00 37.54 1.00 42.70 1.00 37.42 1.00 24.93 1.00 26.39 1.00 24.70 1.00 23.24 1.00 19.33 1.00 18.55 1.00 21.77 1.00 24.14 1.00 21.80 1.00 22.45 1.00 25.27 1.00 28.21 1.00 25.41 1.00 30.19 1.00 23.69.

1.00 24.74 i.00 23.49 1.00 21.77 1.00 20.49 1 00 19.82 I.00 19.29 1.00 21.93 1.00 21.06 1.00 20.64 1.00 20.98 1.00 19.56 1.00 23.22 1.00 24.64 1.00 24.69 1.00 26.41 1.00 23.64 1.00 23.28 1.00 20.55 1.00 22.82 1.00 19.24 1.00 21.12 1.00 22.08 1.00 23.27 1.00 22.54 1.00 21.98 1.00 25.48 1.00 21.33 1.00 19.52 1.00 23.10 1.00 23.09 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 320

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1985 1986 1987 1988 1990 1991 1992 1993 1994 1995 1996 1998 1999 2000 2001 2002 2003 2004 2005 2007 2008 2009 2010 2011 2012 2013 2014 2016 2017 2018 2019 2020 2021 2022 2023 2025 2026 2027 2028 2029 2030 2032 CB PHE 1686

CG

CD

CD

CE

CE

CZ

C

0

N

CA

C

0

N

CA

CB

CG

CG

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD2 CE2 CE3 CD1 NEl CZ2 CZ3 CH2

C

0

N

CA

PHE

1 PHE 2 PHE I PHE 2 PHE

PHE

PHE

PHE

GLY

GLY

GLY

GLY

VAL

VAL

VAL

1VAL 2 VAL

VAL

VAL

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

GLU

GLU

1686 1686 1686 1686 1686 1686 1686 1686 1687 1687 168.7 1687 1688 1688 1688 1688 1688 1688 1688 1689 1689 1689 1689 1689 1689 1689 1689 1690 1690 1690 1690 1690 1690 1690 1690 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1692 1692 20.409 -4.550 7.095 20.192 -5.767 7.962 19.378 -5.694 9.096 20.808 -6.987 7.649 19.185 -6.809 9.913 20.622 -8.109 8.455 19.809 -8.023 9.585 22.569 -3.919 8.240 22.739 -4.450 9.350 23.553 -3.773 7.358 24.913 4.163 7.685 25.407 -3.276 8.822 26.094 -3.755 9.727 25.008 -1.996 8.794 25.372 -1.024 9.831 25.048 0.458 9.423 25.439 1.424 10.540 25.820 0.846 8.161 24.62] -1.403 31.100 25.204 -1.420 12.187 23.339 -1.734 10.969 22.542 2.161 12.122 21.072 -2.392 11.714 19.981 -2.42"7 12.805 18.614 -2.295 12.164 20.048 -3.700 13.658 23.158 -3.447 12.717 23.202 -3.592 13.937 23:614 -4.379 11.871 24.256 -5.604 i2.376 24.730 -6.533 11.255 23-.809 -7.501 10.515 24.662 -8.259 9.523 23.135 -8.487 11.458 25.471 -5.204 13.189 25.710 -5.747 14.273 26.240 -4.255 12.660 27.431 -3.761 13.341 28.129 -2.706 12.493 29.456 -2.268 13.039 29.701 -1.163 13.925 31.100 -1.070 14.103 28.870 -0.236 14.575 30.688 -2.798 12.736 31.675 -2.078 13.371 31.690 -0.085 14.900 29.459 0.745 15.371 30.861 0.812 15.523 27.114 -3.195 14.727 27.871 .3 .393 15.662 25.985 -2,506 14.862 25.574 -1.938 16.155 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.00 1.0 1.00 1.00 1.00C 1.00C 1.00 1. 00 1.00 1.00 1.00 1.310 1. 00 1. 00 1. 00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1. 00 1.00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 0 22.77 0 25.82 0 25.54 0 23.88 0 24.25.

0 22.67 0 26.30 0 21.77 0 20.47 0 20.63 0 19.29 0 21.64 19.46 22.19 21.99 23.20 21.22 21.,25 I 23.33 I 24.98 24.36 23.92 22 57 23.41 19.14 22. 25.22 25.58 25.47 26.26 26.22 26.21 25.45 21.17 26.51 29.07 26.26 25.08 25.16.

27.49 25.81 22.63 26.70 23.03 25.19 18.66 25.66 23.00 24.63 27.79 26.48 24.98 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 321

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2033 2034 2035 2036 2037 2038 2039 2040 2042 2043 2044 2045 2046 2047 2048 2049 2051 2052 2053 2054 2055 2056 2057 2058 2059 2060 2061 2063 2064 2065 2067 2068 2069 2070 2072 2073 2074 2075 2076 2077 2078 2079 2081 2082 2083 2084 2086 2087 2088 2089 2091 2092 CB GLU CG GLU CD GLU OE1 GLU OE2 GLU C GLU O GLU N ILE CA ILE CB ILE CG2 ILE CG1 ILE CDI ILE C ILE O ILE N PHE CA PHE CB PHE CG PRE CDI PHE CD2 PHE CEI PHE CE2 PHE CZ PHE C PHE 0 PHE N THR CA THR CB THR OGI THR CG2 THR C THR O TER.

N LEU CA LEU CB LEU CG LEU CDI LEU CD2 LEU C LEU O LEU N GLY CA GLY C GLY O GLY N GLY CA GLY C GLY O GLY N SER CA SER CB SER 1692 1692 1692 1692 1692 1692 1692 1693 1693 1693 1693 1693 1693 1693 1693 1694 16.94 1694 1694 1694 1694 1694.

1694 .1694 1694 1694 1695 1695 1695 1695 1695 1695 1695 1696 1696 1696 1696 1696 1696 1696 1696 1697 1697 1697 1697 1698 1698 1698 1698 1699 1699 1699 24.335 24.507 23.255 22 433 23.067 25.260 25.602 24.593 24.231 23.373 23.171 22.005 21.208 25.496 25.672 26.442 27.664 28.261 27.315 26.793 26.844 25. 808 25.863 25.337 28.663 29.697 28.344 29.170 29.665 28.553 30.538 28.307 28.707 27.130 26.188 26.704 26.974 27.447 25.726 25.892 26.083 25.386 25.072 26.241 26.297 27.177 28.319 27.966 27.115 28.633 28.413 28.747 060 0.107 0.933 0 704 1.815 -3.036 -2 .927 087 -5.214 -6.287 -7.564 682 -6 .485 -5.847 -5.961 -6 .133 779 -7.598 -8.649 -8 .599 "9.625 -9.505 -10. 533 -10.'478 906 -6.403 -4.616 -3 .698 -2.474 :I710 -2 -914 -3.230 -2 346 3. 841 -3 .523 -4 043 -5.539 843 -6.297 -2.036 -1.457 -1.432 016 0.847 2. 035 0.261 1.023 2.109 1.929 3.247 4.385 5.692 15.994 1.00 22.29 15.056 1.00 18.31 14.978 14.066 15.840 17.163 18.341 16.698 17.555 16.777 17.638 16.382 15.346 38.107 19.316 17.229 17.679 16.542 16.048 14.770 16.919 14.370 16.536 15.268 18.438 18. 902 18.575 19.348 18. 535 18.046 17.395 20.519 21.289 20.651 21.720 23.060 23.194 24.597 22.907 21.837 22.889 20.771 20.811 20.381 20.701 .19.639 19.178 18.173 17.301 18.295 17.414 18.164 1.00 25.10 1.00 26.95 1.00 27.05 1.00 25.18 1.00 26.12 1.00 27.16 1.00 25.91 1.00 25.70 1.00 18.73 1.00 23.45 1.00 15.62 1.00 26.70 1.00 28.19 1.00 28.78 1.00 29.72 1.00 27.18 1.00 25.38 1.00 26.16 1.00 26.37 1.00 31.37 1.00 25.23 1.00 29.46 1.00 30.92 1.00 32.23 1.00 29.46.

1.00 27.17 1.00 23.32 1.00 24.73 1.00 21.34 1.00 28.81 1.00 31.85 1.00 26.30 1.00 25.99 1.00 24.51 1.00 23.32 1.00 26.45 1.00 29.79 1.00 24.90 1.00 28.99 1.00 25.05 1.00 24.31 1.00 27.15 1.00 29.57 1.00 27.33 1.00 27.04 .1.00 29.78 1.00 32.03 1.00 30.60 1.00 31.48 1.00 32.97 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 322 ATOM 2093 OG SER 1699 28.350 6.848 17.436 1.00 37.75 ATOM 2095 C SER 1699 29.323 4.239 16.188 1.00 32.74 ATOM 2096 0 SER 1699 30.541 4.034 16.321 1.00 33.04 ATOM 2097 N PRO 1700 28.732 4.276 14. 979 1.00 31.40 ATOM 2098 CD PRO 1700 27.288 4.320 14. 688 1.00 30.88 ATOM 2099 CA PRO 1700 29.507 4.153 13:737 1.00 30.55 ATOM 2100 CB PRO 1700 28.420 4.024 12.657 1.00 30.13 ATOM 2101 CG PRO 1700 27.228 3.535 13.398 1.00 31.10 ATOM 2102 C PRO 1700 30.300 5.427 13.509 1.00 31.19 ATOM 2103 0 PRO 1700 29.766 6.522 13.651 1.00 35.48 ATOM 2104 N TYR 1701 31.574 5.277 13.175 1.00 29.51 ATOM 2106 CA TYR 1701 32.446 6.412 12.899 1.00 30.10 ATOM 2107 CB TYR 1701 32.084 7.029 11.541 1.00 32.84 ATOM 2108 CG TYR 1701 32.102 6.078 10.353 1.00 38.43 ATOM 2109 CD1 TYR 1701 30.921 5.795 3.643 1.00 40.14 ATOM 2110 CEl TYR 1701 30.930 5.000 8.513 1.00 39.07 ATOM 2111 CD2 TYR 1701 33.298 5.522 9.890 1.00 38.19 ATOM 2112 CE2 TYR 1701 33.320 4.726 8.754 1.0.0 41.52 ATOM 2113 CZ TYR 1701 32.134 4.471 8.067 1.00 44.97 ATOM 2114 OH TYR 1701 32.151 3.700 6.919 1.00 54.77 ATOM 2116 C TYR 1701 32.426 7.524 13. 965 1.00 30.38 ATOM 2117 0 TYR 1701 32.009 8.655 13.685 00 30.54 ATOM 2118 N PRO 1702 32.947 7'.239 15.170 1.00 30.61 ATOM 2119 CD PRO 1702 33 .578 5.985 15.608 1.00 29.72 ATOM 2120 CA PRO 1702 32'.971 8.239 16.2413 1.00 28.48 -ATOM 2121 CB PRO 1702 33.554 7.463 :17.429 1.00 28.43 ATOM 2122 CG PRO 1702 33.320 6. 025 17.085 1.00 30.63 ATOM 2123 C PRO 1702 33.897 9.385 15.881 1.00 26.93 ATOM 2124 0 PRO 1702 34.998 9.156 15.418 1.00 26.21 ATOM 2125 N GLY 1703 33.440 10.613 16.084 1.00 29.51 ATOM 2127 CA GLY 1703 34.239 11.787 15.767 1.00 28.57 ATOM 2128 C GLY 1703 34.374 12.143 14.296 1.00 28.97 ATOM 2129 0 GLY 1703 35.055 13.104 13.962 1.00 29.54 ATOM 2130 N VAL 1704 33.726 11.380 13.418 1.00 30.90 ATOM 2132 CA VAL 1704 33.798 11.616 11.975 1.00 29.48 ATOM 2133 CB VAL 1704 .33.806 10.289 11.228 1.00 28.23 ATOM 2134 CG1 VAL 1704 34.074 10.525 9.750 1.00 31.57 ATOM 2135 CG2 VAL 1704 34.851 9.375 11.822 1.00 28.40 ATOM 2136 C VAL 1704 32.620 12.466 11.477 1.00 33.14 ATOM 2137 0 VAL 1704 31.466 12.045 11.529 1.00 35.67 ATOM 2138 N PRO 1705 32.906 13.681 10.979 1.00 35.22 ATOM 2139 CD PRO 1705 34.217 14.348 11.008 1.00 38.03 ATOM 2140 CA PRO 170.5 31.868 14.587 10.474 1.00 35.96 ATOM 2141 CB PRO 1705 32.534 15.953 10.627 1.00 35.84 ATOM 2142 CG PRO 1705 33.939 15.661 10.279 1.00 37.29 ATOM 2143 C PRO 1705 31.473 14.293 9.031 1.00 37.17 ATOM 2144 0 PRO 1705 32.255 13.690 8.288 1.00 38.39 ATOM 2145 N VAL 1706 30.296 14.780 8.624 1.00 36.10 ATOM 2147 CA VAL 1706 29.743 14.582 7.276 1.00 37.10 ATOM 2148 CB VAL 1706 28.667 15.658 6.942 1.00 38.36 ATOM 2149 CG1 VAL 1706 28.106 15.441 5.-535 1.00 38.93 ATOM 2150 CG2 VAL 1706 27.536 15.595 7.952 1.00 40.79 SSSD/55145. vOl WO 98/07835 PCT/US97/14885" 323

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

.ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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ATOM

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ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2152 2152 2153 2155 2156 2157 2158 2159 2161 2162 2163 2164 2165 2166 2167 2168 2169 2171 2172 2173 2174 2175 2176 2177 2178 2180 2181 2182 2183 2184 2185 2186 2187 2188 2189 2190 2192 2193 2194 2195 2196 2197 2201 2202 2203 2205 2206 2207 2208 2209 2210 2211

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD

OE1 OE2

C

0

N

CA

CB

CG

CDI

CD2

C

0

N

CA

CB

CG

CD1 CD2

CEI.

CE2

CZ

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG

CD1 CD2

C

0

VAL

VAL

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

1706 1706 1707 1707 1707 1707 1707 1708 1708 1708 1708 1708 1708 1708 1708 1708 1709 1709 1709 1709 1709 1709 1709 1709 1710 1710 1710 1710 1710 1710 1710 1710 1710 1710 1710 1711 1711 1711 1711 1711 1711 1711 1711 1711 1712 1712 1712 1712 1712 1712 1712 1712 30.762 30.927 31.477 32.472 33.059 33.588 34.153 33.936 34.981 35.555 36.212 37.471 38.199 37. 747 34-- 369 35.035 33 .089 32.376 30.975 30.065 30.652 28 .717 32 .291 32.490 32.011 31.915 31.658 30.287 29.287 29.991 28.012 28.715 27.725 33.202 33.183 34.310 35.664 36.642 38.103 38.981 40.413 41.116 35.999 36.670 35.541 35.776 35.241 35.971 35.186 37.389 35.022 35.571 14.559 13.543 15.663 15.793 17.206 14.762 14.445 14.273 13.256 13.178 14.464 14.871 13.986 16,092 11.911 11. 045 11. 745 10. 519 10. 531 9.366 8.036 9.574 -10.325 9.209 11. 408 11.333 12.710 13.231 12.395 14.565 12.882 15.058 14.208 10.771 9.815 11.336 10.971 11.932 11.716 12.731 12.686 11.422 9.501 8.836 9.000 7.599 7.295 7.870 7.593 7.297 6.738 5.796 6.138 5.461 5.967 4 .910 4.918 4 .945 3.908 6.132 6 .241 7.660 8.179 7.430 6.909 7.392 5.855 5.260 6.178 5.860 6.474 6.073 6.503 6.597 4.350 3.856 3.623 2.169 1.567 1.827 2.303 1.613 2.566 1.875 2.354 1.609 0.825 2.085 1.697 2.379 2.042 2.755 2.238 2.600 2.015 1.231 3.164 3.532 4.942 6.166 7.440 6.266 2.530 1.957 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 i. 00 1.00 1 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 00 1.00 1.00 1.00 .1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 37.09 38.75 37.08 35.52 38.30 34.20 33.48 34.20 36. 08 40.39 45.41 50.66 54. 73 52. 35.22 34 .04 33.30 31.44 26.89 26.05 22.75 26.15 31.18 29.88 30.16 31.64 33.44 37.78 41.46 40.72 41.30 42.99 40.95 32.38 32.26 31.26 29.73 33.49 39.79 43.35 46.23 53.67 29.34 28.77 30.40 28.72 27.71 28.23 20.80 27.01 30.03 29.28 SSSD/55145. vOl WO 98/07835 PCT/US97/14885' 324 ATOM 2212 N LEU 1713 33.752 7.073 2.325 1.00 31.98 ATOM 2214 CA LEU 1713 32.904 6.339 1.403 1.00 34.30 ATOM 2215 CB LEU 1713 31.467 6.872 1.447 1.00 37.65 ATOM 2216 CG LEU 1713 30.663 6.450 2.686 1.00 37.06 ATOM 2217 CD1 LEU 1713 29.367 7.217 2.781 1.00 36.80 ATOM 2218 CD2 LEU 171-3 30.399 4.950 2.641 1.00 37.02 ATOM 2219 C LEU 1713 33.451 6.344 -0.011 1.00 35.45 ATOM 2220 0 LEU 1713 33.468 5.298 -0.662 1.00 38.18 ATOM 2221 N LYS 1714 33.920 7.498 -0.481 1.00 33.22 ATOM 2223 CA LYS 1714 34.487 7.590 -1.821 1.00 31.46 ATOM 2224 CB LYS 1714 34.881 9.027 -2.158 1.00 31.32 ATOM 2225 CG LYS 1714 33.724 9.962 -2.399 1.00 33.49 ATOM 2226 CD LYS 1714 32.814 9.439 -3.491 1.00 39.40 ATOM 2227 CE LYS 1714 31.613 10.364 -3.720 1.00 44.79 ATOM 2228 NZ LYS 1714 30.674 9.841 -4.771 1.00 50.41- ATOM 2232 C LYS 1714 35.706 6.678 -1.953 1.00 32.53 ATOM 2233 0 LYS 1714 35*.998' 6.155 -3.025 1.00 35.46 ATOM 2234 N GLU 1715 36.420 6.488 -0.856 1.00 33.50 ATOM 2236 CA GLU 1715 37.602 5.644 -0.864 1.00 34.92 ATOM 2237 CB GLU 1715 38.617 6.177 0.143 1.00 37.20 ATOM 2238 CG GLU 1715 39.085. 7. 571 -0.221 1.00 44.59 ATOM 2239 CD GLU 1715 39.654 8.372 0.946 1..0 51.44 ATOM 2240 QEl GLU 1715 39.820 7.826 2.065 1.00 51.40 ATOM 2241 0E2 GLU 1715 .39.930 9.573 0.726 1.00 54.23 ATOM 2242 C GLU 1715 37.278 4.183 -0.581 1.00 35.09 ATOM 2243 0 GLU 1715 38.184 3.357 0.482 1.00 37.59 ATOM 2244 N GL.Y 1716 35.991 3.866 -0.455 1.00 33.79 ATOM 2246 CA GLY 1716 35.576 2.498 -0.197 1.00 30.96 ATOM 2247 C GLY 1716 35.852 1:976 1.198 1.00 29.06 ATOM 2248 0 GLY 1716 35.906 0.766 1.416 1.00 29.28 ATOM 2249 N HIS 3.717 35.995 2.8.79 2.155 1. 00 28.16 ATOM 2251 CA HIS 1717 36.282 2.489 3.532 1.00 29.80 ATOM 2252 CB HIS 1717 36.534 3.743 4.378 1.00 33.13 ATOM 2253 CG HIS 1717 36.794 3.469 5.826 1.00 36.22 ATOM 2254 CD2 HIS 1717 37.955 3.375 6.516 1.00 35.38 ATOM 2255 NDl HIS 1717 35.782 3.279 6.746 1.00 37.81 ATOM 2257 CEl HIS 1717 36.309 3.080 7.942 1.00 36.97 ATOM. 2258 NE2 HIS 171.7 37.624 3.134 7.830 1.00 35.83 ATOM 2260 C HIS 1717 35.171 1.645 4.153 1.00 29.26 ATOM 2261 0 HIS 1717 33.987 1.900 3.940 1.00 31.43 ATOM 2262 N ARC 1718 35.571 0.666 4.955 1.00 28.11 ATOM 2264 CA ARC 1718 34.632 -0.212 5.640 1.00 30.67 ATOM 2265 CB ARG 1718 34.592 -1.583 4.973 1.00 27.32 ATOM 2266 CG ARG 1718 34.058 -1.586 3.557 1.00 28.77 ATOM 2267 CD ARC 1718 32.609 -1.111 3.484 1.00 28.84 ATOM 2268 NE ARG 1718 32.032 -1.167 2.131 1.00 24.96 ATOM 2270 CZ ARG 1718 32.141 -0.206 1.204 1.00 23.90 ATOM 2271 NH1 ARG 178 32.824 0.912 1.454 1.00 20.04 ATOM 2274 N112 ARC 1718 31.513 -0.338 0.045 1.00 20.04 ATOM 2277 C ARC 1718 .35.091 -0.350 7.101 1.00 33.92 ATOM 2278 0 ARC 1718 36.300 -0.449 7.377 1.00 36.48 ATOM 2279 N MET 1719 34.134 -0.355 8.028 1.00 33.22 SSSD/55145. vOl WO 98/07835 PCT1US97/14885 325 ATOM 2281 CA MET 1719 34.428 -0.459 9.448 1.00 32.33 ATOM 2282 CB MET 1719 33.148 -0.285 10.277 1.00 34.72 ATOM 2283 CG MET 1.719 32.454 1.066 10.076 1.00 35.04 ATOM 2284 SD MET 1719 31.025 1.447 11.141 1.00 34.06 ATOM 2285 CE MET 1719 29.757 0.470 10.409 1.00 33.14 ATOM 2286 C MET 1719 35.068 -1.797 9.747 1.00 35.53 ATOM. 2287 0 MET 1719 34.896 -2.756 8.991 1.00 35.48 ATOM 2288 N ASP 1720 35.826 -1.843 10.840 1.00 3 8 ATOM 2290 CA ASP 1720 36.521 -3.049 11.281 1.00 39.03 ATOM 2291 CB ASP 1720 37.659 -2-.678 12.237 1.00 43. 11 ATOM 2292 CG ASP 1720 38.743 -1.846 11.569 1.00 46.69 ATOM 2293 ODi ASP 1720 38.587 -1.536 10.364 1.00 54.08 ATOM 2294 OD2 ASP 1720 39.750 -1.503 12.239 1.00 45.93 ATOM 2295 C ASP 1720 35.580 -4.023 11.972 1.00 38.-SO ATOM -2296 0 ASP 1720 34.554 -3.617 12.528 1.00 37. 73' ATOM 2297 N LYS 1721 35.961 -5.298 11.981 1.00 38.10 ATOM 2299 CA LYS 1721 35.151 -6.339 12.600 1.00 38.12 ATOM 2300 CE LYS 1721 35.727 -7.733 12.323 1.00 38.20 ATOM 2301 CG LYS 1721 34.825 -8.858 12.825 1.00 38.48 ATOM 2302 CD LYS 1721 35.375 -10.238 12.543 1.00 37.49 ATOM 2303 CE LYS 1721 36.32.0 -10.691 13.625 1.00 39 11 ATOM 2304 NZ LYS 1721 36.448 -12.167 13.628 1.00 .40.75 ATOM 2308 C LYS 1721 35.092 -6.142 14.091 1.00 40.24 ATOM 2309 0 LYS 1721 .36.136 -6.032 14: 73 9 1 0 42.70 ATOM 2310 N PRO 1722 33.875 -6-.082 14.658 1.00 41.23 ATOM 2311 CD PRO 1722 32.547 153 14.019 1.00 38.63 ATOM 2312 CA PRO 1L722 33.743 -5.901 16.104 11.00 41.71 ATOM 2313 CE PRO 1722 32.223 -5.957 16.306 1. 00 38.90 ATOM 2314 CG PRO 1722 .31.6-79 -5.442 15.016 1.00 34.19 ATOM 2315 C PRO 1722 34.418 -7.079 16.819 1.00 43.96 ATOM 2316 0 PRO 1722 34.542 -8.174 16.250 1.00 43.02 ATOM 2317 N SER 1723 34.915 -6.860 18.028 1.00 46.76 ATOM 2319 CA SEP 1723 35.493 -7.973 18.747 1.00 50.74 ATOM 2320 CE SER 1723 36.265 -7.500 19.980 1.00 49.47 ATOM 2321 OG SER 1723 35.400 -7.130 21.035 1.00 53.87 ATOM 2323 C SER 1723 34.259 -8.782 2.9.143 1.00 53.24 ATOM 2324 0 SER 1723 33.136 -8.259 19.130 1.00 53.97.

ATOM 2325 N ASN 1724 34.443 -10.064 19.426 1.00 56.59 ATOM 2327 CA ASN 1724 33.316 -10.899 19.825 1.00 59.55 ATOM 2328 CB ASN 1724 32.739 10.3 86 21.162 1.00 66.12 ATOM 2329 CG ASN 1724 33.824 -10.128 22.213 1.00 71.34 ATOM 2330 ODi ASN 1724 34.661 -10.990 22.485 1.00 73.38 ATOM 2331 ND2 ASM 1724 33.831 -8.926 22.779 1.00 74.19 ATOM 2334 C ASN 1724 32.256 -10.900 18.711 1.00 57.31 ATOM 2335 0 ASN 1724 31.073 -10.662 18.940 1.00 59.27 ATOM 2336 N CYS 1725 32.723 -11.132 17.493 1.00 54.50 ATOM 2338 CA CYS 1725 31.881 -11.203 16.300 1.00 50.89 ATOM 2339 CE CYS 1725 31.827 -9.848 15.576 1.00 50.09 ATOM 2340 SG CyS 1725 30.893 -9.833 14.006 1.00 44.81 ATOM 2341 C CYS 1725 32.596 -12.235 15.439 1.00 47.28 ATOM 2342 0 CYS 1725 33.820 -12.172 15.288 1.00 48.97 ATOM 2343 N THR 1726 31.863 -13.229 14.950 1.00 42.60 145. vOl WO 98/07835 PCT/US97/14885 326

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2345 2346 2347 2349 2350 2351 2352 2354 2355 2356 2357 2358 2361 2362 2363 2365 2366 2367 2368 2369 2370 2371 2372 2373 .2375 2376 2377 2378 2379 2380 2381 2382 2384 2385 2386 2387 2388 2389 2390 2391 2392 2394 2395 2396 2398 2399 2400 2401 2402 2403 2404 2405 CA THR CB THR OG1 THR CG2 THR C THR 0 THR N ASN CA ASN CB ASN CG ASN ODI ASN ND2 ASN C ASN O ASN N GLU CA GLU CB GLU CG GLU CD GLU OEl GLU OE2 GLU C GLU 0 GLU N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU C LEU N TYR CA TYR CB TYR CG TYR CD1 TYR CEI TYR CD2 TYR CE2 TYR CZ TYR OH TYR C TYR 0 TYR N MET CA MET CB MET CG MET SD MET CE MET C MET O MET N MET 1726 1726 1726 1726 1726 1726 1727 1727 1727 1727 1727 1727 1727 1727 1728 1728 1728 1728 3.728 1728 .728 1728 1728 .729 1729 1729 1729 1729 1729 1729 1729 1730 1730 1730 1730 1730 1730 1730 1730 1730 1730 1730 1730 1731 1731 1731 1731 1731 1731 1731 1731 1732 32.472 -14.275 31.520 -15.494 30.290 -15.087 31.210 -16.084 32.858 -13.748 32-.373 -12.704 33.724 -14.473 34.133 -14.044 .35.290 -14.880 36.580 -14.593 37.188 -13.539 37.010 -15.536 32.958 -14.159 32.883 -13.431 32.041"-15.076 30.854 -15.312 30.109 -16.551 28.973 -17.000 28.329 -18.306 28.409 -18.633 27.734 -18.996 29.925 -14.104 29.521 -13.574 29.608 -13.671 28.741 12.530 28.351 -*12.389 27.311 -13.431 27.131 -13.388 25.988 -13.167 29.359 -11.252 28.638 -10.367 30.688 -11.143 31.378 -9.959 32.849 -9.940 33.591 -8.723 33.093 -7.449 33.725 -6.324 34.759 -8.849 35.408 -7.724 34.882 -6.462 35.473 -5.316 31.287 -9.962 31.062 -8.928 31.443 -11.139 31.366 -11.313 31.611 -12.779 31.315 -13.149 31.801 -14.840 32.926 -14.502 29.992 -10.869 29.863 -10.268 28.971 -11.153 14.139 13.984 13.363 15.326 12.776 12.357 12.080 10.742 10.221 10 .953 10.781 11.778 9.786 8 .793 10.093 9.273 9.765 8.855 9.297 10.504 8.440 9.313 8.272 1.0.527 10. 710 12.170 12.E75 :4.089 11.842 10.175 9.693 10.251 9.734 1.0.154 9.649 9.879 9.378 8.904 8.393 8.631 8.111 8.208 7.585 7.623 6.187 5.840 4.403 3.994 2.606 5.695 4.619 6.501 1.00 39.22 1.00 36.36 1.00- 36.62 1.00 33.12 1.00 37.99 1.00 39.57 1.00 37.02 1.00 38.17 1.00 40.63 1.00 44.79 1.00 46.57 1.00 48.30 1.00 38.22 1.00 39.53 1.00 37.33 1.00 34.24 1.00 32.82 1.00 35.84 1.00 42.16 1.00 46.78 1.00 38.81 1.00 33.05 1.00 29.58 1.00 32.09 1.00 32.45 1. 00 32.64 1.00 34.65 1.00 37. 18 1.00 27 .77 1.00 32.68 1.00 33.97 1.00 31.70 1.00 30.19 1.00 27.88 1.00 26.63 1.00 27.37 1.00 27.56 1.00 24.07 1.00 24.81 1.00 28.56 1.00 29.08 1.00 29.50 1.00 29.16 1.00 31.05 1.00 34.59 1.00 41.42 1.00 52.20 1.00 64.38 1.00 63.03 1.00 34.53 1.00 35.08 1.00 33.32 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 327

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

-ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2407 2408 2409 2410 2411 2412 2413 2414 2416 2417 2418 2419 2420 2421 2422 2423 2425 2426 2427 2428 2429 2431 2432 2435 2438 2439 2440 2442 2443 2444 2445 2446 2447 2448 2449 2451 2452 2453 2454 2455 2456 2458 2459 2460 2461 2462 2463 2464 2465 2467 2468 2469

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CE

CG

CD

NE

cz

NH]

NH2

C

0

N

CA

CB

CG

OD1 0D2

C

0

N

CA

CB

SG

C

0

N

CA

CB

CG

CD2 CE2 CE 3 CD1 N'E 1 CZ2 CZ3 CH2

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ASP

ASP

AS P

ASP

ASP

ASP

ASP

ASP

CYS

CYS

CYS

CYS

CYS

CYS

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

1732 1732 1732 1732 1732 1732 1732 1733 1733 1733 1733 1733 1733.

1733 1733 1734 1734 1734 1734 1734 1734 1734 1734 1734.

1734 1734 1735 1735 1735 1735 1735 1735 3. 735 1735 1736 1736 1736 1736 1736 1736 1737 1737 1737 1737 1737 1737 1737 1737 1737 1737 1737 1737 27.594 26.634 25.172 24.071 23.738 27.484 26.794 28.139 28.161 29.001 28 .368 29.375 29.106 28.830 28.357 29.932 30.673 32.012 32 .953 33 .159 33 .864 35.187 35.967 35.729 29.873 3.0.029 29.036 28.193 27.591 28.632 29- 626 28.458 27.082 26.692 26.574 25.538 25.005 23.978 26.104 25.377 27.401 28.080 29.107 28.558 29.254 28.387 30.538 27.317 27.210 28.760 30.910 30 .025 -10.770 -11 .346 -11 .071 -11.709 -13 .369 -9.243 -8.680 -8 .586 -7.128 -6.665 -6.906 -6 .210 7..395 -6.623 -5.682 -7.269 -6 .889 -7 .623 7.267 -5 .766 -5.243 -5.305 -5.861 -4.850 -7.098.

-6 .334 -8 .137 -8.412 -9.811 -10.895 10.645 -11.990 -7.375 .992 -6.929 5.887 -5.692 -7.013 -4.542 -3.732 -4.325 -3.113 -2.682 -2.415 -2.564 -2.122 -3.027 -1.914 -1.732 -2.125 -3.031 -2.584 6.194 7.236 6 .938 8 .183 7.471 6. 158 5. 303 7 .114 7.189 8 .376 9.710 11.021 12.280 5. 921 5.281 5. 551 4.355 4.308 5.451 5. 558 4.393 4.223 5. 148 3 .094 3 .065 2.121 3. 025 1.859 1. 933 1.773 1. 052 2.366 1. 760 0.656 2 .913 2 .965 4.401 5 .053 2.456 1.887 2.670 2.248 3.291 4 .654 5. 897 6.923 6.243 4 .970 6.328 8 .276 7 .594 8 .588 1.00 31.78 1.00 30.42 1.00 30.28 1.00 27.41 1.00 22.35 1-b0 31.10 1.00 31.08 .1.00 31.22 1.00 30.93 1.00 31.91 1.00 33.63 1.00 34.53 1.00 34.12 1.00 32.49 1.00 33.61 1.00 32. 11' 1.00 31.13 1.00 28 :68 1.00 27.19 1.00 26.80 1.00 35.67 1.00 38.03.

1.00 38.07 1.00 38.87 1.0.0 29.53.

1.00 29.11 1.00 29.48 1.00 26.82 1..00 30.25 1.00 35.13 1.00 35.19 1.00 39.35 1..00 23.88 1.00 24.83 1.00 22.13 1.00 21.74 1.00 20.46 1.00 19.59 1.00 20.51 1.00 16.07 1.00 21.58 1.00 20.57 1.00 17.02 1.00 20.35 1.00 20.42 1.00 21.18 1.00 21.60 1.00 19.86 1.00 21.0.3 1.00 21..70 1.-OG 21.73 1.00 23.06 S5SD/55 145. vOl WO 98/07835 PCTIUS97/14885 328

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2470 2471 2472 2474 2475 2476 2477 2478 2480 2481 2483 2484 2485 2487 2488 2489 2490 2491 2493 2494 2495 2496 2497 2498 2499 2500 2501 2502 2503 2504 2505 2506 2508 2509 2510 2512 2513 2514 2516 2517 2518 2519 2520 2521 2524 2525 2526 2528 2529 2530 2531 2532 C TRP 0 TRP N HIS CA HIS CB HIS CG HIS CD2 HIS NDl HIS CEl HIS NE2 HIS C HIS O HIS N ALA CA ALA CB ALA

ALA

o ALA N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL O VAL N PRO CD PRO CA -PRO CB PRO CG PRO C PRO O PRO N SER CA SER CB SER OG SER C SER 0 SER N GLN CA GLN CB GLN CG GLN CD GLN OE1 GLN NE2 GLN C GLN O GLN N ARG CA ARG CB ARG CG ARG CD ARG NE ARG 1737 1737 1738 1738 1738 1738 1738 1738 1738 1738 1738 1738 1739 1739 1739 1739 1 739 1740 1740 1740 1740 1740 1740 1740 1741 1741 1741 1741 1741 1741 1741 1742 1742 1742 1742 1742 1742 1743 1743 1743 1743 1743 1743 1743 1743 1743 1744 1744 1744 1744 1744 1744 28.770 29.758 28. 269 28.885 28.263 29. 105 29.599 29.571 30.320 30.352 28 .734 27.705 29 .792 29.829 31.193 28B. 76 5 28.207 28.529 27.526 27.969 26.979 29.331 26.234 26;173 25.173 25.096 23 .868 22 .979 23.925 23.275 22 .735 23.431 22 '888 22.986 24.334 23 .553 22 .994 24.753 25.504 26.993 27.263 26.585 26.999 25.535 25.270 25 .685 24.525 24.230 23.727 24.718 24.084 24.963 -3.281 -2.607 -4.185 -4.352 -5 .522 -6.005 -5.353 -7.299 -7.422 -6.253 -3.034 -2.350 -2.658 1.437 1.285 -1 .418 -0.367 -2 .573 -2.706 -3.737 3.792 -3.375 -3.196 4.349 -2.357 065 -2.686 -1.536 -0 .410 -4.057 -4 .748 -4 .471 -5.745 -5 .819 -5 .784 -6 .978 -8.085 -6 793 -7 .910 -7.773 -7.768 -8.938 -10.087 -8.649 -8.148 -9.173 -7.244 -7.376 -6 .055 -4.909 -3.577 -2.475 0.899 0.610 O0.063 -1.243 -2.013 -3 .162 -4.246 -3.252 -4 .333 -4.954 -2.017 -1.931 -2 727 -3.517 -4 .117 -4 .617 -4.930 -5.235 -6 .292 -7 .378 -8.503 -7 .926 5.639 -5.175 5.653 6 .369 5 .058 5. 545 -5 .710 -5 .418 -4 .548 -6.674 -7.167 -8.696 -9.131 -6 .589 -6.677 -6.037 -5.485 -5 .807 -7.295 -8.014 -7.864 -8.787 -4 .007 -3.456 -3.389 976 -1.415 -1 .523 -1.134 -1 .517 1.00 24.98 1.00 25.84 1.00 27.61 1.00 25.81 1.00 24.74 1.00 26.07 1.00 25.45 1.00 24.60 1.00 24.62 1.00 23.97 1.00 26.41 1.00 25.20.

1.00 26.45 1.00 25.61 1.00 25.87 1.00 26.67 1.00 28.28 1.00 25.10 1..00 24.14 1.00 24.27 1.00 20.03 1.00 26.74.

1.00 23.91 1.00 26.37 1.00 24.55 1.00 17. 73 1.00 22.27 1.00 17.82 1.00 23.27 1.00 24.04 1.00 25.86 1.00 24. 1.00 24.42 1.00 23.95 1.00 22.98 1.00 25.20 1.00 23.68 1.00 25.46 1.00 25.64 1.00 24.02 1.00 22.75 1.00 26.21 1.00 28.67 1.00 21.57 1.00 24.86 1.00 25.24 1.00 23.38 1.00 22.41 1.00 22.24 1.00 22.53 1.00 19.82 1.00 22.51 SSSD/55145. vOl WO 98/07835 PCT/UJS97/14885 329

ATOM

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2534 2535 2538 2541 2542 2543 2544 2545 2546 2547 2548 2549 2550 2552 2553 2554 2556 2557 2558 2559 2561 2562 2563 2564 2565 2566 2567 2568 2569 2570 2571 2573 2574 2575 2576 2577 2578 2582 2583 2584 2586 2587 2588 2589 2590 2591 2594 2595 2596 .2598 2599 2600 CZ ARG NHI ARG NH2 ARG C ARG 0 ARG N PRO CD PRO CA PRO CB PRO CG PRO C PRO 0 PRO N THR CA THR CB THR OG1 THR CG2 THR C THR 0 THR N PHE CA PHE CB PHE CG PHE CD1 PHE CD2 PHE CEI PHE CE2 PHE CZ PHE C PHE 0 PHE N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS 0 LYS N GLN CA GLN CE GLN CG GLN CD GLN OE1 GLN NE2 GLN C GLN 0 GLN N LEU CA LEU CB LEU CG LEU 1744 1744 1744 1744 1744 1745 1745 1745 1745 1745 1745 1745 1746 1746 1746 1746 1746 1746 1746 1747 1747 1747 1747 1747 1747 .1747 1747 1747 1747 1747 1748 1748 1748 1748 1748 1748 1748 1748 1748 1749 1749 1749 1749 1749 1749 1749 1749 1749 1750 1750 1750 1750 24.592 23.332 25.491 23.163 22.428 23.143 24.052 22.129 22.623 23.286 20.800 20.743 19.724 18.420 17..386 17.382 17.746 18.060 18. 787 16. 953 16.536 15.442 15. 961 16. 729 15. 668 17.186 16. 124 16.883 16.062 16.248 15.490 15.048 14.471 14.050 13.633 13.244 12.213 16.257 16.161 17.397 18.617 19.692 19.338 20.442 20.175 21.699 19.177 19.586 19.267 -1.201 -0.814 -0.310 -8 .458 -8 .755 -9.155 -9.107 -10.190 -10.942 -9.864 -9.506 -8.300 -10.256 -9.697 -10.342 7.i1.. 755 -10.078 -9.970 -10.674 -9.406 -9.675 -8.710 7.350 -7.170 -6.240 -5.909 -4.967 -4.809 -11 .124 -11 .823 -11.588 -12.973 -13.227 -14.663 -14.932 -16.394 -16.795 -13.907 -14.863 -13.604 -14.394 -13.925 -13.954 -13.331 -12.528 -13.702 -14.266 -15.260 -13.035 -1.663 -1.458 -2.060 -1.833 -2.786 -0.688 0.470 -0.522 0.711 1.504 -0.256 0.020 -0.373 -0.112 -1.041 -0.822 -2.487 1.344 2.055 1.810 3.178 3.613 3.982 5.130 3. 196 5.484 3.548 4.696 3.217 4.212 2 .111 2.009 0.621 0.416 -0.998 -1.163 -0.153 2.264 3. 034 1.640 1.804 0.837 -0.628 -1.477 -2.368 -1.194 3.212 3.826 3. 703 5.054 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1 .00 1 .00 1. 00 S.00 1 .00 1.00 1 .00 1 .00 1.00 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 22. 92 18.28 22.15 24.61 26. 94 23.21 22.38 22.24 21.13 20.24 23 .11 25.93 20.82 20.47 18.61 21.86 21.13 20.84 22.08 21.58 21.15 20.34.

23.18 22.26 23 41 17.31 17.93 19.06 21.61 22.19 22.00 24.34 23.61 27.45 28.97 35.95 41.69 27.58 29.73 25.88 23.72 27.00 32.28 36.35 37.63 38.60 23.44 23.52 21.73 20.90 19.787-12.796 19,752-11.308 20.654 -10.439 5.359- 1.00 18.60 4.485 1.00 16.53 SSSD/55145.. vOl WO 98/07835 PCT/US97/14885 330

ATOM

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2601 2602 2603 2604 2605 2607 2608 2609 2610 2611 2612 2613 2615 2616 2617 2618 2619 2620 2621 2622 2623 2625 2626 2627 2628 2629 2630 2631 2632 2634 2635 2636 2637 2638 2639 2640 2641 2643 2644 2645 2646 2647 2648 2649 2650 2652 2653 2654 2655 2656 2658 2659 CD1 LEU CD2 LEU C LEU O LEU N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL O VAL N GLU CA GLU CB GLU CG GLU CD GLU OE1 GLU OE2 GLU C GLU O GLU N ASP CA ASP CB ASP CG ASP ODI ASP OD2 ASP C ASP .O ASP N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N ASP CA ASP CB ASP CG ASP ODI ASP OD2 ASP C ASP 0 ASP N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NH1 ARG 1750 1750 1750 1750 1751 1751 1751 1751 1751 1751 1751 1752 1752 1752 1752 1752 1752 1752 1752 .1752 1753 1753 1753 1753 1753 1753 1753 1753 1754 1754 1754 1754 -1754 1754 1754 1754 1755 1755 1755 1755 1755 1755 1755 1755 1756 1756 1756 1756 1756 1756 1756 1756 20.190 22.100 18.982 19.534 i7.671 16.793 15.353 14.453 14.978 17.127 17.111 17.418 17.773 :17 .765 16.399 16.394 15. 397 17.377 19.3.40 19.330 20.069 21.411 22.341 22.498 22. 222 22 .908 21.379 21. 971 20.652 20.568 19.-881 20.810 20.045 21.932 19.860 20.270 18.834 18..109 16.944 16.100 15.731 15.813 19.040 18.978 19.926 20.884 21.598 22.733 23.299 23.791 24.890 25.630 -8.979 4.579 1.00 13.28 -10.612 -13.548 -14.056 13.607 -14.289 -14.072 -14.970 -12.648 -15.774 -16.369 -16.381 -17.789 -18.317 -18.218 -18.742 -18.495 -19.410 -17 .984 -18.878 -17.096 17.174 16.144 -16.358 17.470 -15.401 -16.986 -17.773 -15.978 -15.730 -14.394 -13.225 -11.903 -13.168 -16.870 -17.290 -17.419 -18.519 -18.930 -20.005 -19.869 -20.995 -19.703 -20.180 -19.923 -21.015 -21.145 -22.157 -22.274 -20.999 -20.380 -20.914 4.939 6.108 7.084 5.917 6.845 6.432 7.220 6.684 6.925 8.007 5.778 5.755 4.321 3.651 2.219 1.497 1.822 6.405 7.237 6.083 6.64"7 5.998 4.502 4 .007 3.811 8.i63 8.901 8.633 10.070 10.355 10.016 9.905 11.063 10.763 11.832 10.130 10.732 9.843 10.467 11.651 9.774 10.952 11.979 9.989 10.059 8.704 8.645 7.237 6.702 7.122 8.091 1.00 14.74 1.00 21.25 1.00 21.26 1.00 21.64 1.00 21.21 1.00 19.03 1.00 23.34 1.00 22.78 1.00 25.56 1.00 25.61 1.00 28.61 1.00 32.38.

1.00 37.26 1.00 44.76 1.00 50.37 1.00 52.52 1.00 51.96 1.00 32.27 1.00 31.18 1.00 33.20 1.00 35.13 1.00 37 1.00 41.13 1.00 43.01 1.00 44.26 1.00 33.84 1.00 36.22 1.00 30.73 1.00 28.51 1.00 25.20 1.00 26.72 1.00 24.18 1.00 25.69 1.00 28.74 1.00 29.08 1.00 29 97 1.00 31.58 1.00 36.47 1.00 39.40 1.00 45.91 1.00 45.68 1.00 32.29 1.00 31.66 1.00 32.32 1.00 32.73 1.00 34.47 1.00 37.78 1.00 43.87 1.00 48.78 1.00 52.92 1.00 55.88 SSSD/55145. v01 WO 98/07835 PCT/US97/14885 331 ATOM 2662 NI{2 ARG 175 6 25.237 -19.214 6.593 1.00 52.53 ATOM 2665 C ARG 1756 21.889 -20.761 11.186 1.00 33.76 ATOM 2666 0 ARG 1756 22.131 -21.619 12.049 1.00 34.53 ATOM 2667 N -ILE 1757 22.432 -19.553 11.204 1.00 33.49 ATOM 2669 CA ILE 1757 23.405 -19.176 12.205 1.00 32.71 ATOM 2670 CB ILE 1757 23.980 -17.764 11.919 1.00 31.86 ATOM 2671 CG2 ILE 1757 25.111 -17.454 12.869 1.00 31.71 ATOM 2672 CG1 ILE 1757 24.520 -17.704 10.488 1.00 31.41 ATOM 2673 CD1 ILE 1757 25.075 -16.366 10.096 1.00 27.68 ATOM 2674 C ILE 1757 22.807 -19.236 13.604 1.00 34.20 ATOM 2675 0 ILE 1757 23.399 -19.833 14.495 1.00 35.83 ATOM 2676 N VAL 1758 21.620 -18.667 13.792 1.00 35.40 ATOM 2678 CA VAL 1758 20.981 -18.653 15.108 1.00 37.49 ATOM 2679 CB VAL 1758 19.501 -18.160 15.061 1.00 34.42 ATOM 2680 CG1 VAL 1758 18.899 -18.199 16. *456 1.00 37.37 AllTOM 2681 CG2 VAL 1758 19.403 -16.742 14.519 1.00 30.02 ATOM 2682 C VAL 1758 21.010 -20.050 15.725 1.00 41.64 ATOM 2683 0 VAL 1758 21.533 -20.246 16.817 1.00 43.69 ATOM 2684 N ALA 1759 20.492 -21.01.5 14-96. 1.00. 44.52 ATOM 2686 CA ALA 1759 20.434 -22.415 15.387 1.00 45.20 ATOM 2687 CB ALA 1759 19.833 -23.268 14.277 1.00 43.44 ATOM 2688 C ALA 1759 21.7.91 -22.968 15.795 1.00 45.91 ATOM 2689 0 ALA 1.759 21.890 -23.780 16.7310 1.00 47.41 ATOM 2690 N LETJ 1760 22.833 22.'511 15.120 1.00 47.70 ATOM 2692 CA LEU 1760 24.190 -22.960 15.399 1.00 50.91 ATOM 2693 CB LEU 1760 25.015 -22.912 14.109 1.00 52.93 ATOM 2694 CG LEU 1760 24.448 -23.723 12.947 1.00 57.55 ATO0M 2695 CD1 LEU 1760 .25.189 -23.390 11.660 1.0.0 60.76 ATOM 2696 CD2 LEU 1760 24.5*39 -25.208 13.273 1.00 58.66 ATOM 2697 C LEU 1760 24.882 -22,111 16.472 1.0.0 52.07 ATOM 2698 0 LEU 1760 25.967 -22.459 16.953 1.00 51.95 ATOM 2699 N THR 1761 24.267 -21.000 16.850 1.00 52.05 ATOM 2701 CA TER 1761 24.868 -20.131 17.836 1.00 53.28 ATOM 2702 CB THR 1761 24.362 -18.693 17.673 1.00 54.58 ATOM 2703 OGi THR 1761 24.633 -18.259 16.339 1.'00 53.68 ATOM 2705 CG2 THR 1761 25.090 -17.762 18.621 1.00 55.45 ATOM 2706 C THR 1761 24.715 -20.619 19.272 1.00 53.31 ATOM 2707 0 THR 1761 23.629 -20.986 19.713 1.0.0 53.89 ATOM 2708 N SER 1762 25.832 -20.617 19.993 1.00 53.51 ATOM 2710 CA SER 1762 25.876 -21.045 21.383 1.00 53.15 ATOM 2711 CB SER 1762 27.340 -21.131 21.830 1.00 57.27 ATOM 2712 OG SER 1762 27.492 -21.872 23.028 1.00 61.22 ATOM 2714 C SER 1762 25.110 -20.048 22.257 1.00 49.15 ATOM 2715 0 SER 1762 25.229 -18.831 22.071 1.00 46.61 ATOM 3466 N ALA 461 79.636 26.047 14.493 1.00 61.05 ATOM 3468 CA ALA 461 79.609 24.852 13.654 1.00 58.10 ATOM 3469 CB ALA~ 461 78. 335 24.024 13.935 1.00 60.39 ATOM 3470 C ALA 461 79.694 25.239 12.179 1.00 54.65 ATOM 3471 0 ALA 461 79.653 24.382 11.297 1.00 54.0 ATOM 3472 N. ALA 462 79.867 26.537 11.935 1.00 51.68 ATOM 34.74 CA ALA 462 79.972 27.085 10.584 1.00 48.47 ATOM 3475 CB ALA 462 80.099 28.619 10.633 1.00 46.99 145. vOl WO 98/07835 PCTIUJS97/14885 332 ATOM 3476 C ALA 462 81.123 26.489 9.766 1.00 44.86 ATOM 3477 0 ALA 462 80.918 26.097 8.625 1. -00 43.40 ATOM 3478 N TYR 463 82.329 26.447 10.335 1.00 42.23 ATOM 3480 CA TYR 463 83.493 25.913 9.629 1.00 39.04 ATOM 3481 CB TYR 463 84.642 26.921 9.620 1.00 39.01 ATOM 3482 CG TYR 463 84.354 28.126 8.743 1.00 41.95 ATOM 3483 CD1 TYR 463 84.073 29.373 9.308 1.00 42.40 ATOM 3484 CE1 TYR 463 83.754 30.466 8.512 1.00 42.02 ATOM 3485 CD2 TYR 463 84.311 28.009 7.345 1.00 40.70 ATOM 3486 CE2 TYR 463 83.992 29.099 6.542 1.00 37.09 ATOM 3487 CZ TYR 463 83.716 30.320 7.134 1.00 39.19 ATOM 3488 OH TYR 463 83.401 31.406 6.360 1.00 40.66 ATOM 3490 C TYR 463 84.011 24.554 10.050 1.00 37.78 ATOM 3491 0 TYR 463 84.627 23.863 9.237 1.00 38.35' ATOM 3492 N GLU 464 83.746 24.143 11.285 1.00 37.67 ATOM 3494 CA GLU 464 84.212 22'.841 11.747 1.00 38.57 ATOM 3495 CE GLU 464 85.707 22.890 12.024 1.00 41.44 ATOM 3496 CG GLU 464 86.093 23.870 13.108 1.00 47.87 ATOM 3497 CD GLU 464 87.583 24.135 13.169 1.00 53.44 ATOM 3498 OE1 GLU 464 87.998 24.983 13.990 1.00 56.72 ATOM 3499 0E2 GLU 464 88.344 23.513 12.397 1.00 54.85 ATOM 3500 C GLU 464 83.504 22.393 13.001 1.00 38.15 ATOM 3501 0 GLU 464 83.291 23.187 13.905 1.00 39.59 ATOM 3502 N LEU 465 83.121 21.124 13.051 1.00 37.13 ATOM 3504 CA LEU 465 82.457 20.608 14 .236 1.00 37.93 ATOM 3505 CE LED 465 81.502 19.456 13.894 1.00C 33.43 ATOM 3506 CG LEU 465 80.455 19.609 12.787 1.00 31.12.

ATOM 3507 CD1 LEU 465 79.415 18.500 12.944 1.00 24.85 ATOM 3508 CD2 LEU 465 79.797 20.980 12.855 1.00 29.05 ATOM 3509 C LEU 465 83.540 20.090 15.166 1.00 41.02 ATOM 3510 0 LEU 465 84.703 19.93E 14.763 1.0.0 40.24 ATOM 3511 N PRO 466 83.198 19.884 16.441 1.00 43.58 ATOM 3512 CD PRO 466 81.974 20.359 17.115 1.00 45.33 ATOM 3513 CA PRO 466 84.170 19.374 17.415 1.00 44.72 ATOM. 3514 CB PRO 466 83.433 19.505 18.743 1.00 46.18 ATOM 3515 CG PRO 466 82.486 20.679 18.496 1.00 48.84 ATOM 3516 C PRO 466 84.447 17.909 17.101 1.00 44.52 ATOM. 3517 0 PRO 466 83.616 17.228 16.509 1.00 43.38 ATOM 3518 N GLU 467 85.610 17.421 17.492 1.00 47.75 ATOM 3520 CA GLU 467 85.932 16.035 17.218 1.00 51.03 ATOM 3521 CE GLU 467 87.354 15.913 16.659 1.00 56.11 ATOM 3522 CG GLU 467 87.615 14.557 16.000 1.00 62.27 ATOM 3523 CD GLU 467 88.927 14.489 15.242 1.00 66.39 ATOM 3524 OE1 -GLU 467 89.688 15.490 15.243 1.00 69.85 ATOM 3525 0E2 GLU 467 89.182 13.418 14.643 1.00 66.09 ATOM 3526 C GLU 467 85.749 15.136 18.435 1.00 49.62 ATOM 3527 0 GLU 467 85.767 15.601 .19.578 1.00 49.62 ATOM 3528 N ASP 468 85.516 13.856 18.166 1.00 48.07 ATOM 3530 CA ASP 468 85.352 12.843 19.198 .1.00 46.32 ATOM 3531 CE ASP 468 83.880 12.679 19.587 1.00 45.15 ATOM' 3532 CG ASP 468 83.678 .1J..740 20.779 1.00 44.19 ATOM 3533 0D1 ASP 468 82.544 11.709 21.309 1.00 42.04 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 333 ATOM 3534 OD2 ASP 468

ATOM

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3535 3536 3537 3538 3539 3540 3541 3542 3543 3544 3546 3547 3548 3549 3550 3552 3553 3556 3559 3560 3561 3563 3564 3565 3566 3567 3568 3569 3570 3572 3573 3574 3575 3576 3577 3579 3580 3581 3582 3583 3584 3585 3586 3587 3589 3590 3591 3592 3593 3594 3595

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

0

N

CA

CB

CG

CD2 CE2 CE3 CD1

NEI

CZ2 CZ3 CH2

C

0

N

CA

CB

CG

CD

OEI

OE2

C

0

N

CA

CB

CG

CD1 CD2

C

0

ASP

ASP

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP.

TRP

TRP

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

468 468 469 469 469 469 469 469 469 470 470 470 470 470 470 470 470 470 470 470 471 471 471 471 471 471 471 471 471 471 471 471 471 471 472 472 472 472 472 472 472 472 472 473 473 473 473 473 473 473 473 84.629 11.033 85.877 11.556 85.141 10.815 87.181 11.308 88.111 12.189 87.885 10.130 89.208 10.187 89.456 11.662 87.170 8.806 87.188 7.905 86.495 8.717 85.786 7.506 85.083 7.704 85.885 8.424 85.014 8.705 83.802 9.417 82.921 9.877 83.127 9.687 81.843 10.527 84.736 7.058 84.411 5.877 84.182 8.01.4 83.124 7.736 81.890 8.515 81.259 7.958 80.512 6.740 80.061 6.610 80.174 5. 74.4 81.246 8.503 80.525 7.697 79.289 5.522 79.409 4.660 78.973 4.560 83.432 8.065 82.690 7.670 84.533 8.770 84.895 9.184 86.065 10.174 86.221 11.038 85.082 12.035 84.515 12.558 84.777 12.318 85.219 8.034 85.896 7.082 84.667 8.094 84.944 7.095 83.714 6.234 84.020 5.091 84.786 4.000 82.759 4.518 85.380 7.828 84.720 8.781 21. 188 18.580 17.928 18 .732 19.464 18.215 18.968 19.042 i8 .473 17.629 19.613 19.999 21.331 22.375 23.564 23.184 24.057 25.354 23 637 19.004 18.941 18.268 17.314 17.739 18.952 19.026 20.355 18.092 20.199 21.051 20. 776 18.509 19.839 15.872 14.968 15.651 14.308 14.365 13 .103 12.872 13.857 11. 694 13.364 13.745 12.158 11.146 10.847 9.867 10. 578 9.273 9.883 9.457 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1. 00 1 00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 38 .14 45. 54 45.94 45.89 45.11 45. 91 45.90 45.73 45.48 46.83 42.12 41.21 43 .14 45.68 45.98 47.28 50.54 47.56 54.59 40.57 43.13 38.07 35.09 33.42 31 .71 34 81 33.17 37.60 25.70 28.79 35.80 35.52 34.51 35.77 37.45 34.76 34.51 32.30 36.57 36.34 36.01 31.95 33.90 33.77 33.58 34.82 32.59 33.78 32.94 35.34 37.95 39.55 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 334

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

A-TOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM'

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3596 N PRO 474 3597 CD PRO 474 3598 CA PRO 474 3599 CB PRO 474 3600 CG PRO 474 3601 -C PRO 474 3602 0 PRO 474 3603 N ARG 475 3605 CA ARG 475 3606 CB ARG 475 3607 CG ARG 475 3608 CD ARG 475 3609 NE ARG 475 3611 CZ ARG 475 3612 NH1 ARG 475 3615 NH2 ARG 475 3618 C ARG 475 3619 0 ARG 475 3620 N ASP 476 3622 CA ASP 476 3623 CR ASP 476 3624 CG ASP 476 3625 OD1 ASP' 476 3626 OD2 ASP 476 3627 C ASP 476 3628 0 ASP 476 3629 N ARG 477 3631 CA ARG 477 3632 CB ARG 477 3633 CG ARG 477- 3634 CD ARG 477 3635 NE ARG 477 3637 CZ ARG 477 3638 NH1 ARG 477 3641 NH2 ARG 477 3644 C ARG 477 3645 0 ARG 477 3646 N LEU 478 3648 CA LEU 478 3649 CB LEU 478 3650 CG LEU 478 3651 CD1 LEU 478 3652 CD2 LEU 478 3653 C LEU 478 3654 0 LEU 478 3655 N VAL 479 3657 CA VAL 479 3658 CR VAL 479 3659 CG1 VAL 479 3660 CG2 VAL 479 3661 C VAL 479 3662 0 VAL 479 86.522 7.423 9.299 1.00 38.99 87.455 6.453 9.899 1.00 38.76 87.094 8.004 8.080 1.00 39.37 88.382 7.201 7.906 1.00 40.18 88.767 6.883 9.310 1.00 37.76 86.165 7.794 6.890 1.00 40.94 85.865 6.653 6.532 1.00 43.98 85.762 8.886 6.245 1.00 40.66 84.850 8.840 5.101 1.00 40.66 84.776 10.216 4.448 1.00 37.94 84.354 11.300 5.415 1.00 36.12 84.340 12.697 4.800 1.00 35.92 83.932 13.677 5.801 1.00 30.14 82.671 13.878 6.170 1.00 28.45 81.688 13.197 5.599 1.00 28.41 82.410 14.666 7.197 1.00 27.85 85 .141 84 .223 86 .419 86 .836 88 .344 89 .105 89. 569 89.216 86 .436 86.678 85 .900 85 .443 86.040.

87 .481 88 .169 87. 515 87. 932 89. 000 87.269 83 915 83 .339 83.274 81. 832 81.374 79 .872 79.393 79.590 81.432 81.938 80. 562 80. 113 80.468 80. 001 81. 972 78. 609 77. 846 7.766 4.046 1.00 41.44 7.189 3.470 1.00 41.40 7.475 3.830 1.00 44.99 6.477 2.849 1.00 50.62 6.540 2.644 1.00 54.47 5.969 3.819 1.00 60.03 4.810 3.722 1.00 65.09 6.669 4.846 1.00 62.62 5.054 3.263 1.00 51.16 4.091 2.530 1.00 53.06 4.916 4.471 1.00 49.58- 3.623 4.968. 1.00 17.34 3.359 6.341 1.00 48.85 2.924 6.265 1.00 52.11 3.079 7.591 1.00 53.63 2.345 8.665 1.00 54.86 2.363 9.927 1.00 57.15 3.076 10.264 1.00 55.98 1.691 10.855 1.00 58.31 3.563 5.020 1.00 44.70 2.780 5.770 1.00 44.63 4.366 4.179 1.00 41.95 4.440 4.118 1.00 38.58 5.609 4.980 1.00 33.17 5.731 5.183 1.00 29.07 4.592 6.052 1.00 28.25 7.059 5.836 1.00 30.79 4.710 2.674 1.00 38.93 5.647 2.071 1.00 41.75 3.880 2.107 1.00 37.96 4.086 0.730 1.00 37.87 2.882 -0.192 1.00 36.47 3.145 -1.612 1.00 34.43 2.651 -0.187 1.00 34.33 4.299 0.775 1.00 38.10 3.366 1.019 1.00 40.13 SSSD/55145. vOl WO 98/07835 PTU9148 PCT/US97/14885 335 ATOM 3663 N LEU 480 78.184 5.537 0.552 1.00 38.05 ATOM 3665 CA LEU 480 76.766 5.879 0.606 1.00 35.90 ATOM 3666 CB LEU 480 76.568 7.393 0.475 1.00 33.98 ATOM 3667 CG LEU 480 77.276 8.257 1.536 1.00 32.84 ATOM 3668 CDI LEU 480 77.003 9.749 1.273 1.00 29.68 ATOM 3669 CD2 LEU 480 76.828 7.861 2.943 1.00 26.03 ATOM 3670 C LEU 480 76.015 5.146 -0.476 1 .00 34.99 ATOM 3671 0 LEU 480 76.573 4.864 -1.526 1.00 36.12 ATOM 3672 N GLY 481 74.753 4.836 -0.223 1.00 35.21 ATOM 3674 CA GLY 481 73.965 4.120 -1.204 1.00 34.79 ATOM 3675 C GLY 481 72.544 4.608 -1.332 1.00 36.31 ATOM 3676 0 GLY 481 72.237 5.775 -1.046 1.00 38.30 ATOM 3677 N LYS 482 71.665 3.705 -1.761 1.00 35.59 ATOM 3679 CA LYS 482 70.257 4.007 -1.959 1.00 35.24 ATOM 3680 CB LYS 482 69.488 2.698 -2.207 1.00 35.69 ATOM 3681 C LYS 482 69.585 4.763 -0.823 1.00 36.31 ATOM 3682 0 LYS 482 69.752 4.421 0.352 1.00 34.90 ATOM 3683 N PRO 483 68.787 5.786 -1.157 1.0OD 38.08- ATOM 3684 CD PRO 483 68.432 6.320 -2.483 1.00 39.57 ATOM 3685 CA PRO 483 68.097 6.566 -0.135 1.00 41.08 ATOM 3686 CB PRO 483 67.300 ?.560 -0.987 1.00 39.80 ATOM 3687 CG PRO 483 68.2.68 7.819 -2.157 1.00 37. 87' ATOM 3688 C PRO 48.3 67.130 5.652 0.606 1.00 42.11.

ATOM 3689 0 PRO 483 66.306 4.994 -0.025 1.00 42-01 ATOM 3690 N LEU 484 67.199 5.624 1.937 1. 00' 41.06 ATOM 3692 CA LEU 484 66.293 4.823 2.751 1.00 38.47 ATOM 3693 CB LEU 484 67.040 4.307 3.990 1.00 32.45 ATOM 3694 CG .LET) 484 67.968 3.098 3.809 1.00 27.68 ATOM 3695 CD1 LEU 484 68.569 2.710 5.147 1.00 20. 29' ATOM 3696 CD2 LET) 484 67.181 1.964 3.225 1.00 23 ATOM 3697 C LET) 484 65.084 5.637 3.180 1.00 42. 18.

ATOM 3698 0 LET) 484 65.227 6.699 3.814, 1.00 44.50 ATOM 3699 N GLY 485 63.893 5.170 2.817 1.00 45.68 ATOM 3701 CA GLY 485 62.692 5.863 3.220 1.00 49.88 ATOM 3702 C GLY 485 62.216 7.008 2.337 1.00 53.01 ATOM 3703 0 GLY 485 62.438 7.005 1.117 1.00 50.26 ATOM 3704 N GLU 486 61.592 8.020 2.949 1.00 56.24 ATOM 3706 CA GLU 486 61.064 9.183 2.257 1.00 58.07 ATOM 3707 CB GLU 486 59.666 8.845 1.682 1.00 55.60 ATOM 3708 C GLU 486 60.995 10.477 3.088 1.00 39.35 ATOM 3709 0 GLU 486 60.019 11.226 3.000 1.0.0 61.44 ATOM 3710 N GLY 487 62.027 10.747 3.879 1.00 59.60 ATOM 3712 CA GLY 487 62.066 11.964 4.652 1.00 59.75 ATOM 3713 C GLY 487 61.337 11.959 5.974 1.00 61.44 ATOM 3714 0 GLY 487 61.231 12.979 6.627 1.00 61.96 ATOM 3715 N ALA 488 60.820 10.800 6.377 1.00 59.69 ATOM 3717 CA ALA 488 60.134 10.709 7.657 1.00 57.27 ATOM 3718 CB ALA 488 59.489 9.337 7.825 1.00 58.05 ATOM 3719 C ALA 488 61.137 10.970 8.754 1.00 56.28 ATOM 3720 0 ALA 488 60.810 11.446 9.834 1.00 57.31 ATOM 3721 N PHE 489 62.389 10.630 8.480 1.00 54.40 ATOM 3723 CA PHE 489 63.462 10.830 9.466 1.00 54.56 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 336 ATOM 3724 CB PHE 489 64.161 9.500 9.770 1.00 49.88 ATOM 3725 CG PHE 489 63.222 8.454 10.352 1.00 45.21 ATOM 3726 CD1 PHE 489 62.505 7.585 9.516 1.00 43.48 ATOM 3727 CD2 PHE 489 63.017 8.344 11.738 1.00 40.99 ATOM 3728 CEl PHE 489 61.625 6.653 10.039 1.00 36.69 ATOM 3729 CE2 PHE 489 62.138 7.411 12.25- 1.00 35.02 ATOM 3730 CZ PHE 489 61.433 6.558 11.407 1.00 34.73 ATOM 3731 C PHE 489 64.456 11.896 8.974 1.00 56.31 ATOM 3732 0 PHE 489 65.372 12.276 9.692 1.00 59.05 ATOM 3733 N GLY 490 64.285 12.375 7.735 1.00 56.56 ATOM 3735 CA GLY 490 65.141 13.400 7.143 1.00 55.60 ATOM' 3736 C GLY 490 65.899 12.778 5.993 1.00 54.79 ATOM 3737 0 GLY 490 65.357 11.854 5.366 1.00 57.10 ATOM 3738 N GLN 491 67.073 13.304 5.634 1.0.0 53.44 ATOM 3740 CA GLN 491-. 67.829 12.658 4.562 1.00 52.60 ATOM 3741 CB GLN 491 68.760 13.580 3.777 1.00 53.48 ATOM 3742 CG GLN 491 69.422 12.818 2.629 1.00 57.19 ATOM 3743 CD GLN 491 70.046 13.696 1.548 1.00 62.09 ATOM 3744 OE1 GLN 491 70.313 14.893 1.701 1.00 70.26 ATOM 3745 NE2 GLN 491 70.453 13.082 0.441 1.00 62.78 ATOM 3748 C GLN 491 68.632. 11.518 5.165 1.00 49.89 ATOM 3749 0 GLN 491 69.669 11.704 5.805 1.0049.56 ATOM 3750 N VAL 492 68.103 10.318 4.984 1.00 47.83 ATOM 3752 A VAL 492 68.705 9.093 5.456 1.00 46.38 ATOM 3753 CB VAL 492 67.760 8.320 6.412 1.00 45.61 ATOM 3754 CG1 VAL 492 68.412 7.045 6.932 1.00 46.70 ATOM 3755 CG2 VAL 492 67.361 9.211 7.606 1.0.0 46.97 ATOM 3756 C VAL 492 69.004 8.200 .4.253 1.00 45.23 ATOM 3757 0 VAL 492 68.181 8.044 3.349 1.00 45.17 ATOM 3758 N VAL 493 70.210 7.654 4.208 1.00 43.75 ATOM 3760 CA VAL 493 70.599 6.780 3.109 1.00 44.71 ATOM 3761 CB VAL 493 71608 7.471 2.148 1.00 46.20 ATOM 3762 CG1 VAL 493 71.159 8.902 1.838 1.00 46.16 ATOM 3763 CG2 VAL 493 73.045 7.428 2.706 1.00 42.06 ATOM 3764 C VAL 493 71.205 5.482 3.624 1.00 44.09 ATOM 3765 0 VAL 493 71.701 5.402 4.745 1.00 43.73 ATOM 3766 N LEU 494 71.102 4.448 2.809 1.00 43.38 ATOM 3768 CA LEU 494 71.682 3.158 3.142 1.00 43.29 ATOM 3769 CB LEU 494 70.988 2.030 2.366 1.00 43.38 ATOM 3770 CG LEU 494 71.563 0.614 2.431 1.00 39.77 ATOM 3771 CDI LEU 494 71.809 0.201 3.850 1.00 36.38 ATOM 3772 CD2 LEU 494 70.600 -0.337 1.760 1.00 42.50 ATOM 3773 C LEU 494 73.139 3.280 2.725 1.00 42.72 ATOM 3774 0 LEU 494 73.435 3.929 1.720 1.00 43.83 ATOM 3775 N ALA 495 74.044 2.698 3.499 1.00 40.80 ATOM 3777 CA ALA 495 75.456 2.785 3.183 1.00 43.80 ATOM 3778 CB ALA 495 76.059 4.032 3.821 1.00 43.76 ATOM 3779 C ALA 495 76.171 1.546 3.682 1.00 46.68 ATOM 3780 0 ALA 495 75.668 0.838 4.551 1.00 48.52 ATOM 3781 N GLU 496 77.330 1.258 3.104 1.00 49.13 ATOM 3783 CA GLU 496 78.112 0.103 3.519 1.00 49.79 ATOM 3784 CB GLU 496 78.524 -0.732 2.318 1.00 53.83 SSSD/55145. vOl WO 98/07835 P~~TIUS97/14885 337

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3785 CG GLU 3786 CD GLU 3787 0E1 GLU 3788 0E2 GLU 3789 C GLU 3790 0 GLU 3791 N ALA 3793 CA ALA 3794 CB ALA 3795 C ALA 3796 0 ALA 3797 N ILE 3799 CA ILE 3800 CB ILE 3801 CG2 ILE 3802 CG1 ILE 3803 CD). ILE 3804 C ILE 3805 0 ILE 3806 N GLY 3808 CA GLY 3809 C GLY 3810 0 GLY 3811 N LEU 3813 CA LEU 3814 CB LEU 3815 CG LEU 3816 CD). LEUJ 3817 CD2 LEU 3818 C LEU 3819 0 LEU 3820 N PRO 3821 CD PRO 3822 CA PRO 3823 CB PRO 3824 CG PRO 3825 C PRO 3826 0 PRO 496 496 496 496 496 496 497 497 497 497 497 498 498 498 498 498 498 498 498 499 499 499 499 500 500 500 500 500 500 500 500 505 505 505 505 505 505 505 77.350 -1.224 77.623 -2.561 76.704 -3.411 78.751 -2.760 79.333 0.601 80.192 1.236 79.373 0.375 80.503 0.810 80.048 1.156 81.544 -0.30.1 82.191 1.473 82.821 0.061 83.892 -0.92'8 84.843 -0.797 85.990 -1.795 84.077 -1.006 83.411 0.254 84.702 -0.802 85.133 0.293 84.835 -1.926 85.600 -1.974 1.496 1.00 61.33 0.862 1.00 64.74 0.883 1.00 70.08 0.356 1.00 64.12 4.230 1.00 48.46 3.631 1.00 48.79 5.530 1.00 49.25 6.334 1.00 49.99 7.732 1.00 48.16 6.373 1.00 51.53 6.409 1.00 52.41 6.335 1.00 52.35 6.369 1.00 52.03 5.145 1.0.0 52.83 5.253 1.00 51.43 3.830 1.00 53.85 3.271 1.00 55.62 7.654 1.00 52.74 8.026 1.00 52.14 8.354 1.00 52.58 9.592 1.0'0 53.03 85 165 -1.113 10.771 1.00 53.67 86.012 -0.544 11.463 1.00 53.99 83.862 -1.045 11.034 1.00 53.60 83.337 -0.245 12.141 1.00 51.00 81.841 -0.499 12-317 1.0.0 49.38 80.901 -0.024 11.212 1.00 47.62 79.483 -0.454 11.543 1.00 47.25 80.992 1.486 11.081 1.00 47.38 84.060 -0.573 13.433 1.00 51.05 84.396 -1.734 13.670 1.00 53.76 87.588 -5.968 10.545 1.00 81.81 88.588 -6.677 11.357 1.00. 81.96 88.105 -4.664 10.109 1.00 80.56 89.501 -4.622 10.735 1.00 80.75 89.868 -6.070 10.860 1.00 82.32 88.139 -4.477 8.588 1.00 78.53 88.462 -3.400 8.085 1.00 77.85 87.792 -5.532 7.865 1.00 77.09 87.747 -5.484 6.411 1.00 75.57 88.799 -6.415 5.806 1.00 75.80 86.347 -5.929 6.008 1.00 74.33 86.044 -6.117 4.826 1.00 73.76 85.496 -6.092 7.018 1.00 71.72 84.120 -6.509 6.820 1.00 69.28 83.619 -7.257 8.054 1.00 70.64 83.258 -5.284 6.605 1.00 65.87 83.445 -4.262 7.274 1.00 65.40 82.363 -5.358 5.628 1.00 62.01 81.464 -4.248 5.381 1.00 58.41 81.043 -4.136 3.915. 1.00 57.18 82.251 -3.893 3.046 1.00 61.04 3827 N ASN 506 3829 CA ASN 506 3830 CB ASN 506 3831 C ASN 506 3832 0 ASN 506 3833 N ARG -507 3835 CA ARG 507 3836 CB ARG 507 3837 C ARG 507 3838 0 ARG 507 3839 N VAL 508 3841 CA VAL 508 3842 CB VAL 508 3843 CG1 VAL 508 145. vOl WO 98/07835 PCT/US97/14885 338 ATOM 3844 CG2 VAL 508

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

AT'OM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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ATOM

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ATOM

3845 3846 3847 3849 3850 3851 3853 3854 3855 3856 3858 3859 3860 3861 3862 3863 3867 3868 3869 3871 3872 3873 3874 3875 3876 3877 3879 3880 3881 3882 3883 3885 3886 3887 3888 3889 3890 3891 3893 3894 3895 3896 3897 3898 3902 3903 3904 3906 3907 3908 3909 C VAL O VAL N THR CA THR CB THR OGi TR CG2 THR C THR O THR N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS O LYS N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL 0 VAL N ALA CA ALA CB ALA C ALA C) ALA N VAL CA VAL CB VAL CG1l VAL CG2 VAL C VAL 0 VAL N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS 0 LYS N MET CA MET CB MET CG MET SD MET 508 508 509 509 509 509 509 509 509 510 510 510 510 510 510 510 510 510 511 511 511 511 511 511 511 512 512 512 512 512 513 513 513 513 513 513 513 514 514 514 514 514 514 514 514 514 515 515 515 515 515 80.310 -5.383 80.257 -4.552 79.964 -5.716 79.572 -3.501 78.396 -3.610 78.705 -3.144 79.938 -3.727 77.606 -3.565 77.381 -2.674 77.675 -1.507 76.238 -3.208 75.202 -2.372 74.069 -3.259 73.226 -2.622 73.825 -2.807 73.118 -3.931 73.317 -5.251 74.734 -1.499 74.480 -2.020 74.679 -0.183 74.265 0.720 75.480 1.389 76,315 0.346 76.353 2-175 13.408 21 812 *73.305 1.914 7-2.756 2.598 71.953 3.701 70.557 3.640 72.670 4.965 73.140 5.036 72.768 5.949 73.442 7.217 74.631 7.482 75.384 8.722 75.570 6.292 72.509' 8.407 71.900 8.646 72.402 9.143 71.575 10.357 71.017 10.537 70.074 9.456 69.462 9.860 68.450 8.840 67.206 8.823 72.451 11.568 73.584 11.673 71.918 12.495 72.668 13.690 73.464 13.391 72.557 13.070 73.391 12.475 3 .466 6 .246 6 .529 6 .665 7. 501 8 .934 9. 356 9 .903 6 .865 6 .625 6 .470 5 .889 5.365 4 .284 2 .899 2 .152 2 .813 7 .075 8. 162 6.891 7 .957 8 .690 9 .420 7. 706 7.360 6 .147 8.207 7. 715 8 .278 8 .173 9. 319 7 .275 7. 569 6.601 7. 015 6.550 7.476 6.431 8. 578 8 .654 10. 068 10.531 11.855 12.337 11. 517 8. 312 8. 794 7.522 7.119 5.846 4.665 3.218 1.00 60.74 1.00 56.61 1.00 55.82 1.00 54.85 1.00 49.28 1.00 47.98 1.00 43.39 1.00 47.57 1.00 46.71 1.00 48.59 1.00 44.75 1.00 44.42 1.00 46.34 1.00 54.93 1.00 58.33 1.00 59.17 1.00 56.09 1.00 40.83 1.00 38.59 1. 00 36.28 1.00 31.41 .1.00 32.80 1.00 29.97 1.00 30.20 1.00 28.40 1..00 27.45' 1.00 27.30 1.00 26.66 1.00 24.24 1.00 28.52 1.00 26.66 1.00 29.18 1.00 29.65 1.00 28.93 1.00 25.51 1.00 29.45 1.00 30.45 1.00 30.15 1.00 33.29 1.00 33.28 1.00 38.67 1.00 45.73 1.00 53.93 1.00 63.59 1.00 71.90 1.00 29.45 1.00 25.64 1.00 29.42 1.00 30.46 1.00 29.63 1.00 32.48 1.00 33.06 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885' 339 ATOM 3910 CE MET 515 73.734 10.809 3.715 1.00 30.26 ATOM 3911 C MET 515 71.700 14.839 6.848 1.00 30.75 ATOM 3912 0 MET 515 70.478 14.654 6.8G7 1.00 33.07 ATOM 3913 N LEU 516 72.238 16.027 6.608 1.00 30.32 ATOM 3915 CA LEU 516 71.414 17.194 6.304 1.00 30.21 ATOM 3916 CB LtU 516 72.112 18.487 6.748 1.00 26.54 ATOM 3917 CG LEU 516 72.452 18.668 8.227 1.00 23.97 ATOM 3918 CD1 LEU 516 73.345 19.858 8.412 1.00 24.27 ATOM 3919 CD2 LEU 516 71.198 18.850 9.023 1.00 21.46.

ATOM 3920 C LEU 516 71.197 17.265 4.800 1.00 33.44 ATOM 3921 0 LEU 516 72.016 16.784 4.015 1.00 34.50 ATOM 3922 N LYS 517 70.082 17.863 4.400 1.00 36.36 ATOM 3924 CA LYS 517 69.783 18.048 2.993 1.00 34.58 ATOM 3925 CB LYS 5217 68.281 18.255 2.784 1.00 38.96 ATOM 3926 CG LYS 517 67.409 17.155 3.380 1.00-44.34 ATOM 3927 CD LYS 517 66.128 16.920 2.572 1.00 52.11 ATOM 3928 CE LYS 517 65.138 18.083 2.637 1.00 58.29 ATOM 3929 NZ LYS 517 63.915 17.833 1.786 1.00 60.90 ATOM 3933 C LYS 517 70.567 19.304 2.597 '1.00 33.51 ATOM 3934 0 LYS 517 71.024 20.064 3.460 1.CO 30.34 ATOM .3935 N SER 518 70.701 19.539 1.296 1.00 34.39 ATOM 3937 CA SER 518 71.444. 20.693 0.788 1.00 35.84 ATOM 3938 CB SER 518 71.537 20.618 -0.731 1.00 33.66 ATOM 3939 OG SER 518 '70.282 20.258 -1.266 1.00 38.73 ATOM 3941 C SER 518 70.879 22.045 1.198 1.00 36.91' ATOM 3942 0 SER 518 '71 .591 23.050 1.206 1.00 37.32 ATOM 3943 N ASP 519 69.598 22.069 1.538 1.00 37.88 ATOM 3945 CA ASP 519 68.945 23.313 1.936 1.00 '38.63 ATOM 3946 CB ASP 519 67.517 23.364 1.375 1.03 42.23' ATOM 3947 CG ASP 519 66.669 22.151 1.775 1.00 48.87 ATOM 3948 001 ASP 519 67.070 21.380 2.681 1.00 49.21 ATOM 3949 0D2 ASP 519 65.582 21.972 1.181 1.00 54.93 ATOM 3950 C ASP 519 68.916 23.537 3.443 1.00 38.06 ATOM 3951 0 ASP 519 68.246 24.451 3.916 1.00 39.38 ATOM 3952 N ALA 520 69.622 22.692 4.191 1.00 36.24 ATOM 3954 CA ALA 520 69.631 22.795 5.648 1.00 34.69 ATOM 3955 CB ALA 520 70 359 21.613 6.259 1.00 35.68 ATOM 3956 C ALA 520 70.213 24.087 6.173 1.00 33.54 ATM 3957 0 ALA 520 71.039 24.718 5.522 1.00 34.83 ATOM .3958 N THR 521 69.815 24.452 7.384 1.00 34.45 ATOM 3960 CA THR 521 70.315 25.668 8.001 1.00 36.51 ATOM 3961 CB THR 521 69.148 26.592 8.493 1.00 39.14 ATOM 3962 OGi THR 521 68.529 26.031 9.659 1.00 41.61 ATOM 3964 CG2 THR 521 68.081 26.750 7.409 1.00 40.14 ATOM 3965 C THR 521 71.228 25.303 9.170 1.00 36.35 ATOM 3966 0 THR 521 71.376 24.125 9.510 1.00 32.23 ATOM 3967 N GLU 522 71.868 26.310 9.756 1.00 39.33 ATOM 3969 CA GLU 522 72.747 26.092 10.89b 1.00 44.59 ATOM 3970 CB GLU 522 73.364 27.424 11.335 1.00 51.80 ATOM 3971 CG GLU. 522 74.463 27.311 12.418 1.00 64.10 ATOM 3972 CD GLU 522 75.811 26.815 11.886 1.00 69.12 ATOM 3973 OE1 GLU 522 76.784 27.605 11.869 1.00 69.26 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 340 ATOM 3974 0E2 GLtJ 522 75.900 25.629 11.502 1.00 73.62 ATOM 3975 C GLU 522 71.953 25.447 12.042 1.00 44.53 ATOM 3976 0 GLU 522 72.482 24.617 .12.786 1.00 44.95 ATOM 3977 N LYS 523 70.679 25.814 12.167 1.00 42.99 ATOM 3979 CA LYS 523 69.826 25.264 13.216 1.00 42.17 ATOM 3980 CB LYS 523 68.519 26.053 13.-329 1.00 45.99 ATOM 3981 CG LYS 523 67.583 25.582 14.433 1.00 48.74 ATOM 3982 CD LYS 523 66.296 25.027 13.832 1.00 57.24 ATOM 3983 CE LYS 523 65.405 24.383 14.884 1.00 60.31 ATOM 3984 NZ LYS 523 64.309 23.586 14.247 1.00 65.17 ATOM 3988 C LYS 523 69.563 23.793 :12.935 1.00 39.03 ATOM 3989 0 LYS 523 69.581 22.973 13.850 1.00 40.65 ATOM 3990 N ASP 524 69.331 23-457 11.672 1.00 34.91 ATOM 3992 CA ASP 524 69.122 22.068 .11.294 1..00 33.12 ATOM 3993 CB ASP 524 68.876 21.942 9.790 1.00 34.84 ATOM 3994 CG ASP 524 67.482 22.352 9.389 1.00 36.47 ATOM 3995 ODi ASP 524 66.552 22.193 10.204 1-.00 41.59 ATOM 3996 0D2 ASP 524 67.307 22.815 8.248 1.00 38.19 ATOM 3997 C ASP 524 70.383 21.284 11.6.53 1.00 33.94 ATOM 3998 0 ASP 524 '70.-301 20.154 12.139 1.00 37.40 ATOM 3999 N LEU 525 71.554 21.869 11.404 1.00 32.39 ATOM 4001 CA LEU 525' 72.799 21.186 11.729 1.00 31.50 ATOM 4002 CB LEU 525 .74.018 21.998 11.278. 1.00 29.05 ATOM 4003 CG LEU 525 75.363 21.375 11. 660 1.00 28,38 ATOM 4004 CD1 LEU 525 75.521 19.990 11.365 1.00 27.27 ATOM 4005 CD2 LEU 525 76'.'519 :32. 283 1. 295 1-00 26.26 ATOM 4006 C LEU 525 72.848 20. 941. 13.231 1.00 30.27 *ATOM 4007 0 LEU 525 73.104 19.828 13.67E 1.00 33.58 ATOM 4008 N SER 526 72.563 21.982 14.000 1.00 29.63 ATOM 4010 CA SER 526 72.544 21.914 15.459 1.00 30.26 ATOM 4011 CB SER 526 72.046 23.251 16.013 1.00 32.03 ATOM 4012 OG SER 526 71.923 23.199 17.417 1.00 37.02 ATOM 4014 C SER 526 71.640 20.796 15.980 1.00 29.72 ATOM 4015 0 SER 526. 71.924 20.162 16.998 1.00 27.54 ATOM 4016 N ASP 527 70.525 20.588 15.291 1.00 28.97 ATOM 4018 CA ASP 527 *69.581 19.556 15.664 1.00 29.28 ATOM 4019 CB ASP 527 68.289 19.71.0 14.855 1.00 29.08 ATOM 4020 CG ASP 527 67.497 20.977 15.225 1.00 30.05 ATOM 4021 ODI ASP 527 67.750 21.597 16.292 1.00 24.32 ATOM 4022 0D2 ASP 527 66.591 21.335 14.436 1.00 34.69 ATOM 4023 C ASP 527 70.175 18.164 15.436 1.00 30.65 ATOM 4024 0 ASP 527 70.115 17.297 16.312 1.00 30.12 ATOM 4025 N LEU 528 70.769 17.958 14.265 1.00 30.50 ATOM 4027 CA LEU 528 71.358 16.669 13.946 1.00 29.54 ATOM 4028 CB LEU 528 71.850 16.647 12.487 1.00 26.03 ATOM 4029 CG LEU 528 72.409 15.320 11.942 1.00 24.26 ATOM 4030 CD1 LEU 528 71.466 14.142 12.259 1.00 21.51 ATOM 4031 CD2 LEU 528 72.644 15.437 10.450 1.00 15.05 ATOM 4032 C LEU .528 72.494 16.342 14.933 1.00 30.51 ATOM 4033 0 LEU 528 72.641 15.192 15.354 1-.00 29.79 ATOM 4034 N ILE 529 73.281 17.351 3-5.305 1.00 30.86 ATOM 4036 CA ILE 529 74.367 17.138 16.253 1.00 28.41 145. vOl WO 98/07835 PCTIUS97/14885 341

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A4TOM

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4037 4038 4039 4040 4041 4042 4043 4045 4.046 4047 4049 4050 4051 4053 4054 4055 4056 4057 4058 4059 4060 4061 4063 4064 4065 4066 4067 4068 4069 4070 4072 4073 4074 4075 4076 4077 4078 4079 4080 4082 4083 4084 4085 4086 4087 4088 4089 4091 4092 4093 4094 4095 CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE O ILE N SER CA SER CB SER 00 SER C SER o SER N GLU CA GLU CB GLU CG GLU CD GLU OE1 GLU 0E2 GLU C GLU O GLU N MET CA MET CB MET CG MET SD MET CE MET C MET O MET N GLU CA GLU CB GLU CG GLU CD GLU OE1 GLU 0E2 GLU C GLU O GLU N MET CA MET CE MET CG MET SD MET CE MET C MET O MET N MET CA MET CE MET CG MET SD MET CE MET 529 529 529 529 529 529 530 530 530 530 530 530 531 531 531 531 531 531 531 531 531 532 532 532 532 532 532 532 532 533 533 533 533 533 533 533 533 533 534 534 534 534 534 534 534 534 535 535 535 535 535 535 75. 266 76.355 75.901 76 .912 73 .821 74 .286 72 .836 72.271 71.158 70.224 71.740 71 .896 71.156 70.629 69,. 822 69.253 68 .354 67.481 68. 516 71 .734 71.569 72.842 73 .976 75 .080 76.461 '77 .641 77. 791.

74 .499 74.. 742 74.610 75.109 75.300 76.391 77.766 78 .297 78 322 74.185 74.642 72.883 71. 913 70.484 69.591 67.787 67.409 72 .102 72 .258 72 .194 72 .399 72.577 71.337 71.377 71.346 18. 349 18 .064 18. 710 19. 806 16. 813 15.873 .17. 574 17 .310 18.293 18 .323 15.881 15. 190 15.413 14. 065 13. 801 12.394 12.131 11.2.49 12 793 13 .025 12. 032 13. 235 '12. 320 '12. 813 12 .225 12. 702 14 .462 12.272 11. 197 13 .445 13 .570 15. 039 15. 724 15.087 15.136 14. 555 12. 886 12. 197 13 .052 12 .432 12. 859 12. 915 12.849 14. 560 10. 908 10.224 10.394 8. 961 8 .623 *8.876 7. 980 9.275 16.406 17.432 15.084 15.251 17.641 18.285 18.101 19.418 19.735 18.670 19.479 20.492 18.378 18.351 17.087 17.058 15.883 16.002 14.847 18.488 19.192 17.786 17. 835 16.890 17.138 15. 84 0 16.193 19. 26C 19.809 19.871 21.233 -21 .594 20.765 20.951 22.084 19.969 22.225 23 .147 22.025 22.900 22.533 23 .791 23.608 23.291 22.785 23.791 21.563 21.368 19.884 19.042 17.502 16.310 2 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 100 1.00 1.00 1.00 1.00 1.00 1.00 2 .00 1.00 1.00 1.00 1.00 1.00 1. 00 0.50 0.50 0.50 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 .24.75 25.51 17.82 18.14 30.17 30.11 30.29 33.14 36.09 49.01 33.80 37.06 30.13 29.18 32.42 33.35 34. 76 40.42 35.88 28.27 26.75 27.80 27.82 29.43 24. 34 27.83 21. 29.53 30.14 30.25 31.95 32 35.71 36.71 40.19 33. 99 33 .06 33.49 33.12 32.48 30.60 28.70 27.55 26.84 31.10 32.80 30.50 29.25 28.10 27.48 26.94 33.72 PRT1 PRT1 PRT1 5SSD/55 145. vOl WO 98/07835 PCTIUS97/14885 342 ATOM 4096 C MET 535 73.621 8.514 22.155 1.00 29.29 ATOM 4097 0 MET 535 73.640 7.412 22.710 1.00 29.06 ATOM 4098 N LYS 536 74.644 9.367 22.185 1.00 31.75 ATOM 4100 CA LYS 536 75.869 9.073 22.930 1.00 33.24 ATOM 4101 CB LYS 536 76.950 10.108 22.628 1.00 31.29 ATOM 4102 CG LYS 536 77.602 10.007 21.258 1.00 31.09 ATOM 4103 CD LYS 536 78.570 11.154 21.103 1.00 28.76 ATOM 4104 CE LYS 536 79.219 11.220 19.755 1.00 26.70 ATOM 4105 NZ LYS 536 80.059 12.461 19.742 1.00 27.38 ATOM 4109 C LYS 536 75.630 9.014 24.451 1.00 35.30 ATOM 4110 0 LYS 536 76' '201 8.172 25.137 1.00 35.61 ATOM 4111 N MET 537' 74.788 9.902 24.972 1.00 35.67 ATOM 4113 CA MET 537 74.51.7 9.908 26.408 1.00 38.27 ATOM 4114 CB MET 537 73.858 11.221 26.844 1.00 43.86 ATOM 4115 CG MET 537 74.801 12.420 26.884 1.00 55.46 ATOM 4116 SD MET 537 76.189 12.272 28.062 1.00 63.44 ATOM 4117 CE MET 537. 75.383 12.822 29.591 1.00 62.14 ATOM 4118 C MET 537 73.657 8.734 26.845 1.00 37.10 ATOM 4119 0 MET 537 73.855 8.188 27.920 1.00 39.26 ATOM 4120 N ILE 538 72..723 8.*320 26.003 1.00 34.96 ATOM 4122 CA ILE 538 71.819 7.219 26.320 1.00 32.78 ATOM 4123 CB ILE 538 '70.618 7.202 25.342 1.00 32.48 ATOM 4124 CG2 ILE 538 69.782 5.'943 25.537 1.00 32.27 ATOM 4125 CG1 ILE 538 69.756 8.449 25.538 1.00 31.77 ATOM 4126 CDI ILE 538 68.746. 8.651 24.409 1.00) 34.25 ATOM 4127 C ILE 538 72.456 5.823 26.365 1.00 30.54 ATOM 4128 0 ILE 538 72,.146 5..039 27.250 1.00 33.37 ATOM 4129 N GLY 539 73.293 5.481 25.399 1.00 27.09 ATOM 4131 CA GLY 539 73.892 4.162 25.419 1.00 28.72 'ATOM 4132 C GLY 539 73.173 3.135 24.552 1.00 31.16 ATOM 4133 0 GLY 539 72.069 3.379 24.060 1.00 32.34.

ATOM 4134 N LYS 540 73.808 1.981 24.370 1.00 31.68 ATOM 4136 CA LYS -540 73.264 0.912 23.537 1.00 34.64 ATOM 4137 CB LYS 540 74.399 0.032 23.029 1.00 33.47 ATOM 4138 CG LYS 540 75.331 0.730 22.095 1.0'0 39.67 ATOM 4139 CD LYS 540 76.396 -0.209 21.573 1.00 41.48 ATOM 4140 CE LYS 540 77.228 0.475 20.501 1.00 48.72 ATOM 4141 NZ LYS 540 76.442 0.800 19.254 1.00 54.86 ATOM 4145 C LYS 540 72.206 -0.010 24.143 1.00 36.68 ATOM 4146 0 LYS 540 72.276 -0.370 25.324 1.00 41.03 ATOM 4147 N HIS 541 71.233 -0.396 23.319 1.00 35.61 ATOM 4149 CA HIS 541 70.190 -1.335 23.711 1.00 34.24 ATOM 4150 CB HIS 541 69.074 -0.702 24.526 1.00 33.44 ATOM 4151 CG HIS 541 68.118 -1.711 25.083 1.00 34.60 ATOM 4152 CD2 HIS 541 68.059 -2.310 26.292 1.00 33.77 ATOM 4153 NDl HIS 541 67.143 -2.316 24.309 1.00 34.19 ATOM 4155 CEl HIS 541 66.539 -3.248 25.020 1.00 36.87 ATOM 4156 NE2 HIS 541 67.074 -3.272 26.228 *1.00 34.05 ATOM 4158 C HIS 541 69.624 -2.023 22.474 1.00 36.31 ATOM 4159 0 HIS 541 69.342 -1.378 21.457 1.00 38.40 ATOM 4160 N LYS 54.2 69.407 -3.331 22.586 1.00 "36.42 ATOM 4162 CA LYS 542 68.923 -4.155 21.469 1.00 35.10 145. vOl WO 98/07835 PCT/US97/14885 343

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4163 4164 4165 4166 4168 4169 4170 4171 4172 4175 4176 4177 4179 4180 4181 4182 4183 4184 4185 4186 4188 4189 4190 4191 4192 4193 4194 4195 4197 4198 4199 4200 4201 4204 4205 4206 4208 4209 4210 4211 4212 4213 4214 4215 4217 4218 4219 4220 4221 4222 4223 4224 CB LYS C LYS O LYS N ASN CA ASN CB ASN CG ASN ODI ASN ND2 ASN C ASN O ASN N ILE CA ILE CB ILE CG2 ILE CG1 ILE CDI ILE C ILE O ILE N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE Q ILE N ASN CA ASN CB ASN CG ASN ODI ASN ND2 ASN C ASN O ASN N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N LEU CA LEU CB LEU CG LEU CDI LEU CD2 LEU C LEU O LEU N GLY 542 542 542 543 543 543 543 543 543 543 543 544 544 544 544 544 544 544 544 545 545 545 545 545 545 545 545 546 546 546 546 546 546 546 546 547 547 547 547 547 547 547 547 548 548 548 548 548 548 548 548 549 68.680 67.674 67.507 66.785 65.541 64.361 64.365 64.633 64.077 65.424 64.326 66.556 66.611 67 .040 66.244 68.532 69.008 67.617 68.410 67.504 68.453 67. 913 69.027 66 .754 67. 152 69. 720 69.719 70.800 72 075 72 .752 71. 908 71 .804 71 .290 73 .034 73 .011 73 .866 74 .880 75 .284 76.413 75 .953 76 .864 76 .107 76 .610 76 .543 77 .694 77.388 76 .148 76 .034 76. 196 78. 941 80.063 78. 746 -5.602 -3.646 -3.822 -3 .046 561 -3.081 -4 597 -5.128 -5.292 -1 .050 -0.481 -0.419 1. 002 1. 962 1.682 1. 848 2.839 1. 118 0. 194 2. 184 2 .396 350 3 .727 2 692 1.481 2. 968 4 .075 2. 200 2. 567 1. 308 0. 613 1. 088 505 3 303 3. 126 4. 151 4. 904 6. 165 7. 032 7. 768 8. 014 3 .999 3. 343 3. 919 3 .104 2 .244 1. 341 0. 513 0.436 3. 965 3.488 5. 229 21.915 20.802 19.612 21.580 21.015 21.842 21.979 23.050 20.904 20.719 20.765 20.397 20.028 21.208 22.467 21.522 22.581 18.870 18.633 18.078 16.992 15.921 14.955 15.167 14.339 17.633 18-160 17.560 18.161 18.718 19.772 20.899 19.406 17.238 16.015 17.837 17.101 17.875 17.297 16.069 18.348 16.861 17.789 15.607 15.259 14.029 14.158 12.906 15.394 15.030 15.167 14.675 1.00 34.24 1.00 32.40 1.00 32.37 1.00 32.12 1.00 33.01 1.00 34.26 1.00 32.20 1.00 32.23 1.00 30.50 1.00 32.21 1.00 31.13 1.00 30.52 1.00 29.01 a.00 25.83 1.00 24.46 1.00 27.54 1.00 22.70 1.00 29.49 1.00 27.26 1.00 28.74 1.00 27.06 1.00 23.64 1.00 .23.96 1.00 23.13 1.00 20.61 1.00 26.93 1.00 28.63 1.00 28,53 1.00 29.39 1.00 29.14 1.00 30.21 1.00 30.'74 1.00 30.79 1.00 30.78 1.00 33.04 1.00 31.07 1.00 31.37 1.00 27.32 1.00 24.17 1.00 18.06 1.00 22.50 1.00 33.38 1.00 33.58 i.-0 32.72 1.00 31.50 1.00 26.30 1.00 25.93 1.00 28.37 1.00 15.84 1.00 33.69 1.00 37.41 1.00 34.10 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 344 ATOM 4226 CA GLY 549 79.871 6.116 14.454 1.00 31.50 ATOM 4227 C GLY 549 79.425 7.429 13.839 1.00 31.11 ATOM 4228 0 GLY 549 78.221 7.686 13.700 1.00 30.15 ATOM 4229 N ALA 550 80.388 8.268 13.474 1.00 31.02 ATOM 4231 CA ALA 550 80.074 9.540 12.850 1.00 29.00 ATOM 4232 CB ALA 550 79.537 10.526 13.899 1.00 27.87 ATOM 4233 C ALA 550 81.257 10.149 12.102 1.00 27.66 ATOM 4234 0 ALA 550 82.422 9.942 12.474 1.00 25.24 ATOM 4235 N CYS 551 80.944 10.810 10.984 1.00 27.61 ATOM 4237 CA CYS 551 81.924 11.540 10.170 1.00 25.02 ATOM 4238 CB CYS 551 81.754 11.237 8.680 1.00 22.41 ATOM 4239 SG CYS 551 82.155 9.553 8.187 1.00 27.24 ATOM -4240 C CYS 551 81.583 13.009 10.447 1.00 24.31 ATOM 4241 0 CYS 551 80.569 13.525 9.958 1.00 23.55 ATOM 4242 N THR 552 82.367 -13.1657 11.303 1.00 23.22 ATOM 4244 CA THR 552 82.110 15.046 11.664 1.00 25.73 ATOM 4245 CB THR 552 82.138 15.215 13.202 1.00 26.50 ATOM 4246 OGi THR 552 83.479 15.031 13.664 1.00 26.31 ATOM 4248 CG2 THIR 552 81.257 14.171 13-886 1.00 26.64 ATOM 4249 C THR 552 83.134 16.014 11.090 1.00 27.93 ATOM 4250 0 THR 552 82.894 17-216 11.005 1.00 28.35 ATOM 4251 N GLN 553 84.264 15.473 10.663 1.00 30.26 ATOM 4253 CA GLN 553 85.355 16.288 10.153 1.00 29.27 ATOM 4254 CB GLN 553 86.669 15.768 10.763 1..O 29.54 ATOM 4255 CG GLN 553 86.653: 15.655 12.288 1.00 28.00 ATOM 4256 CD GLN 553 86.534 17.007 12 .98 1 1.00 26.86 ATOM 4257 QEl GLN 553 87.440 1-7. 821 12.902 -1.00 30.85 ATOM 4258 NE2 .3LN 553. 85.421 17.239 13.676 1.0.0 23.89 ATOM 4261 C GLN 553 85.475 16-316 8.634 1.00 28.30 ATOM 4262 0 GLN 553 85.221 15.313 7.967 1.00 31.00 ATOM 4263 N ASP 554 85.860 17.480 8.119 1.00 26.89 ATOM 4265 CA ASP 554 86.070 17.725 6.695 1.00 27.85 ATOM 4266 CB ASP 554 87.370 17.081 6.257 1.00 33.44 ATOM 4267 CG ASP 554 88.534 17.564 7.060 1.00 37.63 ATOM 4268 ODi ASP 554 89.038 18.664 6.763 1.00 42.66 ATOM 4269 0D2 ASP 554 88.929 16.843 8.000 1.00 35.80 ATOM 4270 C ASP 554 84..976 17.341 5.715 1.00 28.04 ATOM 4271 0 ASP 554 85.193 16.518 4.826 1.00 31.06 ATOM 4272 N GLY 555 83.824 17.981 5.842 1.00 28.26 ATOM 4274 CA GLY 555 82.720 17.694 4.949 1.00 25..89 ATOM 4275 C GLY 555 81.438 17.567 5.734 1.00 23.07 ATOM 4276 0 GLY 555 81.423 17.795 6.941 1.00 20.20 ATOM 4277 N PRO 556 80.338 17.185 5.076 1.00 22.81 ATOM 4278 CD PRO 556 80.280 16.750 3.679 1.00 *22.33 ATOM 4279 CA PRO 556 79.039 17.032 5.733 1.00 23.99 ATOM 4280 CB PRO 556 78.154 16.499 4.612 1.00 22.41 ATOM 4281 CG PRO .556 79.144 15.801 3.698 1.00 24.36 ATOM 4282 C PRO 556 79.080 16.066 6.911 1.00 26.98 ATOM 4283 0 PRO 556 79.854 15.111 6.934 1.00 28.57 ATOM 4284 N LEU .557 78.237 .16.325 7.896 1.00 29.25 ATOM 4286 CA LETJ 557 78:'168 15.471 9.070 1.00 30.83 ATOM 4287 CB LEU 557 77.550 16.225 10.251 1.00 33.20 SSSD/55145. vOl WO 98/07835 WO 9807835PCT1US97/14885' 345

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4288 4289 4290 4291 4292 4293 4295 4296 4297 4298 42.99 4300 4301 4302 4303 4305' 4306 4307 4309 4310 4311 4312 4313 4314 4315 4317 4318 4319 4320 4321 4322 4323 4324 4326 4327 4328 4329 4330 4331 4332 4334 4335 4336 4337 4338 4339 4340 4341 4342 4344 4345 4346

CG

CD1 CD2

C

0

N

CA

CB

CG

CD1 CE 1 CD2 CE2

CZ

OH

0

N

CA

CB

CO 1 CG2

C

0

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

CG

LEU

LEU

LEU

LEU

LEU

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

VAL

VAL

VAL

VAL

VAL

VAL

VAL

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

VAL

VAL

VAL

VAL

VAL

VAL

VAL

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

TYR

TYR

TYR

TYR

557 557 557 557 557 558 558 558 558 558 558 558 558 558 558 558 558 559 559 559 559 559 559 559 560 560 560 560 560 560 560 560 561 561 561 561 561 561 561 562 562 562 562 562 562 562 562 562 563 563 563 563 77.109 78 .304 76 .365 77 .324 76 .175 77 .913 77 .214 77 .978 78. 066 79.108 79.198 77.109 77.188 78-237 78.298 77.081 78 .077 75 .842 75 .548 74 .326 73 .915 474 .655 75..238 74.131 76 .214 76 .061 77.441 77 :252 78.254 79.671 '75 312 75 .777 74.163 73 .352 72.048 72.367 71. 186 73 .031.

73.404 72.306 71.940 71.448 72 .387 72 .012 72 .772 70.974 70 .898 69.990 71.002 70.080 70.848 70.042 15 .41.6 14 .793 16 .341 14 238 14 .343 13-.071 11. 823 10. 933 11 .481 11. 109 11. 600 12 .368 12 .871 12 .484 12 .965 11 25 10. 855 10. 879 1.0. 175 10 813 9. 992 12 .2.36 B 723 8 402 S. 851 6 .448 5.781 4 3*E9 6 .620 6 .112 5. 633 5 .493 5 .084 4 .265 5. 000 6.302 5 .250 2 .896 2 .623 2. 062 0. 714 -0 .081 0 .001 916 -1 .876 -0 .654 0 .636 1 .453 -0.392 -0 .626 -1 .236 -1 .427 11.475 12.174 12.407 8.780 8.330 9.002 8 .812 7.840 6.430 5.592 4.296 5. 941 4.648 3.825 2.525 10.164 10.835 10.574 11 .821 12.552 13.771 12.982 11.443 10.988 11 .642 i1.281 11. 002 10.465 10.004 9.763 12.339 13.479 .11.951 12. B47 13.251 13.936 12.033 12.202 11.045 12.944 12 .509 13 .712 14.873 16.003 16.255 16.639 11. 405 11.358 10.568 9.455 8.269 7.007 1.00 30.01 1.00 29.05 1.00 29.20 1.00 30.33 1.00 27-.66 1.00 30.68 1.00 29.26 1.00 30.99 1.00 35.01 1.00 36.17 1.00 41.40 1.00 36.44 1.00 40.96 1.00 43.59 1.00 42.91 1.00 28.18 1.00 28.06 1.00 26.72 00 26.7?2 1.00 28.03 1.00 29.85 1.00 29.37 1.00 25.58 1.00 25.73 1.00 24.35 1.00 26.64 1.0'0 26.53.

1.00 27.80 1.00 24.69.

1.00 17.05 1.00 27.95 1.00 25.16 1.00 27.43 1.00 27.69 1.00 25.08 1.00 19.97 1.00 25.55 1.00 30.21 1.00 32.04 1.00 28.88- 1.00 27.69 1.00 26.79 1.00 28.13 1.00 31.86 1.00 33.17 1.00 35.50 1.00 27.34 1.00 29.72 1.00 28.07 1.00 32.50 1-.,00 28.32 1.00 26.56 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 346

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATO M

ATOM

ATOM

ATOM

ATOM

ATOM

4347 CD1 TYR 4348 CEl TYR 4349 CD2 TYR 4350 CE2 TYR 43,51 CZ TYR 4352 OH TYR 4354 C TYR 4355 0 TYR 4356 N ALA 4358 CA ALA 4359 CB ALA 4360 C ALA 4361 0 ALA 4362 N SER 4364 CA SER 4365 CB SER 4366 OG SER 4368 C SER 4369 0 SER 4370 N LYS 4372 CA LYS 4373 CB LYS 4374 CG LYS 4375 CD LYS 4376 CE LYS 4377 NZ LYS 4381 C LYS 4382 0 LYS 4383 N GLY 4385 CA GLY 4386 C GLY 4387 0 GLY 4388 N ASN 4390 CA ASN 4391 CB ASM 4392 CG ASN 4393 ODI ASN 4394 ND2 ASN.

4397 C ASN 4398 0 ASN 4399 N LEU 4401 CA LETJ 4402 CB LEU 4403 CG LEU 4404 CD1 LEU 4405 CD2 LEU 4406 C LEU 4407 0 LEU 4408 N ARG 44.10 CA ARG 4411 CB ARG.

4412 CG ARG 563 563 563 563 563 563 563 563 564 564 564 564 564 565 565 565 565 565 565 56.6 566 566 566 566 566 566 566 566 567 567 567 567 568 56.8 568 568 568 568 568 568 569 569 569 569 569 569 569 569 570 570 570 570 69.338 -0.378 68.620 -0.536 70.011 -2.652 69.300 -2.821 68.605 -1.755 67.876 -1.919 68.930 -1.564 69.151 -2.569 67.711 -1.234 66.529 -2.025 65.557 -1.207 65.919 -2.360 64.958' -1.736 66.455 -3.387 66.018 -3.8-06 66.673 -5.134 66.646 -6.012 64.530 -3.932 64.097 -3.823 63'.743 183 62'.312 -4 .341 61..807 -5.541 62.468 -6.828 62.161 -8.004 62'.734 -9.277 62.692 10 .400 6.448 1.00 30.49 5.258 1.00 32.83 6.350 1.00 29.07 5.151 1.00 30.70 4.619 1.00 33.54 3.460 1.00 40.20 9.878 1.00 36.30 10.562 1.00 36.17 9.454 1.00 39.60 9.750 1.00 38.93 10.570 1.00 40.23 8.394 1.00 41.61 7.977 1.00 45.88 7.745 1.00 41.15 6.421 1.00 40.40 6.070 1.00 40.15 7.175 1.00 33.93 6.164 1.00 40.31 5.025 1.00 45.43 7.197 1.00 39.63 6.992 1.00 38.01 7.783 1.00 38.35 7.308 1.00 38.21 8.208 1.00 38.79 7.621 1.00 38.76 8.598 1.00 42.40 7.249 1.00 37.28 7.415 1.00 39.48 7.237 1.00 34.31 7.428 1.00 32.82 8.761 1.00 31.33 9.778 1.00 29.23 8.754 1.00 29.92 9.974 1.00 31.05 9.991 1.00 31.23 9.087 1.00 34.16 9.385 1.00 37.22 7,999 1.00 35.13 10.235 1.00 31.60 9.324 1.00 31.76 11.490 1.00 34.63 11.979 1.00 35.49 13.500 1.00 36.13 24.210 1.00 34.78 14.034 1.00 35.01 61.488 60.265 62.166 61.497 60 810 61.251 59-.'722 58'. 999 58 .414 57.201 56.095 57.394 57.950 57.535 57.517 56.540 56 .456 55.509 56 .010 55.425 55.141 54 .518 -3.079 132 936 -0.666 -0.473 -1.012 0.294 0.569 1. 991 2 .157 1.685 2.877 -0.486 -1.205 548 -1.511 -1.408 -2.363 -3.804 -1.971 -1.420 11.382 1.00 37.34 -2.447 11.141 1.00 41.49 54.636 -0.213 11.162 1.00 37.19 53.299 0.063 10.591 1.00 39.79 52.979 1.403 10.331 1.00 39.48 51.558 1.638 9.887 1.00 41.93 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 347 ATOM 4413 CD ARG ATOM 4414 NE ARG ATOM 4416 CZ ARG ATOM 4417 NH1 ARG ATOM 4420 NH-2 ARG ATOM 4423 C ARG ATOM 4424 0 ARG ATOM 4425 N GLU ATOM 4427 CA GLU ATOM 4428 CB GLU ATOM 4429 CG GLU ATOM 4430 CD GLU ATOM 4431 OE1 GLU ATOM 4432 0E2 GLU ATOM 4433 C GLU ATOM 4434 0 GLU ATOM 4435 N TYR ATOM 4437 CA TYR ATOM 4438 CB TYR ATOM 4439 CG TYR ATOM 4440 CD1 TYR ATOM 4441 CEl TYR ATOM 4442 CD2 TYR .ATOM 4443 CE2 TYR ATOM 4444 CZ TYR ATOM 4445 OH TYR ATOM 4447 C TYR ATOM .4448 0 TYR ATOM 4449 N LEU ATOM 4451 CA LEU ATOM 4452 CE LEU ATOM 4453 CG LEU ATOM 4454 CD1 LEU ATOM 4455 CD2 LEU ATOM 4456 C LEU ATOM 4457 0 LEU ATOM 4458 N GLN ATOM 4460 CA GLN ATOM 4461 CB GLN ATOM 4462 CG GLN ATOM 4463 CD GLN ATOM 4464 OE1 GLN ATOM 4465 NE2 GLN ATOM 4468 C GLN ATOM 4469 0 GLN ATOM 4470 N ALA ATOM 4472 CA ALA ATOM 4473 CB ALA ATOM 4474 C ALA ATOM 4475 0 ALA ATOM 4476 N ARG ATOM 4478 CA ARG 51.459 2.966 52.329 2.991 53.121 4.008 53.145 5.093 53.921 3.920 53.219 -0.835 52.309 -1.644 54.208 -0.597 54.292 -1.251 55.284 -0.492 54.818 0.941 55.845 1.799 57.047 1.434 55.455 2.854 54.617 -2.744 54.075 -3.558 55.462 -3.104 55.841 -4.498 56.822 -4.584 57.19). -5.987 58.209 6.'714 58.623 -7.960 .36..586 -6.552 56.991 -7.799 58.012 -8.495 58.427 -9.717 54.588 -5.310 54.387 -6.410 53.742 -4.740 52.498 -5.376 51.802 -4.532 52.494 -4.421 51.755 -3.4'02 52.537 -5.788 51.570 -5.549 51.144 -6.656 51.286 -4.448 50.402 -4.476 50.213 -3.071 49.380 '-2.239 49.222 -0.849 49.789 -0.483 48.450 -0.051 50.807- -5.419 49.951 -6.031 52.105 -5.562 52.579 -6.446 54.023 -6.130 52.439 -7.906 52.771 -8.804 51.937 -8.142 51.787 -9.494 9.182 1.00 49.89 8.009 1.00 55.25 7.693 1.00 57.90 8.455 1.00 56.93 6.637 1.00 57.58 9.278 1.00 39.84 9.060 1.00 42.48 8.425 .1.00 38.22 7.135 1.00 38.84 6.266 1.00 40.72 5.999 1.00 49.17 5.284 1.00 58.95 5.278 1.00 67.07 4.736 1.00 61.02 7.240 1.00 37.79 6.488 1.00 37.63 8.204 1.00 36.89 8.437 1.00 36.81 9.612 1.00 33.24 10.080 1.00 33.42 9.450 1.00 31.93 9.936 1.00 30.14 11.208 1.00 34.42 11.704 1.0.0 32.29 11.065 1.00 32.52 11.571 1.00 31.70 8.754 1.00 37.64 8.226 1.00 35.70 9.608 1.00 38.63 10.011 1.0'0 38.21 11.067 1.00 35.40 12.419 1.00 34.55 13.258 1.00 32.02 13.108 1.00 34.58 8.818 1. 00 38.11 8.507 1.00 37.68 8.138 1.00 40.92 6.982 1. 00 45.16 6.447 1.00 44.16 7.369 1.00 45.26 6.863 1.00 47.09 5.838 1.00 50.83 7.573 1.00 48.95 5.861 1.00 45.21 5.215 1.00 49.63 5.646 1.00 43.35 4.604 1.00 42.62 4.284 1.00 43.49 5.022 1.00 42.85 4.254 1.00 44.43 6.229 1.00 42.24 6.747 1.00 41.58 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 348

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4479 4480 4481 4482 4484 4485 4488 4491 4492 4493 4495 4496 4497 4498 4499 4501 4502 4505 4508 4509 4510 4512 4513 4514 4515 4516 4518 4519 4520 4521 4522 4523 4524 4525 4527 4528 4529 4531 4532 4533 4535 4536 4537 4539 4540 4541 4543 4544 4545 4546 4547 4548 CB ARG CG ARG CD ARG NE ARG CZ ARG NHI ARG NH2 ARG C ARG O ARG N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NH1 ARG NH2 ARG C ARG O ARG N GLN CA GLN CB GLN C GLN O GLN N LEU CA LEU CE LEU CG LEU CDI LEU CD2 LEU C LEU O LEU N SER CA SER CB SER OG SER C SER 0 SER N SER CA SER CB SER OG SER C -SER O SER N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS 576 576 576 576 576 576 576 576 576 577 577 577 577 577 577 577 577 577 577 577 594 594 594 '594 594 595 595 595 595 595 595 595 595 596 596 596 596 596 596 597 597 597 597 597 597 598 598 598 598 598 598 598 52.813 54.225 55.280 56.632 57.110 56.359 58.347 50.389 50.187 49.418 48.023 47.197 47.372 46.572 46.428 45.750 45.149 45.643 47.408 47.396 53.246 52.054 51.130 52.447 52 .962 52 .189 52 .524 52 .669 53 .648 53. 442 55.064 51.509 50.316 52.007 51.182 51.960 52.987 50.854 51.479 49.914 49.525 48.530 47.620 50.778 50.934 51.692 52 .930 53 .690 54 .470 55.227 55.894 54.921 725 -9.694 -9.604 -9.607 -8.684 z7. 658 -8.787 -9.762 -10.607 057 -9.222 -8.032 -6.793 -5.635 -4.577 -3.450 -3.225 -2.560 -10. 540 -104840 -13.595 -13.835 -14. 931 14.127 -15. 201 13. 154 -13.245 -11.826 -11.042 -9.55-1.

-11.431 -14.046 -14.039 -14.740 -15.543 -16.770 -16.403 14.681 -13.645 -15. 133 -14.389 -15.196 -15.914 -14.094 -12.998 -15.062 -14. 905 -16.231 -16. 395 -17.724 -37. 989 -18.149 7.849 7.314 8.392 7.826 6.992 6.612 6.541 7.255 8.137 6 .684 7.077 6. 587 7.440 6 .898 7.895 7. 704 6 .548 8 .684 6.603 5.406 7.891 8.728 8.184 10.174 10.507 11.031 12.437 12. 979 12.C99 3.2.202 12.465 13.257 12.953 14.280 15.380 15.667 16.580 16.383 16 .584 17.208 18.398 19.236 18.421 19.220 19.755 19.271 20.026 20.124 21.432 21.479 22.834 23.949 1.00 40.10 1.00 40.58 1.00 42.40 1.00 41.95 1.00 38.22 1.00 38.61 1.00 34.50 1.00 43.28 1.00 43.76 1.00 44.65 1.00 46.69 1.00 45.24 1.00 42.93 1.00 44.63 1.00 47.76 1.00 48.55 1.00 50.64 1.00 50.77 1.00 47.12 1.0.0 48.37 1.00 64.66 1.00 65.10 1.00 65.77 1.00 64.01 1.00 64.42 1.00 61.45 1.00 59.21 1.00 57.54 1.00 56.37 1.00 57.06 1.00 55.57 1.00 58.34 1.00 58.21 1.00 58.00 1.00 56.04 1.00 57.98 1.00 58.94 1.00 54.65 1.00 52.05 1.00 56.10 1.00 57.51 1.00 58.60 1.00 61.95 1.00 57.75 1.00 57.86 1.00 57.88 1.00 57.51 1.00 57.72 1.00 60.14 1.00 62.23 1.00 60.79 1.00 61.46 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 349 ATOM 4552 C LYS 598 53.809 -13 .829 19.389 1.00 55.94 ATOM 4553 0 LYS 598 54.322 -12.955 20.089 1.00 55.84 ATOM 4554 N ASP 599 53.935 -13 .866 18.061 1.00 53.32 ATOM 4556 CA ASP 599 54.737 -12.882 17.334 1.00 50.30 ATOM 4557 CB ASP 599 54.688 -13 .119 15.823 1.00 49.72 ATOM 4558 CG ASP 599 55.426 -14 .383 15.394 1.00 53.97 ATOM 4559 ODi ASP 599 56.176 -14.948 16.214 1.00 58.12 ATOM 4560 0D2 ASP 599. 55.261 -14.822 14.233 1.00 55.58 ATOM 4561 C ASP 599 54.247 -11.474 17.636 1.00 49.53 ATOM 4562 0 ASP 599 55.054 -10.589 17.911 1.00 51.16 ATOM 4563 N LEU 600 52.930* -11.281 17.634 1.00 47.50 ATOM 4565 CA LEU 600 52.354 -9.972 17.909 1.00 45.41 ATOM 4566 CB LEU 600 50.850 -9.948 17. 627 1.00 43.77 ATOM 4567 CG LEU 600 50.429 -10.121 16.169 1.00 41.05 ATOM 4568 CD1 LEU -600 48.941 904 16.048 1.00 41.04 ATOM 4569 CD2 LEU 600 51.160 -9,140 15.294 1.00 39.59 ATOM 4570 C LEU 600 52.638 -9.485 19.318 1.00 46.77 ATOM 4571 0 LEU 600 52.964 -8 .308 19.497 1.00 48.74 ATOM 4572 N VAL '601 52.524 -10.372 20 314 1.00 47.64 ATOM 4574 CA VAL 601 52.804 -10.002. 21.716 1 '00 47.38 ATOM 4575 CB VAL 601 52.321 -11. 070 22.756 1.00 46.58 ATOM 4576 'Gl VAL 601 52.081 10 .403 2.4.114 1.00 45.07 ATOM 4577 CG2 VAL 601. 51.058 -11.759 22.306 1.00 48.86 ATOM 4578 C VAL 601 54.321 9. 811 21.890 1.00 46.04- ATOM 4579 0 VAL 601 54.7S3 -8.935 22.622 1.00 46.13 ATOM 4580 N SEP. 602 55.090 -10.624 21.183 1.00 44.22 ATOM 4582 CA SER 602 -56.534 -10.546 21.233 1.00 42.78 ATOM 4583 CB SEP. 602 57.119 -11.594 20.297 1.00 43.98 ATOM 4584 OG SER 602 58.523- -11.615 20.355 1.00 51.02 ATOM 4586 C SER 602 56.954 -9.135 20.813 1.00 41.74 ATOM 4587 0 SER 602' 57.709 -8.467 21.524 1.00 44.09 ATOM 4588 N CYS 603 56.425 8.667' 19.685 1.00 3 9. 57 ATOM 4590 CA CYS 603 56.699 -7.317 19.177 1.00 36.11 ATOM 4591 CB CYS 603 55.852 -7.058 17.924 1.00 34.72 ATOM 4592 SG CYS 603 55.760 -5.364 17.323 0.50 29.10 PRT1 ATOM 4593 C CYS 603 56.378 -6.272 20.252 1.00 34.50 ATOM 4594 0 CYS '603 57.174 -5.371 20.506 1.00 33.61 ATOM 4595 N ALA 604 55.236 -6.429 20.913 1.00 34.64 ATOM 4597 CA ALA 604 54.811 -5.506 21.964 1.00 37.18 ATOM 4598 CB ALA 604 53.386 -5.850 22.414 1.00 38.20 ATOM 4599 C ALA 604 55.786 -5.516 23.160 1.00 38.91 ATOM 4600 0 ALA 604 56.026 -4.481 23.790 1.00 38.29 ATOM 4601 N TYR 605 56.323 -6.693 23.477 1.'00 39.54 ATOM 4603 CA TYR 605 57.283 -6.854 24.565 1.00 39.29 ATOM 4604 CB TYR 605 57.573 -8 .340 24.791 1.00 40.07 ATOM 4605 CG TYR 605 58.663 -8 .622 25.807 1.00 39.09 ATOM 4606 CD1 TYR 605 58.525 -8.236 27.137 1.00 38.50 ATOM 4607 CEl TYR 605 59.526 -8.505 28.074 1.00 40.76 ATOM 4608 CD2 TYR 605 59.831 -9.283 25.435 1.00 39.73 ATOM 4609 CE2 TYR 605 60.834 -9.553 26.361 1.00 37.45 ATOM 4610 C Z TYR 605 60.678 -9.166 27.677 1.00 40.34 ATOM 4611 OH TYR 605 61.666 -9.466 28.601 1.00 43.16 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 350 ATOM 4613 C TYR 605 58 .582 -6.113 24.224 1.00 39.45 ATOM 4614 0 TYR 605 59.067 -5.291 25.022 1.00 38.75 ATOM 4615 N GLN 606 59.129 -6.410 23.040 1.00 36.41 ATOM 4617 CA GLN 606 60.361 -5.787 22.550 1.00 35.20 ATOM 4618 CB GLN 606 60.695 -6.303 21.150 1.00 34.86 ATOM 4619 CG GLN 606 61.286 -7.695 21.118 1.00 32.21 ATOM 4620 CD GLN 606 61.502 -8.205 19.709 1.00 32.63 ATOM 4621 OE1 GLN 606 62.495 -7.888 19.075 1.00 32.16 ATOM 4622 NE2 GLN 606 60.568 -9.004 19.216 1.00 34.62 ATOM 4625 C GLN 606 60.286 -4.252 22.525 1.00 36.03 ATOM 4626 0) GLN 606 61.209 -3.572 22.989 1.00 38.81 ATOM 4627 N VAL 607 59.188 -3.716 21.998 1.00 33.45.

ATOM 4629 CA VAL 607 58.979 -2.280 21.923 1.00 29.34 ATOM 4630 CB VAL 607 57.651 -1.948 21.189 1.O0 28.80 ATOM -4631 CG1 VAL 607 57.260 -0.495 21.401 1.00 26.68 ATOM 4632 CG2 VAL 607 57.790 2.244 19.699 1.00 24.66 ATOM 4633 C VAL 607 58.965 -1.698 23.339 1.00 31.35 ATOM 4634 0 VAL 607 59.557 -0.643 23.579 1.00 33.86 ATOM 4635 N ALA 608 58.31.7 -2.402 24.270 1.00 30.17 ATOM 4637 CA A.LA 608 58.235 -1.971 25.667 1.00 28.98 ATOM 4638 CB ALA 608 57.255 836 26.440 1.00 28.30 ATOM 4639 C ALA 608 59.598 -1.979 26.352 1.00 28.94 ATOM 4640 0 ALA G0B 59 '889 -1.091 27.155 1.00 27.83 ATOM 4641 N ARG 609 60.436. -2.959 26.032 1.00 28.79 ATOM 4643 CA ARG 609 61.765 -3.023 26 .62B 1-00 30.90- ATOM 4644 CB ARG 609 62 .499 -4.291 26 .206 1.00 35.84 ATOM 46-45 CG ARG 609 61.787 -5.571 26.527 1. 00 41.94 ATOM 4646 CD ARG 609 -62 .782 -6.707 26.575 1.00 44.70 ATOM 4647 NE ARG 609 63 .392 -6.821 27.900 1.00 47.13 ATOM 4649 CZ ARG 609 64. "444 7.589 28.183 1.00 48.71 ATOM 4650 NH1 ARG 609 65.025 -9.314 27.233 1.00 48.33 ATOM 4653 NH2 ARG 609 64.897 -1.655 29.428 1.00 49.11 ATOM 4656 C ARG 609 62.602 -1.815 26.207 1.00 32.38 ATOM 4657 0 ARG 609 63 .215 -1.148 27.058 1.00 32.63 ATOM 4658 N GLY 610 6.2.636 -1.554 24.894 1.00 29.98 ATOM 4660 CA GLY 610 63.384 -0.430 24.358 1.00 25.65 ATOM 4661 C GLY 610 62.969 0.837 25.061 1.00 25.44 ATOM 4662 0 GLY 610 63 1791 1.640 25.463 1.00 27.09 ATOM 4663 N MET 611 61.672 1.009 25.242 1.00 30.41 ATOM 4665 CA MET 611 61.167 2.176 25.943 1.00 31.34 ATOM 4666 CB MET 611 59.653 2.233 25.832 1.00 28.39 ATOM 4667 CG MET 611 59.195 2.595 24.449 1.00 25.17 ATOM 4668 SD MET 611 59.904 4.182 24.005 1.00 26.65 ATOM 4669 CE MET 611 59.458 5.158 25.453 1.00-19.78 ATOM 4670 C MET 611 61.600 2.176 27.412 1.00 34.05 ATOM 4671 0 MET 611 62.008 3.211 27.929 1.00 33.79 ATOM 4672 N GLU 612 61.500 1.026 28.078 1.00 37.16 ATOM 4674 CA GLU 612 61.893 0.913 29.484 1.00 38.85 ATOM 4675 CB GLtJ 612 61.732 -0.533 29.988 1.00 38.96 ATOM 4676 CG GLU 612 62.249 -0.788 31.400 1.00 35.19 ATOM 4677 CD GLU 612 62.316 -2.271 31.783 1.00 35.26 ATOM 4678 OE1 GLU 612 62.605 -3.123 30.912 1.00 29.29 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885* 351

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4679 4680 4681 4682 4684 4685 4686 4687 4688 4689 4690 4691 4692 4694 4695 4696 4698 4699 4700 4701 4702 4703 4704 4705 4707 4708 4709 4710 4711 4713 4714 4715 4717 4718 4719 4721 4722 4723 4724 4725 4726 4730 4731 4732 4734 4735 4736 4737 4738 4739 4743 4744 0E2

C-

0

N

CA

CE

CG

CD1 CE 1 CD2 CE2

CZ

OH

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

GLU

GLU

GLU

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

ALA

ALA

ALA

ALA

ALA

SER

SER

SER

SER

SER

SER

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

612 612 612 613 613 613 613 613 613 613 613 613 613 613 613 614 614 614 614 614 614 614 614 615 615 615 615 615 616 616 616 616 616 616 617 617 617 617 617 617 617 617 617 618 618 618 618 618 618 618 618 618 62.102 63.353 63. 720 64. 176 65. 575 66.333 67. 800 68. 702 70. 048 68.283 69.621 70.499 71. 823 65.642 66.106 65.126 65.128 64.223 64.687 63. 718 66. 099 64.672 65.298 63. 577 63. 028 61.682 64. 021 64. 111 64.752 65.741 66.274 67.106 66.870 67.633 66. 958 67.965 68 .511 69.274 70.502 71.201 72.566 67.378 67. 943 66.221 65.570 66.543 67.234 66.301 66.933 65.965 65.026 64.562 588 1.364 2.060 0. 972 1.362 0. 722 1. 100 0. 527 0. 905 2. 068 2 .454 1. 868 2.249 2. 881 3.541 3 .423 .4 .864 5. 202 4.699 -5 188 5. 184 5.653 6 .639 5 .203 5835 S..187 5. 776 6. 731 4.665 4. 534 3 .091 2 .680 5 .516 5. 902 5. 925 6 .876 6 .494 5 .206 5.348 4.022 4.211 8 .275 9 .155 8 .468 9. 779 10 .833 10 .499 10. 668 10. 121 10 .161 10 .261 11 .393 32.982 29.628 30.584 28.662 28.664 27. 494 27.467 28.364 28.386 26. 581 26.596 27.503 27.538 28.562 29.486 27.460 27.212 26.025 24.659 23 .612 24.363 28.430 28. 816 29.032 30. 222 30.608 31.389 32.175 31. 511 32.577 32.702 31.628 32.287 33.179 31. 024 30.606 29.238 29.236 30.077 30. 232 30. 790 30. 564 29. 934 31.187 31.231 31. 746 33.062 34.236 35.495 36.618 29. 887 29. 781 1.00 1. 00 1. 0.0 1.00 1.00 1.00o 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1. 00 1.00 1. 00 1.00 1.00 1. 00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1. 0.0 1.00 1. 00 1.00 1. 00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 37.85 40.01 38.27 40.33 39.71 39.03 41.41 42 .79 40.21 39.75 39.01 39.56 35.63 38.71 38 .52 37.22 35.66 35.27 33 .09 33.31 31.20 35.64 34.54 36 .61 37 .74 37.74 37.30 37.29 37..18 36 .92 34 .82 28 .79 38 38 37.62 36.~13 35 34.58 35.44 38 .54 41.54 36.55 40.26 36 .42 36.06 42.22 52 .36 61.51 67.28 73.99 34 .94 34.69 145. vOl WO 98/07835 PCTIUS97/14885 352

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4745 4747 4748 4749 4750 4751 4752 4754 4755 4756 4757 4758 4759 4760 4761 4763 4764 4765 4766 4767 4769 4770 4772 4773 4774 4776 4777 4778 4779 4780 4782 4783 4786 4789 4790 4791 4793 4794 4795 4796 4797 4798 4799 4800 4802 4803 4804 4805 4806 4807 4808 4809 N CYS CA CYS CB CYS SG CYS C CY.S O CYS N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE 0 ILE N HIS CA HIS CB HIS CG HIS CD2 HIS ND1 HIS GEl HIS NE2 HIS c HIS u HIS N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NH1 ARG NH2 ARG C ARG 0 ARG N ASP CA ASP CB ASP CG ASP ODi ASP 0D2 ASP C ASP O ASP N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU Q LEU N ALA 619 619 619 619 619 619 620 620 620 620 620 620 620 620 621 621 621 621 621 621 621 621 621 621 622 622 G22 622 622 622 622 622 622 622 622 623 623 623 623 623 623 623 623 624 624 624 624 624 624 624 624 625 65 .051 64 .588 65 .311 64 .920 63 .075 62 .465 62 .477 61 .046 60.440 59.002 60 .486 59 .994 60 .969 61.516 60.356 60.230 59.866 60.049 60 .694 59 .462 59.734 60.481 59.246 59.459 58 .128 57.117 57 .694 58.171 58.837 59.315 60.487 61.326 60.803 56.405 55 .527 56 .806 56 .128 56 .574 55,.736 56 .277 54.535 56 .271 56 .664 56.015 56.099 56 .070 56.049 57.225 56 .072 54.917 53-763 55.214 9.407 9.793 8.966 9.397 9.699 8.645 10.818 10.909 12.129 12.339 11.913 13.084 11:,086 12.040 10. 114 3.0.092 8.668 8.402 7.404 9.173 8.652 7.579 11.103 11.574 11 .36.3 12.323 13.7.32 14.253 15. 591 16.101 15.786 14.965 16.268 12.008 12.763 10. 938 10.538 11. 352 11. 036 11.082 10.715 9.052 8.645 8.244 6.801 6.144 4.618 3.975 4.283 6.320 6.608 5.640 28.872 27.543 26.475 24.778 27.355 27.584 26.960 26.708 27.421 26.986 28.933 29. 710 25.206 24 674 24 .533-- 23.087 22.642 21.173 20.533 20. 187 1 9 .006 19.184 22.499 21. 388 23.178 22. 686 2 2. 617 23 .937 23.759 25.032 25. 575 24.952 2 6.76 9 21.355 20.936 20.668 19.436 18.221 16-.974 15.851 17.119 19.162 18.073 20.179 20.029 21.407 21. 514 20. 799 22.987 19.185 19. 508 18.081 1.00 34.46 1.00 33.12 1.00 34.33 1.00 35.64 1.00 32.13 1.00 30.72 1.00 32.70 1.00 32.75 1.00 33.55 1.00 38.39 1.00 30.71 1.00 30.11 1.0.0 33.31 1.00 33.40 1.00 33.56 1.00 32.30 1.00 29.55 1.00 27.32 1.00 24.26 1.00 25.20 1.00 25.81 1.00 26.65 1.00 35.40 1.00 39.18 1I.0.0 36.39 1.00 36.40 1.00 35.62 1.00 33.79 0.5.0 32.17 0.50 32.82 0.50 34.07 0.50 33.44 0.50 32.70 1.00 36.23 1.00 35.04 1.00 35.84 1.00 35.68 1.00 38.71 1.00 46.29 1.00 52.33 1.00 50.45 1.00 32.98 1.00 30.90 1.00 31.16 1.00 31.71 1.00 28.48 1.00 28.13 1.00 27.00 1.00 29.10 1.00 32.67 .1.00 35.74 1.00 29.82 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 353

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4811 4812 4813 4814 4815 4817 4818 4819 4820 4821 4823 4824 4825 4826 4827 4829 4830 4833 4836 4837 4838 4840 4841 4842 4843 4844 4847 4848 4849 4851 4852 4853 4854 4855 4856 4857 4859 4860 4861 4862 4863 4864 4865 4866 4868 4869 4870 4871 4872 4873 4874 4876 CA ALA CB ALA C ALA O ALA N ALA CA ALA CB3 ALA C ALA O ALA N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NH1 ARG NH2 ARG C ARG O ARG N ASN CA ASN CB A.SN CG ASN 0121 ASN ND2 ASN r, ASN O ASM N VAL CA* VAL CB VAL CG1 VAL CG2 VAL C VAL O VAL N LEU CA LET) CB LET) CG LET) CD1 LEU CD2 LEU C LET) O LEU N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL 0 VAL N THR CA THR 625 625 625 625 626 626 626 626 626 627 627 627 627 627 627 627 627 627 627 627 628 628 628 628 6 28 628 628 628 629 629 629 629 629 629 629 630 630 630 630 630 630 630 630 631 631 631 631 631 631 631 632 632 54.194 53.682 54.895 56.118 54.131 54.687 53.577 55. 569 56.544 55. 208 55. 980 55.289 54.991 54.7 11 54.26 0 52.997 52.056 52.68 9 57.439 58.362 57.634 58.954 58.864 58.539 59. 079 571.639 59. 684 60. 641 5.9.209 59.828 58.,812 59.492 58.205 60.26G 59.454 61.542 62.062 63.297 63.044 64.345 62.111 62.367 62.629 62.246 62.468 61.194 61. 346 59.937 63.697 63.849 64.551 65. 770 5. 106 6. 182 4-031 4.028 3.135 2. 028 1.169 2.573 1. 944 3. 744 4.413 5.728 6.692 8.130 8. 978 9.067 8-380 9. 748 4.686 4.606 4.938 5.234.

6.359 7.687 8.028 8 .426 4.039 4.188 2.853 .610 0.693 -0.604* 1.398 0 ."962 0.839 0.603 021 0.733 2.242 2. 944 2.603 -1.492 -1.852 -2 .346 -3 .790 -4 .607 -6.085 -4.030 -4.286 -3 .999 -5 .052 -5 .574 17.181 16 .245 16.395 16.343 15.770 14 979 14 .365 13 .892 13 .519 13 .378 12 .338 11.914 13-055 12.584 13 .691 14 .091 13 .460 15 .183 12 .785 11.972 14.087 14.645 15.676 15.035 13 .999 15.628 15.225 16 .001 14 .874 15~.315 16 007 16.412 17.207 14 .007 13 .087 13 .904 12.685 12 .210 12 .111 11.972 10.965 12 .961 14 .101 11.946 12 .098 11.659 12 .026 12 .290 11.305 10 .097 11.979 11.365 1.00 28.29 1.00 26.72 1.00 28.40 1.00 .32.12 1.00 28.55 1.00 26.25 1.00 23.54 1.00 23.68 1.00 26.07 1.00 23.80 1.00 26.57 1.00 25.91 1.00 27.60 1.00 33.01 1.00 34.18 1.00 35.88 1.00 38.89 1.00 36.43 1.00 29.03 1.00 29.24 1.00 29.51 1.00 26.41 1.00 25.32 1.00 28.11 1.00 32.09 1.00 27.88 1.00 25.77 1.00 24.77 1.00 26.63 1.00 25.34 1.00 21.26 1.00 22.96 1.00 16.65 1.00 26.79 1.00 28.60 1.00 25.91 1.00 26.95 1.00 22.79 1.00 20.04 1.00 11.86 1.00 19.22 1.00 28.01 1.00 28.26 1.00 30.82 1.00 31.75 1.00 30.04 1.00 29.25 1.00 24.59 1.00 35.24 1.00 34.02 1.00 36.24 1.00 38.23 145. vOl WO 98/07835 PCT/US97/14885 354

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

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ATOM

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ATOM

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ATOM

ATOM

ATOM

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ATOM

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4877 CB THR 4878 OGi THR 4880 CG2 THR 4881 C THR 4882 0 THR 4883 N GLU 4885 CA GLU 4886 CB GLTJ 4887 CG GLU 4888 CD GLU 4889 OE1 GLU 4890 0E2 GLU 4891 C GLU 4892 0 GLU 4893 N ASP 4895. CA ASP 4896 CB ASP 4897 CG ASP 4898 ODI ASP 4899 0D2 ASP 4900 C ASP 4901 0 ASP 4902 N ASN 4904 CA ASN 4905 CB ASN 4906 CG ASN 4907 ODI ASN 4908 ND2 ASN 4911 C ASN 4912 0 ASN 4913 N VAL 4915 CA VAL 4916 CB VAL 4917 CG1 VAL 4918 CG2 VAL 4919 C VAL 4920 0 VAL 4921 N MET 4923 CA MET 4924 CB MET 4925 CG MET 4926 SD MET 4927 CE MET 4928 C MET 4929 0 MET 4930 N LYS 4932 CA LYS 4933 CB LYS 4934 CG LYS 4935 CD LYS 4936 CE LYS 4937 NZ LYS 632 632 632 632 632 633 633 633 633 633 633 633 633 633 634 634 634 634 634 634 634 634 635 635 635 635 635 635 635 635' 636 636 636 636 636 636 636 637 637 637 637 637 637 637 637 638 638 638 638 638 638 638 66.843 -5.836 12.416 1.00 38.21 66.423 -6.908 13.272 1.00 38.31 67.069 -4.582 13.238 1.00 40.22 65.526 -6.854 10.593 1.00 39.17 64.471 -7.457 10.744 1.00 41.26 66.496 -7.259 9. 766 1.00 41.23 66.397 -8.483 8.960 1.00 42.62 67.677 -8.712 8.154 1.00 44.25 67.610 -9.884 7.154 1.00 51.05 66.825 -9.594 5.858 1.00 56.28 66.390 -8.444 5.626 1.00 62.64 66.651 -10.536 5.058 1.00 58.41 66.097 -9.722 9.797 1.00 41.83 65.578 -10.704 9.288 1.00 42.77 66.415 -9.665 11.082 1.00 43.14 66.167 -10.784 11.978 1.00 44.01 67.361 -11.007 12.914 1.00 49.37 68.636 -11.396 12.166 1.00 54.70.

68.683 -12.51.5 11.595 1.00 55.43 69.602 -10.596 12.167 1.00 56.17 64.925 -10.507 12.801 1.00 43.95 64.754 -11.085 13.864 1.00 45.92 64-.075 -9.604 12.316 1.00 44.71 62.822 -9.220 12.980 1.00 43.07 61.854 -10.404 13.018 1.00 45.50 61.606 -10.994 11.653 1.00 45.43 60.997 -10.369 10.788 1.00 49.56 62.114 -12. 190 11.435 1.00 48.18 62.927 -8.*609 14.380 1.00 41.64 62:050 -8.814 15.221 1.00 41.69 63.984 -7.843 14.627 1.00 41.17 64.177 -7.178 15.922 1.00 39.01 65.692 -7.002 16.259 1.00 40.66 65.882 -6.209 17.560 1.00 35.04 66.355 -8.360 16.367 1.00 41.69 63.544 -5.789 15.925 1.00 36.77 63'.817 -4.989 15.045 1.00 38.35 62.696 -5.518 16.908 1.00 35.71 62.049 -4.216 17.031 1.00 33.65 60.783 -4.319 17.884 1.00 38.24 59.737 -5.314 17.371 1.00 41.34 59.128 -4.993 15.695 1.00 42.24 59.249 -6..621 14.976 1.00 39.27 63.001 -3.209 17.668 1.00 32.62 63.524 -3.436 18.765 1.00 30.56 63.173 -2.070 17.008 1.00 32.03 64.073 -1.027 17.492 1.00 28.77 65.351 -1.022 16.654 1.00 27.71 66.245 -2.211 16.896 1.00 25.04 67.429 -2.170 15.976 1.00 24.50 *68.443 -3.187 16.390 1.00 22.85 69.121 -2.803 17.651 1.00 24.79 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 355

ATOM

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ATOM

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ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

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ATOM

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4941 4942 4943 4945 4946 4947 4948 4949.

4950 4951 4952 4954 4955 4956 4957 4958 4960 4961 4962 4963 4964 4965 4966 4967 4969 4970 4971 4972 4973 4974 4975 4976 4977 4978 4979 4981 4982 4983 4984 4986 4987 4988 4989 4990 4991 4992 4993 4995 4996 4997 4998 4999

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD1 CD2 CEl CE2'

CZ

C

0

N

CA

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

C

0

N

LYS

LYS

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ALA

ALA

ALA

ALA

ALA

ASP

ASP

ASP

ASP

ASP

AS P AS P

ASP

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

GLY

GLY

GLY

GLY

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

ALA

ALA

ALA

ALA

ALA

ASP

638 638 639 639 639 639 639 639 639 639 640 640 640 640 640 641 641 641 641 641 641 641 641 642 642 642 642 642 642 642 642 642 642 642 643 643 643 643 644 644 644 644 644 644 644 644 645 645 645 645 645 652 63 .443 62. 977 63 .410 62 .857 62 .800 62 .074 62 .142 60 .634 63 .739 64 .968 63 .108 63 .825 63 .624 63 .338 62 .289 64 .082 63 .749 62 .539 62 .928 64.092 62 .063 63 .545 62 .805 64 .204 64 .099 64.403 65 .786 66 .906 65. 969 68 .180 67 .234 68.344 65.050 64 .967 65 .966 66 .925 66'.694 67.500 65.617 65.306 63 .962 63 .900 62 .541 65.006 65.248 64.850 65.. 629 65.610 66 .495 64 .178 63 .716 52 .340 0. 364 0. 799 1. 032 2 .379 2 .875 4 .208 1 .835 1-748 3 .363 3 .381 4170 5 .176 4 .939 6. 572 6 .706 7 .605 9 .010 9 .489 10 .026 9 .833 :1 .652 9.367 10.294 8 .635 8 .874 7 .581 7 .013 7 537 5 .981 7 .050 .5.494 6 .027 10 .001 10 .469 10.400 11.447 12 .747 13 .666 12 .825 14 .034 13 .907 13 .059 13 .278 13.467 15-.257 15 .175 16.399 17 .656 18 .684 18 .185 18 .488 21 .795 17.446 16 .391 18.601 18.721 20.201 20.279 21.118 21.003 17.955 18.125 37.108 16.339 14.851 16.739 17.371 16.351 16.656 15.840 14 .471 14 .021 13 .823 18-125 18.448 19. 016 20.456 21i.226 20.964 21.607 20.054 21.342 19.789 20.-431 20. 907 22. 047 20.015 20.324 19.571 19.688 18.786 18.019 17.314 16.057 15.413 15.105 18.894 20.053 18.332 19.073 18.382 19.215.

.20.322 14 .895 1 .00 1 .00 1.00 1.00 1. 00 1 .00 1.00 .1.00 1.00 1.00 1 .0.0 1.00 1.00 1 .0.0 1.00 1 .00 1 .00 1. 00 1 .00 1.00 1. 00 1. 00 1 .00 1 .00 2.00 1.00 1 .00 1 .00 1 .00 1 .00 1.00 1. 00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1 .00 1 .00 1 .00 1 .00 1 .00 1 .00 1.00 1.00 1.00 1. 00 1. 00 1.00 1 .00 28 .00 25.60 25.32 25. 91 25.56 22.82 28.00 33.25 26.87 24.13 26.74 30.62 30. 31- 32.53 33.83 33.05 37.66 42.62 50. 92 59. 21 54 37.85 39.10 37.47 36.47 32 .22 30. 32.45- 28.53 30.88 27.74 29.64 39.69 38.22 41.08 40.65 43.53 41.10 48.35 51.11 50.28 54. 03 57.34 56. 52 .68 54. 54 .61 54 53.32 54.09 53 .14 91. 33 145. vOl WO 98/07835 PCTIUS97/14885 356

ATOM

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ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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ATOM'

ATOM

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5001 5002 5003 5004 5005 5006 5007 5008 5010 5011 5012 5013 5014 5015 5016 5017 5018 5020 5021 5022 5024 5025 5026 5027 5028 5029 5030 5031 5032 5034 5035 5036 5038 5039 5040 5041 5042 5043 5047 5048 5049 5051 5052 5053 5054 5055 5056 5060 5061 5062 5064 5065 CA ASP CE ASP CG ASP ODI ASP 0D2 ASP C ASP 0 ASP N TYR CA TYR CB TYR CG TYR CD1 TYR CEl TYR CD2 TYR CE2 TYR CZ TYR OH TYR C TYR 0 TYR N TYR CA TYR CB TYR, CG TYR CD1 TYR CEl TYR CD2 TYR CE2 TYR CZ TYR O1- TYR C TYR O TYR N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS O LYS N LYS CA LYS .CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS O LYS N GLY CA GLY C GLY 652 652 6 52 652 652 652 652 653 653 653 653 653 653 653 653 653 653 653 653 654 654 654 654 654 654 654 654 654 654 654 654 655 655 655 655 655 655 655 655 655 656 656 656 656 656 656 .656 656 656 660 660 660 51.194 51.650 50.488 49.479 50.586 50.352 50.645 49.289 48.381 47.306 47.800 47.047 47.477 49.006 49.443 48.675 49.109 47.701 47,180 47.734 47.087 46.387 45.375 45.781 44.857 44.012 43 .078 43 .506 42. 588 48.012 47 .567 49.290 50.233 51.666 52.688 54.106 55.108 56.528 50.102 50.233 49.787 49.639 48.795 47.313 46.590 45.089 44.362 51.004 51.915 49.270 48.416 47.664 21.914 22.138 22.434 23.032 22.075 20.652 19.641 20.737 19.619 20.003 20.140 20.818 20.915 19.559 19.649 20.325 20.394 19.165 18.057 20.013 19.707 20.959 21.497 22.017 2.431 21.41.9 21.833 22.335 22.717 19.115 18.767 18.971 18.406 18.814 18.252 18.646 17.832 18.184 16.890 16.259 16.319 14.875 14.537 14.802 14.599 14.555 14.518 14.206 14.749 10.021 11.168 13-.092 14. 004 12.555 11.606 12.042 10.414 14.103 13.463 14 .895 15.110 16 .133 17.559 18 .513 19.839 17 .964 .19.280 20.214 21.518 13 .830 13 .759 12.814 11.353 11 .028 12 .014 13 .246 14 .197 11 .753 12.698 13 .918 14 .872 10-503 9 .410 10.836 9.887 10.229 9.251 9.607 8 .789 9.099 9. 896 10.945 8 .737 8 .603 7 .376 7.535 6 .213 6.406 5 .106 8 .487 7.855 5.735 6 .005 7.324 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 0.0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 00 1.00 1.00 1.00 90.97 92 .06 94. 00 95.25 94 .81 90.61 91.26 89.65 88.25 88.16 88.74 90.00 90.70 89. 14 89.49 89.80 89.81 87.32 87.70 86 .51 87.08 88 90.25 90.15 90 .94 1.00 91.22 1.0.0 93.22 1.0.0 92.39 1.00 94.38 1.00 87.34 1.00 88.29' 1.00 86.67 1.00 87.62 1.00 90.01 2.00 95.23 1.00 99.04 1.00102.26 1.00104 .44 1.00 87.61 1.00 87.58 1.00 87.88 1.00 89.03 1.00 90.44 f100 93.30 1.00 96.87 1.00 99.35 1.00102.42 1.00 88.57 1.00 88.38 1.00 61.58 1.00 58.75 1.00 57.22 SSSD/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885* 357

ATOM

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ATOM

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ATOM

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ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5066 0 GLY 5067 N ARG 5069 CA ARG 5070 CB ARG 5071 CG ARG 5072 CD ARG 5073 NE ARG 5075 CZ ARG 5076 NHl ARG 5079 NH2 ARG 5082 C APG 5083 0 ARG 5084 N LEU 5086 CA LEU 5087 CB LEU 5088 CG LEU 5089 CD1 LEU 5090 CD2 LEU 5091 C LEU 5092 0 LEU 5093 N PRO 5094 CD PRO 5095 CA PRO 5096 CB PRO 5097- CG PRO 5098 C PRO 5099 0 PRO 5100 N VAL 5102 CA VAL 5103 C.B VAL 5104 CGl VAL 5105 CG2 VAL 5106 C VAL 5107 0 VAL 5108 N LYS 5110 CA LYS 5111 CB LYS 5112 CG LYS 5113 *CD LYS 5114 CE LYS 5115 NZ LYS 5119 C LYS 5120 0 LYS 5121 N TRP 5123 CA TRP 5124 CE TRP 5125 CG TRP 5126 CD2 TRP 5127 CE2 TRP 5128 CE3 TRP 5129 CD1 TRP 5130 NE1 TRP 660 661 661 661 661 661 661 661 661 661 661 661 662 662 662 662 662 662 662 662 663 663 663 663 663 663 663 664 664 664 664 664 664 664 665 665 665 665 665 665 665 665 665 666 666 666 666 666 666 666 666 666 46.555 11.624 7.437 1.00 58.01 48.231 10.374 8.293 1.00 55.37 47.631 10.247 9.622 1.00.51.19 48.095 8.965 10.337 1.00 51.89 47.756 7.663 9.612 1.00 51.56 48.057 6.443 10.484 1.00 50.77 47.834 5.181 9.772 1.00 50.04 48.015 3.974 10.307 1.00 48.12 48.421 3.855 11.569 1.00 43.28 47.788 2.882 9.578 1.00 43.69 48.041 11.463 10.446 1.00 46.22 48.998' 12.162 10.097 1.00 44.78 47.328 11.703 11.542 1.00 41.80 47.621. 12.837 12.419 1.00 36.78 46.342. 13-596 12.758 1.00 33;.05 45.642 14.279 11.585 1.00 28.24 44.198 14. 611 11.935 1.00 24.66 46.42'9 15.511 11.217 1.00 28.35 48.278 12.328 13.695 1.00 36.10 47.695 11.521 14.431 1.00 34.46 49.526 12.751 13.945 1.00 35.83 50.360 13.537 13.022 1.00 37.72* 50.310 12.365 15.119 1.00 35.68 51.611 13.130 14.914 1.00 35.23 51.756 13.1.34 13,437 1.00) 36.10 49:.660 .12.703 16.453 1.00 35.87 49.958 12.069 17.469 1.00 39.86 48.787' 13'. 705 16.466 1.00 33.54 48.109 47.19.6 48.025 46.093 47.301 47.095 46. 940 46.153 45.596 44.700 44.096 42.967 42.479 46.889 46.295 48.183 48.987 50. 329 50. 263 49. 701 49. 891 49.067 50.743 50. 522 14.076 17.699 1.00 31.24 15.321 17.520 1.00 30.45 16.480 17.051 .1.00 32.54 15.062 16.523 1.00 34.77 12.895 18.233 1.00 31.33 12.782 19.438 1.00 32.66 11.968 17.345 1.00 30.44 10.795 17.719 1.00 28.43 10.133 16.466 1.00 24.82 11.080 15.687 1.00 27.50 10.466 14.442 1.00 26.62 11.326 13.909 1.00 21.64 10.850 12.584 1.00 25.29 9.794 18.615 1.00 29.56 8.836 19.095 1.00 29.57 10.020 18.826 1.00 30.12 9.174 19.704 1.00 31.39 8.845 19.059 1.00 30.40 7.700 18.106 1.00 30.79 7.719 16.785 1.00 30.22 6.430 16.245 1.00 28.24 8.702 16.012 .1.00 30.60 6.435 18.307 1.00 28.07 5.670 17.187 1.00 29.15 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885 358

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

A.TOM

ATOM

ATOM

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ATOM

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ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

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ATOM

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5132 5133 5134 5135 5136 5137 5139 5140 5141 5142 5143 5144 5145 5146 5148 5149 5150 5151 5152 5153 5154 5155 5156 5157 5158 5159 5161 5162 5163 5164 5165 5166 5167 5168 5169 5171 5172 5173 5174 5175 5177 5178 5179 5180 5181 5182 5183 5184 5186 5187 5188 5189 CZ2 TRP CZ3 TRP CH2 TRP C TRP 0 TRP N MET CA MET CB MET CG MET SD MET CE MET C,

MET

O MET N ALLA CA ALA CB ALA C ALA 0 ALA N PRO CD PRO CA PRO CB PRO CG PRO C PRO 0 PRO N GLtJ CA GLUd CB GLU CG GLU CD GLU OE1 GLU OE2 GLU C GLU O GLU N ALA CA ALA CB ALA C ALA O ALA N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU 0 LEU N PHE CA PHE CB PHE CG PHE CD1 PHE 666 666 666 666 666 667 667 667 667 667 667 667 667 668 668 668 668 668 669 669 669 669 669 669 669 670 670 670 670 670 670 670 670 670 671 671 671 671 671 672 672 672 672 672 672 672 672 673 673 673 673 673 49.462 48.640 48 .845 49.242 49. 591 49.028 49.260 49. 163 50. 510 50.358 50. 914 48.389 47.186 49. 027 48.345 49.351 47.603 48. 059 46.474 45. 842 45.677 44.609 44 .421 46.476 47.266 48.050 48. 739 49. 864 49.408 50.225 48 .235 49.0-90 49.362 49.677 50.686 51.412 50. 046 50.558 48. 903 48.163 47. 080 46.388 4'7. .404 45.459 47.535 47.683 46.863 46.203 44. 995 43. 987 43.399 6.107 8.374 7.086 9.902 9.287 11.214 12.065 13 .529 14.194 15.906 15.810 11.839 11.646 11.885 11.733 11. 537 13 .038 14.. 090 13.001 11.827 14 .204 13 .698 12.279 15.372 16.497 15.105 16.158 15.645.

14.646 13.204 12.331 12.931 16.798 17.983 16.008 16.512 15.347 17.410 18.484 16.970 17.702 16. 782 17.103 17.316 15.951 18.964 20.058 18.803 19.911 19.394 18.646 17.477 14.954 14.726 14.213 21.026 22.040 21.007 22. 159 21.751 21.574 21.096 19.386 23.378 23.273 24 .542 25.815 26.929 26.014 25. 566 26 731 27.355 26.980 27 .948 27.499 27.570 27.075 28.607 29.244 30.504 30.252 30.290 30.639 29.986 28.333 28.444 27.440 26.513 25.841 25.465 25.148 24.952 23 .925 23.335 22.005 20.912 21.640 24.512 23.969 25.645 26.314 27.104 26.259 26. 728 1.00 29.38 1.00 31.27 1.00 31.33 1.00 33.92 1.00 35.23 1.00 35.72 1.00 36.43 1.00 37.70 1.00 40.10 1.00 46.91 1.00 40.40 1.00 38.36 1.00 39.53 1.00 39.93 1.00 38.48 1.00 37.61- 1.00 39.48 1.00 39.40- 1.00 42.22 1.00 42.77 1.00 43.91 1.00 44.49 1.00 43 .59 1.00 44.89 1.00 45.48 1.00 43.39 1.00 42. 97 1.00 43.31 1.00 44.78 1.00 43.48 1.00 41.85 1.00 47.18 1.00 43.18 1.00 41.68 1.00 44.65 1.00 44.44 1.00 40.17 1.00 46.49 1.00 45.70 1.00 50.30 1.00 52.07 1.00 54.41 1.00 57.12 1.00 57.65 1.00 56.14 1.00 52.42 1.00 52.71 1.00 52.74 1.00 54.32 1.00 52.92 1; 00 52.38 1.00 53.49 SS5D/55145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 359

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM.

-ATOM

ATOM

5190 5191 5192 5193 5194 5195 5196 5198 5199 5200 5201 5202 5203 5204 5205 5207 5208 5209 5210 5211 5213 5214 5217 5220 5221 5222 5224 5225 5226 5227 5228 5229 5230 5231 5233 5234 5235 5236 5237 5238 5239 5240 5241 5243 5244 5245 5247 5248 5249 5251 5252 5253 CD-2 CEl CE2 cz

C

0

N

CA

CB

CG

OD1 0D2

C

0

N

CA

CB

CG

CD

NE

cz NHl NH2

C

0

N

CA

CB

CG2 CG 1 CD1

C

0

N

CA

CB

CG

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CZ

OH

C

0

N

CA

CE

OG1 CG2

C

0

PE

PE

PE

PE

PHE

PHE

ASP

ASP

ASP

ASP

ASP

ASP

AS P

ASP

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

THR

THR

THR

THR

THR

THR

THR

673 673 673 673 673 673 674 674 674 674 674 674 674 674 675 675 675 675 675 6-75 675 675 675 675 675 676 676 676 676 676 676 676 676 677 677 677 677 677 677 677 677 677 677 677 677 678 678 678 678 678 678 678 43.-624 42 .468 42 .698 42 .118 47.138 47.289 47 .808 48 .703 48 .644 47.299 46 .715 46 .844 50.182 51.010 50 .525 51 .915 52.. 341 51 .542 52 .082 53.360 54 .096 53 .687 55.250 52.853 53 .988 52 .359 .53 108 52.241 52 .804 52 .129 51.324 53.572 52 .770 54 .865 55.412 56 .296 55.524 55.229 54 .514 55.085 54 .376 54 .095 53.399 56.192 57.053 55.830 56.505 55.729 54.663 55.160 56.656 56.231 19.109 16.779 18.420 17. 250 20.732 21.938 20.076 20.772 20. 101 20.234 19. 188 21.384 20.886 21. 273 -20. 526 20. 576 22.020 22.678 24.066 24. 019 25.089 26. 301 24.943 19.932 20.366 18.883 18.153 17.944 16.844 19.257 19.147 16.800 15.892 16.6E;75 15.429 15.700 16.175 17.532 17.965 15.263 15.680 17.028 17.414 14.713 15. 309 13 .461 12.659 12 .634 11.676 14. 010 11.221 10. 888 24 .999 25.957 24.229 24 .710 27.220 27.026 28.165 29.104 30.485 31.152 31.504 31 .337 28. 706 29.541 27.468 26.995 26 .692 25.569 25.202 24.482 24.181 24 .536 23.540 28.03.7 28.211 28.664 29.683 30.958 31.8256 31 .721 32 .963 29.144 28 .951 28.890 28.383 27.167 25.951 25 .762 24 .634 24.985 23.862 23 .692 22.573 29.482 30.124 29.748 30.760 32 .107 32.046 32.429 30.261 29.158 1.00 1.00 1.00 1.00 1.00 1.0.0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1 .0.0 1 .00 1.00 1 .00 1. 00 1.00 1.00 i.00 1.00 1.00 1. 0.0 1.00' 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 51.61 50.49 50. 91 50.09 56.29 58.05 56.38 56 .12 53 .81 52 .48 50.25 51. 16 57 .07 56 .00 57.28 55.64 58 66.91 72. 75.10 71.27 72.12 53.25 52.13 51 .44 49.81 46 .07 40 .98 43.31 45.02.

51.20 52.37 52.81 53 .96 57.26 64.10 65.60 67.15 66.29 67.34 69.24 73.55 52.30 53 .73 48 45.99 46.04 49.79 45.58 43.81 45 .12 145. vOl WO 98/07835 PCT/US97/14885 360 ATOM 5254 N HIS 679 57.250 10.359 31.076 1.00 41.50 ATOM 5256 CA HIS 679 57.414 8.971 30.687 1.00 38.39 ATOM 5257 CB HIS 679 58.390 8.253 31.603 1.00 38.62 ATOM 5258 CG HIS 679 59.798 8.770 31.524 1.00 41.51 ATOM 5259 CD2 HIS 679 60.456 9.690 32.273 1.00 40.12 ATOM 5260 ND1 HIS 679 60.715 8.296 30.613 1.00 41.18 ATOM 5262 PEI HIS 679 61.880 8.892 30.806 1.00 39.44 ATOM 5263 NE2 HIS 679 61.747 9.742 31.807 1.00.41.37 ATOM 5265 C HIS 679 56.068 8.279 30.720 1.00 39.57 ATOM 5266 0 HIS 679 55.909 7.215 30.137 1.00 41.93 ATOM 5267 N GLN 680 55.108 8.863 31.429 1.00 39.84 ATOM 5269 CA GLN 680 53.773 8.290 31.483 1.00 38.92 ATOM 5270 CB GLN 680 53 .021 8.705 32.751 1.00 38.21 ATOM 5271 CG GLN 680 53.518 8.005 34.022 1.00 42.17 ATOM 5272 CD GLN 680 53.651 6.477 33.878 1.00 43.35 ATOM 5273 OE1 GLN 680 52.686 5.737 34.056 1.00 44.05 ATOM 5274 NE2 GLN 680 54.860 6.010 33.564 1.00 37.17 ATOM 5277 C GLN 680 53.012 8.674 30.221 1.00 39.33 ATOM 5278 0 GLN 680 52.220 7.883 29.709 1.00 40.26 ATOM 5279 N SER 681 53.299 9.854 29.673 1.00 38.00 ATOM 5281 CA SER 681 52.636 10.251 28.441 1.00 37.44 ATOM 5282 CB SER 681 52.963 11.698 28.078 1.00 37.67 ATOM 5283 OG SER 681 54.349 11.937 28.102 1.00 38.03 .ATOM 5285 C SER 681 53.095 9.278 27.356 1.00 38.28 ATOM 5286 0 SER 681 52.302 8.866 26.510 1.00 39.41 ATOM 5287 N ASP 682 54.362 8.866 2"7.431 1.00 36.81 ATOM 5289 CA ASP 682 54.920 7.888 26.495 1.00 36.41 ATOM 5290 CB ASP 682 56.404 7.655 26.765 1.00 37.18 ATOM 5291 CG ASP 682 57.309 8.584 25.968 1.00 40.08 ATOM 5292 ODI ASP 682 58.528 8.317 25.959 1.00 41.94 ATOM 5293 OD2 ASP 682 56.824 9.565 25.352 1.00 39.55 .ATOM 5294 C ASP 682. 54.180 6.561 26.645 1.00 36.93 ATOM 5295 0 ASP 682 54.005 5.818 25.675 1.00 38.23 ATOM 5296 N VAL 683 53.742 6.268 27.866 1.00 36.33 ATOM 5298 CA VAL 683 53.000 5.040 28.143 1.00 36.29 ATOM 5299 CB VAL 683 52.834 4.820 29.683 1.00 35.29 ATOM 5300 CGI VAL 683 51.900 3.653 29.989 1.00 34.98 ATOM 5301 CG2 VAL 683 54.198 4.546 30.312 1.00 30.55 ATOM 5302 C VAL 683 51.648 5.067 27.392 1.00 35.'21 ATOM 5303 0 VAL 683 51.223 4.050 26.845 1.00 32.81 ATOM 5304 N TRP 684 51.027 6.245 27.309 1.00 34.49 ATOM 5306 CA TRP 684 49.759 6.412 26.602 1.00 36.39 ATOM 5307 CB TRP 684 49.200 7.825 26.811 1.00 39.30 ATOM 5308 CG TRP 684 48.006 8.174 25.947 1.00 41.47 ATOM 5309 CD2 TRP 684 46.651 8.381 26.384 1.00 42.41 ATOM 5310 CE2 TRP 684 45.896 8.744 25.247 1.00 41.76 ATOM 5311 CE3 TRP 684 46.004 8.298 27.627 1.00 42.06 ATOM 5312 CD1 TRP 684 48.010 8.410 24.597 1.00 40.55 ATOM 5313 NEI TRP 684 46.749 8.756 24.175 1.00 42.32 ATOM 5315 CZ2 TRP 684 44.522 9.022 25.315 1.00 41.35 ATOM 5316 CZ3 TRP 684 -44.638 8.576 27.692 1.00 41.99 ATOM 5317 CH2 TRP 684 43.917 8.933 26.541 1.00 41.07 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 361 ATOM 5318 C TRP 684 49.964 6.125 25.115 1.00 36.12 ATOM 5319 0 TRP 684 49.152 5.410 24.511 1.00 38.69 ATOM 5320 N SER 685 51.029 6.690 24.534 1.00 33.48 ATOM 5322 CA SER 685 51.395 6.491 23.130 1.00 26.49 ATOM 5323 CB SER 685 52.636 7.300 22.802 1.00 23.40 ATOM 5324 OG SER 685 52.403 8.688 22.992 1.00 30.31 ATOM 5326 C SER 685 51.665 5.015 22.859 1.00 26.25 ATOM 5327 0 SER 685 51.377 4.510 21.782 1.00 28.78 ATOM 5328 N PHE 686 52.214 4.319 23.846 1.00 28.14 ATOM 5330 CA PHE 686 52.470 2.884 23.727 1.00 28.53 ATOM 5331 CB PHE 686 53.245 2.399 24.947 1.00 27.34 ATOM 5332 CG PHE 686 53.567 0.937 24.917 1.00 29.91 ATOM 5333 CD1 PHE 686 54.424 0.419 23.942 1.00 29.23 ATOM 5334 CD2 PHE 686 53.016 0..075 25.861 1.00 28.28 ATOM 5335 CEl PHE 686 54.725 -0.936 23.908 1.00 27.65 ATOM 5336 CE2 PHE 686 53.307 -1.274 25.840 1.00 27.18 ATOM 5337 CZ PHE 686 54.166. -1.787 24.861 1.00 30.06 ATOM 5338 C PHE 686 51.129 2.117 23.618 1.00 31.42 ATOM 5339 0 PHE 686 51.041 1.096 22.930 1.00 29.05 ATOM 5340 N GLY 687 50.093 2.623 24.298 1.00 31.18 ATOM 5342 CA GLY 687 48.783 2.000 24..256 1.00 32.16 ATOM 5343 C GLY 687 48.276 2.026 22.825 1.00 35.03 ATOM 5344 0 GLY 687 47.805. 1.011 22.289 1.00 36.38 ATOM 5345 N VAL 688 48.378 3.188 22.1.86 1.00 33.72 ATOM 5347 CA VAL 688 47.949. 3.307 20.808 1.00 30.28 ATOM 5348 CE VAL 688 47.996 4.761 20.322 1.00 28.62 ATOM 5349 CG1 VAL 688 47.433 4.862 18.905 1.00 26.79 ATOM 5350 CG2 VAL 688 47.202 5.645 21.275 1.00 26.40 ATOM 5351 C VAL 688 48.823 2.406 19.930 1.00 30.01 ATOM 5352 0 VAL 688 48.324 1.782 18.989 1.00 30.37 ATOM 5353 N LEU 689 50.108 2.282 20.273 1.00 29.76 ATOM 5355 CA LEU 689 51.022 1.418 19.510 1.00 29.37 ATOM 5356 CB LEU 689 52.476 1.577 19.982 1.00 25.78 ATOM 5357 CG LEU 689 53.564 0.944 19.097 1.00 23.00 ATOM 5358 CDI LEU 689 54.855 1.741 19.153 1.00 24.44 ATOM 5359 CD2 LEU 689 53.823 0.471 19.479 1.00 21.63 ATOM 5360 C LEU 689 50.583 -0.043 19.634 1.00 29.98 ATOM 5361 0 LEU 689 50.708 -0.806 18.678 1.00 28.75 ATOM 5362 N LEU 690 50.048 -0.409 20.803 1.00 32.38 ATOM 5364 CA LEU 690 49.562 -1.764 21.060 1.00 32.66 ATOM 5365 CB LEU 690 49.114 -1.929 22.517 1.00 32.33 ATOM 5366 CG LEU 690 50.107 -2.192 23.658 1.00 32.00 ATOM 5367 CD1 LEU 690 49.330 -2.201 24.962 1.00 35.74 ATOM 5368 CD2 LEU 690 50.834 -3.513 23.475 1.00 30.76 ATOM 5369 C LEU 690 48.369 -2.018 20.156 1.00 33.29 ATOM 5370 0 LEU *690 48.248 -3.079 19.550 1.00 35.08 ATOM 5371 N TRP 691 47.490 -1.026 20.065 1.00 34.28 ATOM 5373 CA TRP 691 46.304 -1.114 19.221 1.00 33.79 ATOM 5374 CB TRP 691 45.483 0.172 19.364 1.00 32.68 ATOM 5375 CG TRP 691 44.147 0.144 18.669 1.00 31.23 ATOM 5376 CD2 TRP 691 43.888 0.490 17.312 1.00 28.11 ATOM 5377 CE2 TRP 691 42.506 0.310 17.089 1.00 29.96 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 362

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5378 5379 5380 5382 5383 5384 5385 5386 5387 5389 5390 5391 5392 5393 5394 5395 5396 5397 5399 5400 5401 5402 5403 5404 5405 5406 5408 5409 5410 5411 5412 5413 5414 5415 5416 5417 5418 5420 5421 5422 5424 5425 5426 5427 5429 5430 5431 5432 5433 5434 5435 5436 CE3 TRP CD1 TRP NEl TRP CZ2 TRP CZ3 TRP CH2 TRP C TRP O TRP N GLU CA GLU CB GLU CG GLU CD GLU OE1 GLU OE2 GLU C GLU O GLU N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE C ILE N PRE CA PHE CB PHE CG PHE CD1 PHE CD2 PHE CEl PHE CE2 PHE CZ PHE C PHE 0 PHE N THR CA THR CB THR OGI THR CG2 THR C THR 0 THR N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N GLY 691 691 691 691 691 691 691 691 692 692 692 692 692 692 692 692 692 693 693 693 693 693 693 693 693 694 694 694 694 694 694 694 694 694 694 694 695 695 695 695 695 695 695 696 696 696 696 696 696 696 696 697 44 .686 42 .936 41.951 41.909 44 .093 42 719 46 .744 46.139 47.817 48 .355 49.532 49.138 50.318 51.150 50.430 48.810 48 .589 49.439 49.944 50.843 51.275 52 .081 52 .814 48.810 48 .790 47.837 46 .722 46.156 47.158 47.796 47.574 48 .837 48.614 49.254 45.688 44 .844 45 .781 44 .898 44.245 45.246 43.497 45.766 45.333 46.993 47.979 47.622 47.493 47.315 48.718 48.280 48.259 48.597 0.949 16.257 1.00 28.70 -0.225 -0 130 0.555 1 194 1 .002 -1.319 -2.088 -0.636 -0 723 0.233 1.694 2 .585 2 847 3 .017 -2.118 -2.570 -2 .798 -4.153 -4.608 -6.064.

-3 71.1 874 -5.153 5 943 -5.079 -5.999 -6.167 -6.787 -6.017 -8 .111 -5.539 -8.643 -7.855 -5.771 -6.632 -4.626 -4.331 •-2.929 -1.909 -2.795 -4.426 -4.064 919 -5.100 -6.294 -7.657 -8.734 -7.939 -3.872 -3 .931 -2.768 19.208 18.265 15.845 15.021 14.830 17.763 17.029 17.366 16.010 15.826 15.746 15.403 16.301 -14.237 15.658 14.544 16.610 16.396 17.575 17.400 17.669 8 .943 16.232 15.281 17.127 17 .082 18.490 19.428 20.389 19.237 21.137 19.982 20.934 15.986 15.729 15.313 14.191 14.298 14.211 15.603 12.934 11.841 13.119 12.053 11.161 11.838 10.785 12.659 11.197 9.965 11.867 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 0.0 1. 0.0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 0.0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 29.37 30.89 29.50 27.43 29.27 34.12 33 .88 36.37 35.35 31.75 32.63 35.28 37.81 34.85 35.71 37.26 35.05 35.00 35.88 36. 03 34 .66 35 .52 34 .29 33.66 34 .44 35.63 35.26 35.26 33.07 31.74 31.01 31.64 31.84 36.62 38.73 35.76 34.86 32.81 31.61 29.90 35.95 38.88 34.68 32.84 32.65 30.89 31.30 30.76 32.43 31.48 33.65 5145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 363 ATOM 5438 CA GLY 697

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5439 54,40 5441 5443 5444 5445 5446 5448 5449 5450 5452 5453 5454 5455 5456 5457 5458 5459 5460 5461 5463 5464 5465 5466 5467 5468 5469 5470 5471 5473 5474 5475 5476 5477 5478 5479 5480 5481 5482 5484 5485 5486 5487 5489 5490 5491 5492 5493 5494 5495 5496

C

0

N

CA

C

0

N

CA

CB

OG

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

CD1 CE 1 CD2 CE2

CZ

OH

C

0

N

CD

CA

CB

CG

C

0

N

CA

C

0

N

CA

CB

CG1 CG2

C

0

N

CD

GLY

GLY

GLY

GLY

GLY

GLY

SER

SER

SER

SER

SER

SER

PRO

PRO

PRO

PRO

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PRO

TYR

TYR

TYR

TYR

TYR

TYR

TYR

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TYR

TYR

TYR

TYR

PRO

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PRO

PRO

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GLY

GLY

GLY

GLY

VAL

VAL

VAL

VAL

VAL

VAL

VAL

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697 697 698 698 698 698 699 699 699 699 699 699 700 700 700 700 700 700 700 701 701 701 701 701 701 701 701 '701 701 701 701 702 702 702 702 702 702 702 703 703 703 703 704 704 704 704 704 704 704 705 705 48.940 -1.529 47.742 -0.641 47.728 0.172 46.719 -0.798 45.531 0.009 45.771 1.496 46.779 1.926 44.814 2.271 44.858 3.725 44.363 4.290 44.126 5.684 43.927 4.146 42. 734 3.812 44.471 4.799 45.896 5.028 43.630 5.228 44.655 5.573 45..840 5.990 42.742 6.411 43.194 7.363 41.462 6 293 40.459 7.324 40.713 8..548 40.552 8 .272 41.538 8.637 41.387 8.391 39.405 7. 647 39.245 7.395 40.237 7.770 40.091 '7.53 9 40.389 7.736 40.597 8.900 40.096 6.773 39.887 5.336 40.014 7.112 39.836 5.744 39.185 4.946 38.859 8.045 37.716 7.794 39.194 9.151 38.210 10.149 37.985 11.230 37.270 12.194 38.627 11.100 38.466 12.053 38.576 11.364 38.509 12.397 37.475 10.338 39.473 13.194 40.669 12.977 39.001 14.428 11. 188 10. 960 10.048 11.782 11.612 11. 753 12 .299 11.265 11.318 9. 995 10.087 12 .451 12.438 13.491 13.776 14 .611 15.694 14 .919 14.2?47 13 .616 1L4 588 14. 338 15 .225 16 .706 17. .616 18 .978 17 .197 18. 552 19.444 20.804 12 .877 12 .534 11.985 12 .192 10.561 9.899 10.929 10.256 10.654 9.592 9.212 10.250 9.981 11.412 12.505 13 .876 14 .990 14 .045 12.493 12.661 12 .269 1.00 1.00, 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 00 1.00 1.00 1 :00 1 .0.0 1.00' 1.00 1 .0.0 1.00o 1.00 1.00 1 .00.

1.00o

.CI

1.00 1.00 1.03c 1 .0.0 1.00 1.00 1.00 1.00 1.00 1 .0.0 1.0 0 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 32.78 33 .06 34.74 35.53 36.87 34 92 34.08 36.45 35.36 34. 58 41.43 36 .53 37.58 36.03 34. 58 35. 47' 34.59 34 .18 34 .66 34.39 34.11 33. 11 38.13 43 .52- 14. 7 9 49.99 47.59 49.15 50.84 54 .00 30.95 30.64 30.06 25.47 29.36 25.86 24.42 31.49 33. 30.85 27.67 27.39 26.56 27.05 28. 28. 29.36 29.64 30.95 32.90 31.09 37.682 14.795 11.728 1.00 31.49 145. V01 WO 98/07835 PCTIUS97/14885* 364 ATOM 5497 CA PRO 705 39.926 15.561 12.255 1.00 29.66 ATOM 5498 CB PRO 705 39.152 16.618 11.477 1.00 30.16 ATOM 5499 CG PRO 705 37.720 16.289 11.778 1.00 33.76 ATOM 5500 C PRO 705 40.334 16.028 13.654 1.00 29.25 ATOM 5501 0 PRO '705 39.693 15.695 14.659 1.00 24.77 ATOM 5502 N VAL 706 41.396 16.828 13.690 1.00 32.40 ATOM 5504 CA VAL 706 41.976 17.355 14.929 1.00 36.51 ATOM 5505 CB VAL 706 43.023 18.450 14.629 1.00 36.79 ATOM 5506 CG1 VAL 706 43.680 18.903 15.914 1.00 37.79 ATOM 5507 CG2 VAL 706 44.058 17.942 13.653 1.00 37.26 ATOM 5508 C VAL 706 40.977 17.915 15 .94:3 1.00 38.21 ATOM 5509 0 VAL 706 41.052 17.600 17.130 37.65 ATOM 5510 N GLU 707 40.060 18.154 15.467 1.00 40.27 ATOM 5512 CA GLU 707 39.045 19.360 16.324 1.00 40.57 ATOM 5513 CE GLU 707 38.186 20.324 15.499 1.00 40.56 ATOM 5514 C GLU 707 3e.164 18.288 16.958 1.00 41.60 ATOM 5515 0 GLU 707 37.871 18.323 18.158 1.00 41.79 ATOM 5516 N GLU 708 37.784 17.311 16.143 1.00 42.54 ATOM 5518 CA GLU 708 36.947 16.210 16.576 1.00 44.09 ATOM 5519 CB GLU 708 36.509 15.398 15.367 1.00 47.61 ATOM 5520 CG GLU 708 35.687 16.219 14. 3'81 1.00 50.42 ATOM 5521 CD GLU 708 34.511 16.891 15.042 1.00 55.51 ATOM 5522 OE1 GLtJ 708 33.856 16.249 15.899 1.00 58.91 ATOM 5523 0E2 GLU 708 34.244 18.067 14.714 1.00 60.06 ATOM 5524 C GLU 708 37.661 15-338 17.598 1.00 44.63 A~TOM 5525 0 GLU 708 37.058 14.893' 18.585 1.0.0 45.12 ATOM 5526 N LEU 709 38.960 15.141 17.390 1.00 43.72 ATOM 5528 CA LEU 709 39.768 14.346. 18.312 1.00 '39.85.

ATOM 5529 CB LEt) 709 41.212 14.243 17.823 1.00 34.99 ATOM 5530 CG LEU 709 42.037 1.3.359 18.756 1.00 31.80 ATOM 5531 CD1 LEU 709 41.61.9 11.918 18.598 1.00 29.20 ATOM 5532 CD2 LEt) 709 43.495 13.533 18.454 1.00 31.19 ATOM 5533 C LEt) 709 39.751 15.001 19.683 1.00 39.26 ATOM 5534 0 LEt) 709 39.646 14.317 20.714 1.0.0 37.71 *ATOM 5535 N PHE 710 39.872 16.327 19.691 1.00 38.62 ATOM 5537 CA PRE 710 39.862 17.068 20.942 1.00 41.82 ATOM 5538 CB PHE 710 40.016 18.567 20.688 1.00 42.02 ATOM 5539 CG PHE 710 41.383 18.958 20.206 1.00 43.81 ATOM 5540 CD1 PHE 710 42.441 18.043 20.242 1.00 47.07 ATOM 5541 CD2 PHE 710 41.621 20.234 19.718 1.00 42.91 ATOM 5542 CE1 PHE 710 43.716 18.401 19.793 1.00 49.22 ATOM 5543 CE2 PHE 710 42.890 20.602 19.267 1.00 46.73 ATOM 5544 CZ PHE 710 43.942 19.681 19.307 1.00 48.40 ATOM 5545 C PHE 710 38.568 16.787 21.698 1.00 43.80 ATOM 5546 0 PRE 710 38.593 16.502 22.904 1.00 44.54 ATOM 5547 N LYS 711 37.452 16.790 20.968 1.00 44.15 ATOM 5549 CA LYS 711 36.148 16.539 21.569 1.00 42.60 ATOM 5550 CB LYS 711 35.029 16.855 20.577 1.00 44.35 ATOM 5551 CG LYS 711 33.661 16.781 21.200 1.00 48.05 ATOM 5552 CD LYS 711 32.560 .17.205 20.263 1.00 49.23 ATOM 5553 CE *LYS 711 31.212 16.804 20.855 1.00 50.61 ATOM 5554 NZ LYS 711 30.078 17.204 1§.987 1.00 56.56 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 365

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5558 C LYS 5559 0 LYS 5560 N LEU 5562 CA LEU 5563 CB LEU 5564 CG LEU 5565 CD. LEU 5566 CD2 LEO 5567 C LEU 5568 0 LEO 5569 N LEO 5571 CA LEO 5572 CB LEO 5573 CG LETJ 5574 CD1 LEU 5575 CD2 LEO 5576 C LEO 5577 0 LEO 5578 N LYS 5580 CA LYS 5581 CB LYS 5582 CG LYS 5583 CD LYS 5584 CE LYS 5585 NZ LYS 5589 C LYS 5590 0 LYS 5591 N GLO 5593 CA GLU 5594 CB GLO 5595 CG GLO 5596 CD GLU 5597 0E2. GLO 5598 0E2 GLO 5599 C GLO 5600 0 GLO 5601 N GLY 5603 CA GLY 5604 C GLY 5605 0 GLY 5606 N HIS 5608 CA HIS 5609 CB HIS 5610 CG- HIS 5611 CD2 HIS 5612 NDl HIS 5614 CEl HIS 711 711 712 712 712 712 712 712 712 712 713 713 713 713 713 713- 713 713 714 714 714 714 714 714 714 714 714 715i 715 715 715 715 715 715 715 715 716 716 716 716 717 717 717 717 717 717 717 36.045 15.105 22.084 .1.00 41.50 35.589 14.875 23.202 1.00 41.06 36.489 14.144 21.282 1.00 41.61 36.463 12.737 21.687 1.00 43.22 37.070 11.841 20.600 1.00 41.69 36.246 11.404 19.397 1.00 38.07 37.071 10*.460 18.527 1.00 34.55 34.990 10.714 19.891 1.00 37.28 37.253 12.536 22.982 1.00 43.94 36.804 11.832 23.900 1.00 41.71 38.444 13.129 23.029 1.00 A5.26 39.318 13.022 24.191 1.00 46.47 40.647 13.728 23.925 1.00 46.32 41.524 13.012 22.889 1.00 44.05 42.853 13.737 22.734 1.00 39.96 41 758 11.571 23.328 1.00 41.78 38.665 13.519 25.477 1.00 471.50 38.630 12.789 26.472 1.00 48.26 38.098 14.725 25.440 1.00 47.08 37 .43.9 15-302 26.600 1.00 45.59 36.974 16.727 26.293 1.00 47.53 38.126 17.661 26.064 1.00 51.33 37.647 19.044 25.689 1.00 59.12 38.836 19.917 25.273 1.00 64.39 39.843 20.072 26.370 1.00 66.31 36.217* 14.476 27.056 1.00 44.19 3S. 895 35 .565 34 .401 33 512 32 860 31.953 32 .121 31.059 34 .809 33 .964 36 .101 36 .593 36 .548 36 .640 36.469 36 .398 36 .082 35. 987 34 .941 37 .071 36 .701 35 .410 37 .662 38 .767 14.447 28.2414 *1.00 43.04 13.805 26.112 1. 43.89 12.'976 26.424 1.00 44.12 12.785 25.190 1.00 47.40 14.053 24.623 1.00 52.31 13.763 23.427 1.00 56.22 12.699 22.784 1.00 57.16 14.588 23.138 1.00 57.32 11.605 26.956 1.00 42.47 10.718 27.094 1.00 41.03 11.419 27.201 1.00 41.06 10.150 27.718 1.00 41.58 8.985 26.739 1.00 41.60 7.816 27.141 1.00 38.34 9.303 25.450 1.00 42.80 8.278 24.420 1.00 45.03 8.894 23.052 1.00 46.28 7.887 21.940 1.00 48.73 7.157 21.483 1.00 48.67 7.521 21.169 1.00 49.33 6.607 20.290 1.00 45.65 6.370 20.460 1.00 45.87 7.448 24.324 1.00 46.84 7.980 24.319 1.00 48.06 5615 NE2 HIS .717 5617 C HIS 717 5618 0 HIS 717 5619 N ARG 718 5621 CA ARG 718 37.478 6.138 24.217 1.00 48.75 38.573 5.181 24.091 1.00 49.16 145. vOl WO 98/07835 WO 9807835PCTIUS97/14885 366 ATOM 5622 CB ARG ATOM 5623 CG ARG ATOM 5624 CD ARG ATOM 5625 NE ARG ATOM 5627 CZ ARG ATOM 5628 NH1 ARG ATOM 5631 NH2 ARG ATOM 5634 C ARG ATOM 5635 0 ARG ATOM 5636 N MET ATOM 5638 CA MET ATOM 5639 CB MET ATOM 5640 CG MET ATOM 5641 SD MET ATOM 5642 CE MET ATOM 5643 C MET ATOM 5644 0 MET ATOM 5645 N ASP ATOM 5647 CA ASP .ATOM 5648 CB ASP ATOM 5649 CG ASP ATOM 5650 ODI ASP ATOM 5651 0D2 ASP ATOM 5652 C ASP ATOM 5653 3 A.SP ATOM 5654 N LYS ATOM 5656 CA LYS ATOM 5657 CB LYS ATOM 5658 CG LYS ATOM 5659 CD LYS ATOM 5660 CE LYS ATOM 5661 NZ LYS ATOM 5665 C LYS ATOM 5666 0 LYS ATOM 5667 N PRO ATOM 5668 CD PRO ATOM 5669 CA PRO ATOM 5670 CB PRO ATOM 5671 CG PRO ATOM 5672 C PRO ATOM 5673 0 PRO ATOM 5674 N SER ATOM 5676 CA SER ATOM 5677 CB SER ATOM 5678 OG SER ATOM 5680 C SER ATOM 5681 0 SER ATOM 5682 N ASN ATOM 5684 CA ASN ATOM 5685 CB ASN ATOM 5686 CG ASN ATOM 5687 OD1 ASN 38.694 39.005 40.344 40.724 40. 598 40. 094 41. 025 38.257 3 7. 08.6 39. 286 39. 086 40. 355 40.748 42.152 43.471 38.64 9 39.087 37. 797 37. 254 36.221 34.998 34.951 3 4.07 4 38.326 39.397 38.008 38. 892 38. 344 39. 005 4.345 25.370 1.00 46.96 5.164 26.617 1.00 49.78 5.891 26.474 1.00 52.81 6.639 27.672 1.00 52.99 7.961 27.817 1.00 53.38 8.705 26.836 1.00 52.33 8.553 28.928 1.00 49.30 4.293 22.878 1.00 50.73 4.003 22.601 1.00 51.78 3.899 22.136 1.00 50.83 3.072 20.948 1.00 50.56 3.013 20.094 1.00 48.85 4.325 19.438 1.00 45.25 4.119 18.335 1.00 43.24 4.066 19.465 1.00 36.42 1-.671 21.312 1.00 51.07 1.132 22.325 1.00 48.42 1.096 20.462 1.00 53.92 -0.253 20.648 1.00 55.90 -0.597 19.553 1.00 57.16 0.320 19.552 1.00 59.05 1.316 20.312 1.00 63.29 0.042 18.758 1.00 54.85 -1.343 20.638 1.00 55.89 1.190 20.027 1.00 55.28 -2.450 21.304 1.00 56.09 -3.605. 21.370 1.00 56.46 -4.606 22.378 1.00 58. 16 -5.977 22.316 1.00 62.49 38.449 6.873 23.401 1.00 66.40 38.474 -8.329 22.995 1.00 68.27 38.107 -9.194 24.156 1.00 75.61 38.930 -4.241 19.985 1.00 56.00 37.884 -4.532 19.403 1.00 59.26 40.133 -4.439 19.423 1.00 54.10 41.461 -3.968 19.836 1.00 53.72 40.208 -5.046 18.094 1.00 51.82 41.702 -4.953 17.759 1.00 49.09 42.143 -3.768 18.501 1.00 49.06 39.765 -6.498 18.123 1.00 50.10 39.678 -7.120 19.188 1.00 48.82 39.453 -7.020 16.945 1.00 49.87 39.079 -8.410 16.814 1.00 50.27 38.396 -8.643 f15.473 1.00 48.56 39.273 8 .323 14.404 1.00 48.93 40.414 -9.144 16.872 1.00 51.33 41.400 -8.679 16.311 1.00 51.18 40.445 -10.284 17.551 1.00 54.65 41.673 -11.062 17.706 1.00 56.76 42.370 -11.286 16.359 1.00 58.96 41.698 -12.345 15.543 1.00 62.08 41.645 -13 .508 15.948 1.00 67.56 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 367

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5688 5691 5692 5693 5695 5696 5697 5698 5699 5700 5702 5703 5704 5706 5707 5708 5709 5711 5712 5713 5714 5715 5718 5719 5720 5722 5723 5724 5725 5726 5727 5728 5729 5730 5732 5733 5734 5735 5736 5737 5738 5739 5741 5742 5743 5744 5745 5746 5747 5748 5749 5751 ND2

C

0

N

CA

CB

SG

C

0

N

CA

CB

OGI

CG2

C

0

N

CA

CB

CG

OD1 ND2

C

0

N

CA

CB

CG

CD

OE1 OE2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD1

CEI

CD2 CE2 cz OH

C

ASN

ASN

ASN

CYS

CYS

CYS

CYS

CYS

CYS

THR

THR

THR

THR

THR

THR

THR

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

724 724 724 725 725 725 725 725 725 726 726 726 726 726 726 726 727 727 727 727 727 727 727 727 728 728 728 728 728 728 728 728 728 729 729 729 729 729 729 729 729 730 730 730 730 730 730 730 730 730 730 730 41.154 42.622 43.786 42.089 42.852 42.835 43.782 42.158 40.927 42.957 42 .453 43.551 44-588 44.152 41.994 42. 555 40.979 40.482 39.331 39.674 40.778 38.716 41.606 41.589 42. 589 43 .757 44.611 45.881 46 .606 46 .977 46.816 44 .564 44 790 44 .954 45.715 46 .038 47.136 47.118 48.498 44.950 45.522 43.640 42.831 41.414 40.492 40.763 39.937 39.361 38.522 38.817 37.974 42.806 -11.960 -10.381 -10.131 -10.045 -9.418 -7.885 -7.034 -9.884 -9.954 10. 279 -10.773 -11.579 -10.696 12 .587 -9 .608 8.518 -9.83.2 -8.77.4 -9.267 -10.534 -10.689 -11.458 -8.238 -7.080 -9.099 -8.739 -9.983 -9.699 -10.958 -11 .796 -11.102 -7.685 -6.575 -8.020 -7.106 -7.766 -8.836 -9.757 -8.193 -5.794 -4.713 -5.884 -4.692 -5.064 -3.870 -2.865 -1.752 -3.730 -2.616 1.632 -0.542 -3.866 14.403 18.683 18.383 19.845 20.908 20.803 22.119 22.177 22.240 23.155 24.423 25.129 25.562 24.154 25.288 25.195 26.120 26.986 27.864 28.631 29.161 28.689 27.852 28.255 28.114 28.913 29.198 30.006 30.463 29.611 31.686 28.153 28.654 26.926 26.086 24.742 24.848 23.673 24.987 25.908 26.019 25.722 25.557 25.097 24.951 24.013 23.891 25.768 25.654 24.712 24.575 26.856 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1- 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 0.o 1.0.0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 0.0 1.00 1.00 1.00 60.12 57.26 58.40 57.58 57. 02 55.65 52 .17 56 .53 55.99 56 .09 57.09 57.12 59.14 55.09 57.58 58.49 58.48 58.74 66.81 76.72 80.48 82.39 55..48 51.24 55.37 55.53 55.75 58.24 58.16 56.39 58.35 54. 11 55.67 49.65 46. 39.77 36.12 34.89 33.47 45.05 45.58 43.53 43.57 41.49 40.28 36 .86 36.21 39.44 38.13 38.79 40.32 44.45 SSSD/55145. vOl WO 98/07835 PCT1US97/14885 368 ATOM 5752 0 TYR 730 42.786 -2.632 26.818 1.00 43.45 ATOM 5753 N MET 731 42.798 -4.534 28.006G 1.00 46.44 4 ATOM 5755 CA MET 731 42.805 -3.812 29.279 1.00 48.59 ATOM 5756 CB MET 731 42.516 -4.748 30.447 1.00 54.69 ATOM 5757 CG MET 731 41.132 -5.387 30.398 1.00 62.68 ATOM 5758 SD MET 731 39.781 -4.189 30.392 1.00 70.49 ATOM 5759 CE MET 731 39.492 -4.012 32.209 1.00 72.27 ATOM 5760 C MET 731 44.167 -3.139 29.450 1.00 46.48 ATOM 5761 0 MET 731 44.28.0 -2.085 30.086 1.00 44.91 ATOM 5762 N MET 732 45.202 -3.751 28.881 1.00 43.80 ATOM 5764 CA MET 732 46.538 -3.167 28.939 1. 00 43.03 ATOM 5765 CB MET 732 47.593 -4.104 28.322 1.00 39.44 ATOM 5766 CG MET 732 49.028 -3.578 28.427 1.00 36.02 ATOM 5767 SD MET 732 50.312 -4.775 27.979 1.00 36.47 ATOM 5768 CE MET 732 50.547 -5.573 29.530 1.00 41.29 ATOM 5769 C MET 732 46.474 833 28.188 1.00 42.08' ATOM 5770 0 MET 732 46.995 -0.827 28.659 1.00 42.14 ATOM 5771 N MET 733 45.775 -1.822 27.054 1.00 43.14 ATOM 5773 CA MET 733 45.608 -0.609 26.257 1.00 42.24 ATOM 5774 CB MET 733 44.852 -0.877 24.947 1.00 41.41 ATOM 5775 CG MET 733 45.607 -1.730 23.938 1.00 40.23 ATOM 5776 SD MET 733 44.669 2.025 22.419 1.0.0 38. 0 2 ATOM 5777 CE MET 7'3 3 45.183 -3.724 21.962 1.00 28.12 ATOM 5778 C MET 733 44 .820 0.392 27.074 1.00 41.68 ATOM 5779 0 MET 733 45.215 1. 550 27.196 1.00 43.78 ATOM 5780 N ARG 734 43 .713 -0.053 27.4655 1.00 42.59 ATOM 5782 CA ARG 734 42.893 0.839 28.467 1.00 42.92.

ATOM 5783 CB ARG 734 41.642 0. 11 9 28.966 1.00 42.35 .ATOM 5784 CG ARG 73.4 40.753 -374 27.852 1.00 39.76 ATOM 5785 C-'D ARG '734 40.360 0 763 26.959 1.00 41.83 ATOM 5786 NE ARG 734 39.535 1. 745 27.653 1.00 45.36 ATOM 5788 CZ ARG 1 734 38.207 1.693 27.708 1.00 50.22 ATOM 5789 NI{1 ARG 734 .37.542 0.708 27.117 1.00 51.18 ATOM 5792 NH2 ARG 734 37.534 2.642 28.346 1.00 53.24 ATOM 5795 C ARG 734 43.719 1.385 29.630 1.00 42.42 ATOM 5796 C ARG 734 43.610 2.571 29.969 1.00 42.59 ATOM 5797 N ASP 735 44.591 0.544 30.187 1.00 41.40 ATOM 5799 CA ASP 735 45.464 0.959 31.286 1.00 43.33 ATOM 5800 CE ASP 735 46.337 -0.194 31.755 1.00 48.28 ATOM 5801 CG ASP 735 45.556 -1.256 32.496 1.00 54.86 ATOM 5802 ODi ASP 735 45.903 -2.451 32.322 1.00 53.49 ATOM 5803 0D2 ASP 735 44.612 -0.900 33.245 1.00 55.59 ATOM 5804 C ASP 735 46.365 2.107 30.840 1.00 42.65 ATOM 5805 0 ASP 735 46.484 3.124 31.543 1.00 44.03 ATOM 5806 N CYS 736 47.021 1.926 29.693 1.00 38.83 ATOM 5808 CA CYS 736 47.896 2.952 29.140 1.00 35.90 ATOM 5809 CE CYS 736 48.545. 2.468 27.858 1.00 33.62 ATOM 5810 SG CYS 736 49.634 1.087 28.104 1.00 33.92 ATOM 5811 C CYS 736 47.100 4.208 28.855 1.00 35.96 ATOM 5812 0 CYS 736 47.651 5.309 28.830 1.00 35.59 ATOM 5813 N TRP 737 45.793 4.039 -28.668 1.00 38.02 ATOM 5815 CA TRP 737 44.906 5.156 28.372 1.00 40.14 SSSD/55145. vOl WO 98/07835 PCTIUS97/14885' 369 ATOM 5816 CB TRP 737 43.910 4.766 27.274 1.00 40.93 ATOM 5817 CG TRP 737 44.563 4.379 25.977 1.00 42.36 ATOM 5818 CD2 TRP 737 44.018 3.518 24.969 1.00 43.84 ATOM 5819 CE2 TRP 737 44.972 3.437 23.929 1.00 46.42 ATOM 5820 CE3 TRP 737 42.817 2.806 24.845 1.00 42.43 ATOM 5821 CD1 TRP 737 45.793 4.775 25.519 1.00 42.57 ATOM 5822 NEI. TRP 737 46.043 4.214 24.292 1.00 44.22 ATOM 5824 CZ2 TRP 737 44.756 2.666 22.773 1.00 44.97 ATOM 5825 CZ3 TRP 737 42.606 2.042 23.699 1.00 40.74 ATOM 5826 CH2 TRP 737 43.571 1.978 22.682 1.00 40.75 ATOM 5827 C TRP 737 44.157 5.706 29.584 1.00 40.62 ATOM 5828 0 TRP 737 43.085 6.285 29.437 1.00 41.37 ATOM 5829 N HIS 738 44.706 5.533 30.783 1.00 42.09 ATOM 5831 CA HIS 738 44.044 6.059 31.966 1.00 43.78 ATOM 5832 CB HIS 738 44.635 5.463 33.248 1.00 46.52 ATOM 5833 CG HIS 738 43.878 5.844 34.486 1.00 52.24 ATOM 5834 CD2 HIS 738 43.599 7.053 35.025 1.00 50.95 ATOM 5835 NDl HIS 738 43.271 4.914 35. 299 1.00 56.16 ATOM 5837 CEI HIS 738 42.643 5.536 36.285 1.L.00 57.23 ATOM 5838 NE2 HIS 738 42.827 6.835 36.141 1.00 53.22 ATOM 5840 C HIS 738 44.183 7.577 31.964 1.00 42.81 ATOM 5841 0 HIS 738 45.235 8.-09:3 31-654 1.-00 42.12 ATOM 5842 N ALA 739 43.121 8.285 32.324 1.00 45.66 ATOM 5844 CA ALA 739 43.130 9.750 32.350 2.00 49.42 ATOM 5845 CB ALA 739 41.739 10.262 32.681 1.00 53.04 ATOM 5846 C ALA 739 44.167 10. 380 33.291 1.00 50.18 ATOM 5847 0 ALA 739 44.710 11.450 33.006 1.00 51.86 ATOM 5848 N VAIL 740 44.322 9. 780. 34.466 1.00 49.96 ATOM 5850 CA VAL 740 45.299 10.219 35.467 1.00 50.1.7 ATOM 5851 CE VAL 740 44.828 9.849 36.881 1.00 50.33 ATOM 5852 CG1. VAL 740 45:'880 10.209 37.896 1.00 51.40 ATOM 5853 CG2 VAL 740 43.534 10.559 37.193 1.00 50.86 ATOM 5854 C VAL 740 46.626 9.497 35.196 1.00 49.81 ATOM 5855 0 VAL 740 46.749 8.295 35.472 1.00 49.85 ATOM 5856 N PRO 741 47.646 10.230 34.713 1.00 47.92 ATOM 5857 CD PRO 741 47.618 11.683 34.476 1.00 46.97 ATOM 5858 CA PRO 741 48.968 9.686 34.393 1.00 46.47 ATOM 5859 CB PRO 741 49.796 10.941 34.134 1.00 44.38 ATOM 5860 CG PRO 741 48.800 11.877 33.561 1.00 44.86 ATOM 5861 C PRO 741 49.593 8.815 35.480 1.00 47.21 ATOM 5862 0 PRO 741 50.243 7.816 35.176 1.00 46.77 ATOM 5863 N SER 742 49.380 9.181 36.741 1.00 48.87 ATOM 5865 CA SER 742 49.939 8.430 37.860 1.00 50.19 ATOM 5866 CB SER 742 49.753 9.203 39.166 1.00 51.87 ATOM 5867 OG SER 742 48.389 9.514 39.391 1.00 54.19 ATOM 5869 C SER 742 49.331 7.040 38.010 1.00 51.30 ATOM 5870 0 SER 742 49.863 6.192 38.723 1.00 51.14 ATOM 5871 N GLN 743 48.207 6.814 37.343 1.00 53.07 ATOM 5873 CA GLN 743 47.531 5.531 37.414 1.00 53.50 ATOM 5874 CB GLN 743 46.015 5.745 .37.548 1.00 59.34 ATOM 5875 CG GLN 743 45.412 5.307 .38.898 1.00 66.19 ATOM 5876 CD GLN 743 46.133 5 .896 '40. 106 1.00 70.07 145. vOl WO 9807835PCTIUS97/14885 370 ATOM 5877 QEI GLN 743 46.750 5.170 40.885 1.00 73.86 ATOM 5878 NE2 GLN 743 46.047 7.209 40.273 1.00 72.01 ATOM 5881 C GLN 743 47.850 4.613 36.236 1.00 51.14 ATOM 5882 0 GLN 743 47.504 '3.425 36.266 1.00 51.79 ATOM 5883 N ARG 744 48.484 5.153 35.196 1.00 48.31 ATOM 5885 CA ARG 744 48.1849 4.343 34.027 1.00 45.49 ATOM 5886 CB ARG 744 49.326 5.224 32.869 1.00 40.33 ATOM 5887 CG ARG 744 48.322 6.200 32.324 1.00 36.32 ATOM 5888 CD ARG 744 48.944 7.100 31.262 1.00 28.5 ATOM 5889 NE ARG 744 48.050 8.203 30.961 1.00 28.86 ATOM 5891 CZ ARG 744 48.429 9.409 30.547 1.00 30.58 ATOM 5892 NH. ARG 744 49.707 9.700 30.357 1.00 26.02 ATOM 5895 NH2 ARG 744 47.516 10.354 30.386 1.00 30.62 ATOM 5898 C ARG 744 50.016 3.454 34.452 1.00 47.35 ATOM 5899 0 ARG 744 50.794 3.824 35.334 1.00 52.01 ATOM 5900 N PRO 745 50.133 2.251 33.869 1.00 46.36 ATOM 5901 CD PRO 74'5 49.248 1.559 32.921 1.00 45.54 ATOM 5902 CA PRO 745 51.261 1.-402 34.271 1.00 43.41 ATOM 5903 CB PRO 745 50.972 0.078 33.547 1.00 41.77 ATOM 5904 CG PRO 745 50.155 0.491* 32.354 1.00 42.26 ATOM 5905 C PRO 745 52.590. 2.007 33.822 1.00 40.30 ATOM 5906 0 PRO 745 52.621 2.905 32.990 1.00 39.73 ATOM 5907 N THR 746 53.679 1.570 34.433 1.00 39.14 ATOM 5909 CA THR 746 54.997 2.056 34.039 1.00 38.35 ATOM 5910 CB TER 746 55.992 2.104 35.249 1.0.0 36.75 ATOM 5911 OGI THR 746 56.202 0.776 35.769 1.00 32.25 ATOM 5913 CG2 THR 746 55.477. 3.037 36.341 1.00 30.31 ATOM 5914 C THR '746 55.568- 1.102 32.987 1.00 37.90 ATOM 5915 0 TER 746' 55.185 -0.068 32.938 1.00 37.99 ATOM 5916 N PHE 747 .56.490. 1.584 32.157 1.00 35.94 ATOM 5918 CA PHE 747 57.106 0.726 31.161 1.00 35.00 ATOM 5919 CB PHE 747 58.124 1.469 30.309 1.00 30.45 ATOM 5920 CG PHE 747 57.512 2.174 29.142 1.00 27.61 ATOM 5921 CD). PHE 747 56.950 1.450 28.103 1.00 23.68 ATOM 5922 CD2 PHE 747 57.468 3.556 29.094 1.00 27.97 ATOM 5923 CEl PEE 747 56.352 2.088 27.033 1.00 23.56 ATOM 5924 CE2 PEE 747 56.869 4.209 28.027 1.00 26.92 ATOM 5925 CZ PEE 747 56.312 3.470 26.995 1.00 26.21 ATOM 5926 C PEE 747 57.766 -0.477 31.826 1.00 36.37 ATOM 5927 0 PEE 747 57.920 -1.525 31.219 1.00 37.11 ATOM 5928 N LYS 748 58.177 -0.312 33.075 1.00 39.68 ATOM 5930 CA LYS 748 58.797 -1.411 33.807 1.00 42.20 ATOM 5931 CB LYS 748 59.433 -0.895 35.095 1.00 46.17 ATOM 5932- CG LYS 748 59.978 -1.991 35.984 1.00 54.78 ATOM 5933 CD LYS 748 60.794, -1.428' 37.135 1.00 58.53 ATOM 5934 CE LYS 748 61.239 -2.537 38.075 1.00 59.33 ATOM 5935 NZ LYS 748 62.167 -2.025 39.120 1.00 62.36 ATOM 5939 C LYS 748 57.723 -2.463 34.111 1.00 42.78 ATOM 5940 0 LYS 748 57.998 -3.664 34.075 1.00 37.97 ATOM 5941 N GLN 749 56.503 -1.992 34.392 1.00 43.27 ATOM 5943 CA GLN 749 55.365 2.866 34.671 1.00 43.39 ATOM 5944 CB GLN 749 54.146 -2.056 35.146 1.00 47.37 SSSD/55145. vOl WO 98/07835 PTU9148 PCTIUS97/14885

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ALTOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

5945 5946 5947 5948 5951 5952 5953 5955 5956 5957 5958 5959 5960 5961 5962 5964 5965 5966 5967 5968 5969 5970 5972 5973 5974 5975 5976 5977 5978 5979 5980 5982 5983 5984 5985 5986 5987 5988 5989 5991 5992 5993 5994 5995 5996 5997 5998 6000 6001 6002 6003 6004

CG

CD

OE 1 NE2

C

0

N

CA

CB

CG

CDI

CD2 0

N

CA

CB

CG1 CG2 0

N

CA

CB

CG

CD

OE 1 0E2

C

0

N

CA

CB

CG

ODI

0D2

C

0

N

CA

CB

CG

CDI

CD2

C

0

N

CA

CB

CG

0D2.

0D2

GLN

GLN

GLN

GLN

GLN

GLN

LEU

LEtJ

LEU

LEU

LEU

LEU

LEU

-LEU

-VAL

VAL

VAL

VAL

VAL

VAL

VAL

GLU

GLU

GLU

GLU

GL U

GLU

GLU

GLU

GLU

ASP

ASP

ASP

ASP

AS P

ASP

AS P AS P

LEIJ

LEtJ

LEU

LEU

LEU

LEU

LEtI

LEU

ASP

ASP

ASP

ASP

ASP

ASP

749 749 749 749 749 749 750 750 750 750 750 750 750 750 751 751 751 751 751 751 751 752 752 752 752 752 752 752 752 752 753 753 753 753 753 753 753 753 754 754 754 754 754 754 754 754 755 755 755 755 755 755 54.236 53.036 53 .181 51.846 55.006 54.978 54.759 54 .398 54.366 53.316 53 .714 51.952 55.383 54 .990 56.670 57.691 59.115 60.142 59.372 57.458 57.530 57.116 56.869 56.781 58 .090 58 .079.

58 387' 57.789 55.622 55.689 54 .501 53.251 52 .122 51.646 51.592 51.319 53 .381 52 .991 53 .925 54.111 54.696 53.736 54.500 52 .537 55.001 54.815 55.975 56.889 57.898 58.998 59.640 59.236 -1.504 -0.639 0.504 -1.179 -3.607 -4 .841 -2.843 -3.387 -2.279 174 0.019 -1.696 -4.452 -5.470 -4.207 -5.177 -4.639 -5.694 -3.433 -6 .46'8 -7.563 339 7.518 -7.137 -6 .541 -6.243 092 *-7.170 -8.275 -9.474 -7.570 -8.184 -7.160 -6.805 -7.715 -5.618 -8.790 -9.935 -8.020 -8.490 -7.387 -6.263 -5.236 -6.822 -9.716 -10.606 -9.752 -10.873 -10.584 -11.616 -11.680~ -12.354 36.569 36 .938 37.350 3'6 769 33 .389 33.355 32 .327 31.018 29.966 30.112 29.257 29.722 30.581 30.027 30 .804 30.422 30.677 30.351 29.825 31.204 30.646 32 .481 33 .301 34 .783 35.310 36 .792 37.178 37. 573 32. 837 32 .555 32 .708 32 .265 32.249 33 .636 34 .495 33 .864 30.881 30.672 29.940 28.571 27.691 27.298 26.495 26 .502 28.529 27.708 29.424 29.516 30.628 30.717 31.785 29.738 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1 .00 1 .00 1.00 1.00 1.00 1. 0.0 1 .00 1 .00 1.00 1.00 1.00 1 .00 1. 00 1.00 1.00 .00 1. 00 1 .00 1 .00 1.00 1.00 1.00 1. 00 1. 00 1. 00 1. 00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1. 00 1.00 51 .86 54 .76 58.36 59.25 41.66 40.25 41.47 40.00 40.55 39.94 41.03 37.80 39.61 42 .08 40.63 39.65 33 .44 31.57 25.19 43.58 44 .81 46.24 50.55 53 56 56.20 53.45 60.28 50. 51.03 51.12 48.76 51.11 54 .97 58 .37 56.38 48.02 48.32 45.16 44 .82 42 42.92 41.44 42 .86 46.00 45.88 47.37 48.88 49.89 51.73 55.47 50. 98 SSSD/55145. vOl WO 98/07835 PCT/1US9714885 372 ATOM 6005 C ASP 755 56.024 -12.093 29.864 1.00 51.26 ATOM 6006 0 ASP 755 56.021 -13.107 29.155 1.00 50.49 ATOM '6007 N ARG 756 55.227 -11.940 30.917 1.00 52.15 ATOM 6009 CA ARG 756 54.332 -12.989 31.385 1.00 53.30 ATOM 6010 CB ARG 756 53.556 -12.501 32.611 1.00 54.54 ATOM 6011 CG ARG 756 52.389 -13.380 33.029 1.00 54.26 ATOM 6012 CD ARG 756 51.672 -12.772 34.215 1.00 56.76 ATOM 6013 NE ARG 756 51.293 -11.382 33.969 1.00 61.39 ATOM 6015 CZ ARG 756 50.259 -11.002 33.221 1.00 62.60 ATOM 6016 NHI ARG 756 49.487 -11.909 32.642 1.00 61.18 ATOM 6019 NH2 ARG 756 49.986 9.711 33.064 1.00 63.72 ATOM 6022 C ARG 756 53.357 -13.420 30.297 1.00 53.03 ATOM 6023 0 ARG 756 53.243 -14.607 30.000 1.00 54.82 ATOM 6024 N ILE 757 52.687 -12.452 29.680 1.00 51.18 ATOM 6026 CA ILE 757 51.709 -12.732 28.630 1.00 48.68 ATOM 6027 CB ILE 757 51.025 -11.435 28.120 1.00 47.88 ATOM 6028 CG2 ILE 757 50.112 -11.752 26.953 1.00 45.56 ATOM 6029 CG1 ILE 757 50.247 -10.763 29.258 1.00 47.77 ATOM 6030 CD1 ILE 757 49.651 -9.414 28.914 1.00 46.00 ATOM 6031 C ILE 757 52.314 -13.482 27.449 1.00 48.30 ATOM 6032 0 ILE 757 51.694 -14.409 2.6.937 1.00 45.61 ATOM 6033 N VAL 758 53,523 -13.094 27.038 1.00 48 88 ATOM 6035 CA VAL 758 54.202 -1.3.734 25.912 1.00 49.96 ATOM 6036 CB VAL '758 55.602 -13.101 25.615 1.00 47.80 ATOM 6037 CG1 VAL 758 56.313 -13.864 24.502 1.00 44.17 ATOM 6038 CG2 VAL 758 55.461 -11.660 25.188 1.00 46.65 ATOM 6039 C VAL '758 54.378-15.217 26.196 1.00 54.00 ATOM 6040 0 VAL 758 54.218 -16.050 25.306 1.00 53.52 ATOM 6041 N ALA 759 54.697 -15.540 27.445 1.00 57.83 ATOM 6043 CA ALA 759. 54.898 -16.926 27.844 1.00 61.94 ATOM 6044 CB ALA 759 55.447 -16.987 29.257 1.00 62.30 ATOM 6045 C ALA 759 53.592 -17.702 27.761 1.00 65.09 ATOM 6046 0 ALA 759 53.555 -18.823 27.254 1.00 66.39 ATOM 6047 N LEU 760 52.519 -17.090 28.248 1.00 66.99 ATOM 6049 CA LEU 760 51.209 17.720 28.246 1.00 68.78 ATOM 6050 CB LEU 760 50.314 -17.090 29.320 1.00 68.07 ATOM 6051 CG LEU 760 50.729 -17.330 30.777 1.00 67.01 ATOM 6052 CDI LEU 760 49.808 -16.563 31.722 1.00 67.93 ATOM 6053 CD2 LE 760 50.701 -18.819 31.083 1.00 65.17 ATOM 6054 C LEU 760 50.510 -17.666 26.892 1.00 71.19 ATOM 6055 0 LEU 760 49.342 -18.039 26.787 1.00 73.15 ATOM 6056 N THR 761 51.210 -17.201 25.860 1.00 73.38 ATOM 6058 CA THR 761 50.626 -17.113 24.518 1.00 73.92 ATOM 6059 CB THR 761 50.963 -15.760 23.829 1.00 72.65 ATOM 6060 OGI THR 761 50.353 -14.690 24.555 1.00 74.44 ATOM 6062 CG2 THR 761 50.435 -15.731 22.420 1.00 70.32 ATOM 6063 C THR 761 51.080 -18.276 23.636 1.00 74.66 ATOM 6064 0 THR 761 52.276 -18.520 23.463 1.00 75.08 ATOM 6065 SG CYS 1603 19.100 -9.073 19.903 0.50 30.84 PRT2 ATOM -6066 CG MET 534 69.385 -12.295 23.393 0.50 33.69 PRT2 ATOM 6067 SD -MET 534 69.112 13.312 24.832 0.50 34.44 PRT2 ATOM 6068 CE MET 534 70.067 12.429 26.060 0.50 36.92 PRT2 SSSD/55145. vOl WO 98/07835 PCT/US97/14885 373 ATOM 6069 SG CYS 603

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2716 2719 2722 2725 2728 2731 2734 2737 2740 2743 2746 2749 2752 2755 2758 2761 2764 2767 2770 2773 2776 2779 2782 2785 2788 2791 2794 2797 2800 2803 2806 2809 2812 2815 2818 2821 2824 2827 2830 2833 2836 2839 2842 2845 2848 2851 2854 2857 2860 2863 2866 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 56.370 -7.959 71.864 25.128 39.862 4.160 83.875 19.969 83.585 20.356 75.100 16.407 86.616 19.701 52.270 10.726 55.346 9.394 56.794 4.380 52.425 4.653 41.527 5.347 44.868 9.058 64.548 -2.881 77.179 13.205 79.309 16.826 83.279 11.681.

13.978 -9.614 38.294 0.616 27.114 6.248 .34.369 -1.759 20.500 2.296 50.938 -11.733 17.066 -5.917 27.873 8.078 31.459 0.037 27.088 -12.845 28.577 -17.329 88.863 14.111 -2.311 -3.712 34.895 -4.269 80.531 18.007 5.519 3.787 -10.523 5.304 29.538 -8.848 5.866 3.469 31.810 3.038 19.879 2.087 61.882 2.577 21.062 -6.897 -15.562 8.847 40.043 2.380 19.176 11.322 67.221 8.965 87.877 18.828 74.676 17.083 29.458 16.709 66.590 7.242 85.038 21.651 -4.762 3.091 19.509 4.951 34.833 5.465 16.451 2,.721 16.115 10.572 7.953 6.948 9.707 24.472 22.489 32.527 13.421 22.682 21.659 29.048 23.892 18.132 16.069 0.374 5.237 5.051 16.798 28.237 38.257 -2.027 15.136 6.873 27.724 12.884 8.054 11.489 18.658 9.739 10.628 11.469 20.187 13.367 0.203 -3.828 32.790 -4.255 22.744 8.610 0.332 17.535 18.789 4.253 10.527 15.359 5.881 3.313 5.063 24.635 0.50 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 L .00O 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 41.20 PRT2 26.20 42.43 23.41 30.15 46.78 44.37 40.13 29.09 28.02 18.63 32.60 34.90 32.56 30.36 55.69 21.18 23.81 48.89 19.82 43.83 53.46.

51.73 29.88 46.40 33.38 37.01 37.31 41.25 30.72 28.99 23.83 20.39 20.31 43.26 21.16 65.03 34.62 43.01 26.18 40.33 65.14 33.04 14.78 50.00 43.45 37.44 27.63 27.12 13.83 33.74 32.77 SSSD/55145. v01 WO 98/07835 PCT/US97/14885

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

.ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2869 2872 2875 2878 2881 2884 2887 2890 2893 2896 2899 2902 2905 2908 2911 2914 2917 2920 2923 2926 2929 2932 2935 2938 2941 2944 2947 2950 2953 2956 2959 2962 2965 2968 2971 2974 2977 2980 2983 2986 2989 2992 2995 2998 3001 3004 3007 3010 3013 3016 3019 3022 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 34.907 60.000 -7.341 55.218 68.597 73.486 3.555 38.079 29.817 49.332 41.366 10.52.3 -1.001 30.278 '8.115 73.460 -8.041 66.672 21.770 59.587 16.676 -15.177 33.105 0.334 17.489 27.373 -8.546 1.508 -4.985 17.673 20..319 0.366 19.688 10.581 -17.187 7.568 -1.418 12.161 6.912 20.957 -8.367 10.933 -9.690 1.501 3.96 9 -13.468 -4.658 16.435 4.304 18.707 -3.332 -4.643 20.943 -6.482 -13.158 7.529 2.738 -2.795 2.568 3.870 6.378 -1.891 -3.024 3.019 3.536 -2.419 -6.134 -15.481 13.739 27.982 6.308 25.430 16.955 19.260 -8.166 5.669 -1.649 12.262 28.834 0.864 21.574 13.217 3.317 22.744 24.939 28.739 4. 990 5.018 -3.023 4. 524 13.267 10.999 5.445 6 16.8 9.673 8.809 6.965 1.736 2.883 22.243 -1.678 6.681 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 0.0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.0oo p 39.47 31.38 40.22 40.99 45.39 49.23 20.02 27.07 44.28 42.78 37.60 45.18 35.58 48.75 16.04 34-79 44.96 62.39 32.98 37.78 42.74 19.90 40.43 31.20 16.38 39.52 17.89 33.71 29.65 22.73 20.39 22.15 13.22 43.14 38.38 21.50 39.45 30.27 31.03 37.94 44.71 50.74 38.15 51.37 34.12 70.04 30.78 41.40 20.93 57.99 54.77 25.61 4.476 -12.368 11.861 1.00 6.421 1.053 -3.368 1.00 -13.766 1.683 5.565 1.00 15.689 -7.291 -0.140 1.00 -1.762 -5.389 3.937 1.00 12.642 5.184 -4.424 1.00 69.601 27.513 2.309 1.00 24.342 -13.465 -0.010 1.00 60.354 -4.675 33.978 1.00 10.408 5.632 3.428 1.00 -9.676 -3.916 4.621 1.00 73.207 -2.076 10.677 1.00 -3.042 5.487 30.579 1.00 36.627 0.829 11.645 1.00 21.685 6.318 16.814 1.00 31.434 0.662 19.231 1.00 5.793 -8.713 22.177 1.00 -13.037 8.412 17.695 1.00 SSSD/55145. v01 WO 98/07835 PCT/US97/14885 375

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3025 3028 3031 3034 3037 3040 3043 3046 3049 3052 3055 3058 3061 3064 3067 3070 3073 3076 3079 3082 3085 3088 3091 3094 3097 3100 3103 3106 3109 3112 3115 3118 3121 3124 3127 3130 3133 3136 3139 3142 3145 3148 3151 3154 3157 3160 3163 3166 3169 3172 3175 3178 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 TIP3 26. 597 24.406 -1.809 59.590 4.442 8.101 76.065 48.821 2.703 82.922 8.998 -8.590 8.115 51". 643 20.737 73.254 5.343 .34.390 9.552 8.463 7.397 35.796 45.044 45.209 -2.800 85.885 13.136 75.900.

13.075 11.166.

13.814 -6.419 25.578 -16.472 86.531 32.292 45.116 81.035 2.905 31.895 74.974 7.514 71.606 68.337 0.191 68.043 3.644 52.117 -10.220 76. 944 10.053 34.348 -10.647 1.951 12.914 13.738 -11.011 2.869 1.631 15.839 -11.324 26.478 -6.359 4.563 -1.3.800 6.187 3.915 3.698 -11.780 2.307 -11.846 4.098 6.952 -1.428 10.052 11..756 15.170 11.248 -2.420 3.542 7.580 -10.189 -16.459 -3.460 -12.834 11.136 12.711 -4.665 7.369 12.317 -7.019 -6.253 -2.640 6.734 5.595 -5.037 -9.669 18.153 8.512 11.302 6.750 1.425 -11.958 14.128 -1.184 18.037 3.754 33.131 1.724 0.801 26.158 14.239 8.959 12.953 -3.309 4.397 8.351 10.821 15.522 20.947 22.588 16.660 6.934 -1.454 2.826 0.072 11.102 21.279 16.902 9.428 1.867 20.641 -2.817 0.573 3.327 16.599 3.624 6.388 7.151 1.511 11.774 16.907 -2.101 20.885 12.464 -1.116 22.198 8.955 6.903 10.710 4.478 18.644 4.981 -0.793 17.014 18.169 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.0.0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 25.85 30.72 43.57 26.96 46.96 37.28 46.49 34.18 39.16 43.77 39.51 32.53 41.64 31.70 17.40 27.49 36.63 64.04 28.23 30.21 33.87 30.27 28.75 31.80 32.72 25.28 20.56 39.79 34.49 36.71 21.18 32.62 43.32 64.77 28.72 30.98 30.59 41.72 26.20 36.12 58.90 37.81 54.82 40.80 47.40 36.67 40.16 40.22 25.00 46.95 38.99 42.98 SSSD/55145. v01 WO 98/07835 PCTIUS97/14885 376

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM.

ATOM...

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3181 3184 3187 3190 3193 3196 3199 3202 3205 3208 3211 3214 3217 3220 3223 3226 3229 3232 3235 3238 3241 3244 3247 3250 3253 3256 3259 3262 3265 3268 3271 3274 3277 3280 3283 3286 3289 3292 3295 3298 3301 3304 3310 3313 3316 3319 3322 3325 3328 3331 3334 3337 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 OH2 TIP3 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 279 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 2.472 29.861 32.608 42.408 88.019 70.091 77.332 -0.743 34.224 -9.619 11. 725 -8.492 32.082 -8.471 -1.100 80.411 67.266 -0.460 -0.107 -0.955 -5.269 -7.000 2.919 5.370 63.828 79.461 59.131 14.248 59.294 32.270 72.089 1.038 -0.484 81.532 -17.528 27.542 34.962 -3.244 42.673 52.865 26.791 -7.584 55.298 51.654 20.092 28.988 26.359 36.827 17.012 27.980 31.396 -8.230 16.629 1.00 39.28 1.764 -17.351 18.047 10.498 -4.165 5.434 -8.232 15.617 7.593 5.841 14.057 3.374 9.925 -6.507 0.680 20.862 4.230 6.721 8.958 9.229 10.196 7.005 10.843 12.793 0.958 -11.907 -1.085 2.993 13.672 16.139 -8.592 5.267 15.288 3.859 10.591 4.381 -3.943 7.836 12.074 13.926 9.157 15.955 19.308 7.039 1.734 2.749 2.974 -20.743 -14.283 1.595 5.993 11.473 11.188 5.885 25.232 24.000 4.456 1.556 7.404 7.590 13.866 18.430 24.255 15.528 15.823 -1.548 1.362 2.716 1.388 2.243 3.928 0.987 8.420 22.770 18.507 7.222 -4.437 33.283 20.001 22.904 14.174 30.679 17.279 24.112 14.666 27.739 8.937 22.289 22.272 19.808 6.269 20.455 22.767 7.056 -3.437 -4.689 18.493 13.983 6.114 -1.941 15.463 1.00 36.29 1.00 59.48 1.00 39.61 1.00 57.85 1.00 64.48 1.00 55.68 1.00 61.30 1.00 36.76 1.00 36.55 1.00 33.56 1.00 43.88 1.00 50.87 1.00 41.24 1.00 31.24 1.00 49.76 1.00 43.71 1.00 29.46 1.00 34.57 1.00 37.76 1.00 38.77 1.00 55.41.

1.00 46.54 1.00 36.98 1.00 63.91 1.00 47.46 1.00 51.47 1.00 43.6? 1.00 56.42 1.00 47.71 1.00 49.99 1.00 40.01 1.00 48.08 1.00 79.71 1.00 56.21 1.00 53.58 1.00 60.92 1.00 35.88 1.00 37.44 1.00 35.63 1.00 76.14 1.00 44.54 1.00 50.69 1.00 53.00 1.00 32.98 1.00 42.52 1.00 43.12 1.00 57.91 1.00 62.01 1.00 79.57 1.00 53.29 1.00 43.25 10.244 -16.264 SSSD/55145. v01 WO 98/07835 PCT/US97/14885 377 ATOM 3340 OH2 TIP3 208

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

SATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM'

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3343 3346 3349 3352 3355 3358 3361 3364 3367 3370 3373 3376 3379 3382 3385 3388 3391 3394 3397 3400 3403 3406 3409 3412 3415 3421 3424 3427 3430 3433 3436 3439 3442 3445 3448 3451 3454 3457 3460 4620 4621 4622 4623 4624 4625 4626 4627 4628 4629 4630 4631 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2 OH2

C

Cl1

N

C2 C3 C4 C5 C6 0 C7 C8 C9 TIP3 209 TIP3 210 TIP3 211 TIP3 212 TIP3 213 TIP3 214 TIP3 215 TIP3 216 TIP3 217 TIP3 218 TIP3 219 TIP3 220 TIP3 221 TIP3 222 TIP3 223 TIP3 224 TIP3 225 TIP3 226 TIP3 227 TIP3 228 TIP3 229 TIP3 230 TIP3 231 TIP3 232 TIP3 233 TIP3 234 TIP3 235 TIP3 236 TIP3 237 TIP3 238 TIP3 239 TIP3 240 TIP3 241 TIP3 242 TIP3 243 TIP3 244 TIP3 245 TIP3 246 TIP3 247 SUG 1000 SUG 1000 SUG 1000 SUG 1000 SUG 1000 SUG 1000 SUG 1000 SUG 1000 SUG 1000 SUG 1000 SUG 1000 SUG 1000 7.255 -12.421 11.250 11.426 34.344 31.230 37.062 35.231 63.913 36.511 90.623 49.822 60.367 17.954 66.176 75.201 -2.895 6.045 36.238 -5.516 46.577 6.496 -3.691 1.811 86.148 10.549 64.680 11.380 3.136 72.296 50 .258 58.051 43.530 67.081 87.660 71.779 25.965 -18.336 30.703 22.617 67.815 67.387 67.823 66.401 65.825 66.259 67.239 66.155 67.372 67.155 63.369 65.284 -11.909 14.520 9.879 12.574 13.104 18.082 12.036 3.150 13.371 6.165 4.459 -11.758 -10.286 -21.378 -1.266 19.402 10.302 -4.015 5.898 16.713 -11. 931 6.048 -5.054 -3.444 11.480 7.581 -8.130 -17.736 -4.782 1.006 -3.179 9.469 20.498 16.597 21.694 28.586 -8.124 10.487 11.410 -16.025 4.441 3.706 2.445 4.224 5.499 6.212 5.690 3.220 1.047 2.121 2.460 3.356 5.440 1.00 45.52 11.103 1.00 56.32 -1.498 1.00 28.34 -1.341 1.00 37.79 -1.291 1.00 51.83 8.054 1.00 44.77 -1.875 1.00 53.61 10.692 1.00 60.59 26.770 1.00 59.44 15.409 1.00 70.98 6.671 1.00 52.23 10.881 1.00 46.12 16.662 1.00 68.41 7.048 1.00 68.51 30.784 1.00 39.19 20.800 1.00 43.98 3.534 1.00 44.97 25.279 1.00 63.74 12.819 1.00 32.89 14.089 1.00 51.60 26.964 1.00 37.76 33.722 1.00 27.51 20.691 1.00 38.16 -0.149 1.00 54.03 23.402 1.00 57.66 5.716 1.00 48.45 20.697 1.00 69.67 13.500 1.0.0 54.61 21.980 1.00 57.12 -1.987 1.00 41.40 32.723 1.0.0 74.99 11.776 1.00 44.10 30.344 1.00 43.69 15.934 1.00 45.80 .5.373 1.00 50.39 7.932 1.00 61.12 27.084 1.00 42.13 12.859 1.00 73.36 16.381 1.00 39.24.

-2.906 1.00 63.22 11.493 1.00 20.00 10.364 1.00 20.00 9.937 1.00 20.00 9.501 1.00 20.00 9.765 1.00 20.00 10.884 1.00 20.0 11.736 1.00 20.00 8.401 1.00 20.00 8.275 1.00 20.00 8.828 1.00 20.00 5.852 1.00 20.00 7.382 1.00 20.00 SSSD/55145. v01 WO 98/07835 PCTIUS97/14885 378 ATOM 4632 CIO SUG 1000 64.603 2.300 6.514 1.00 20.00 ATOM 4633 Cil SUG 1000 64.167 0.392 5.481 1.00 20.00 ATOM 4634 C12 SUG 1000 63.106 1.251 5.206 1.00 20.00 ATOM 4635 N13 SUG 1000 65.103 1.023 6.293 1.00 20.00 ATOM 4636 C14 SUG 1000 61.898 0.897 4.346 1.00 20.00 ATOM 4637 C15 SUG 1000 62.476 3.715 5.826 1.00 20.00 ATOM 4638 C16 SUG 1000 61.259 3.598 6.771 1.00 20.00 ATOM 4639 01 SUG 1000 60.814 5.963 6.429 1.00 20.00 ATOM 4640 C17 SUG 1000 60.520 4.912 6.988 1.00 20.00 ATOM 4641 02 SUG 1000 59.496 4.795 7.873 1.00 20.00 ATOM 4642 C SUG 1001 5.413 2.967 18.087 1.00 20.00 ATOM 4643 Cl SUG 1001 5.891 2.927 19.417 1.00 20.00 ATOM 4644 N SUG 1001 5.553 2.021 20.431 1.00"20 .00 ATOM 4645 C2 SUG 1001 6.828 3.875 19.872 1.00 20.00 ATOM 4646 C3 SUG 1001 7.304 4.884 18.988 1.00 20.00 ATOM 4647 C4 SUG 1001 6.822 4.909 17.678 1.00 20.00 ATOM 4648 C5 SUG 1001 5.890 3.964 17.233 1.00 20.00 ATOM 4649 C6 SUG 1001 7.145 3.576 21.318 1.00 20.00 ATOM 4650 0 SUG 1001 6.101 1.6-8 22.552 1.00 20.00 ATOM 4651 C7 SUG 1001 6.237 2.343 21.530 1.00 20.00 ATOM 4652 C8 SUG 1001 9.967 4.392 23.809 1.00 20.00 ATOM 4653 C9 SUG 1001 7.997 4.264 22.102 1.00 20.00 ATOM 4654 CIO SUG 1001 8.753 3.835 23.357 1.00 20.00 ATOM 4655 Cli SUG 100.1 9.331 2.736 25.189 1.00 20.00 ATOM 4656 C).2 SUG 1001 10.320 3.689 24.962 1.00 20.00 ATOM 4657 N13 SUG 1001 8.354 2.808 24.203 1.00.20.00 ATOM 4658 C14 SUG 1001 11.547 3.900 :25.b43 1.00 20.00 ATOM 4659 C15 SUG 1001 10.759 5.550 23.175 1.00 20.00 ATOM 4660 C16 SUG 1001 11.987 5.063 22.373 1.00 20.00 ATOM 4661 01 SUG 1001 12.243 7.308 21.475 1.00 20.00 ATOM 4662 C17 SUG 1001 12.621 6.142 21.504 1.00 20.00 ATOM 4663 02 SUG 1001 13.657 5.670 20.762 1.00 20.00 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 379 TABLE 4 Atom No.

Atom A.A A.A Type Type No.

Z OCC B

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1 2 3 4 5 6 "7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

N

CA

CB

C

0

N

CA

CB

CG

CD1 CD2

C

.0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

CD

OE1 OE2

C

0

N

CA

CB

CG

ODI

OD2

C

0

N

CD

CA

CB

CG

C

0

N

CA

GLU

GLU

GLU

GLU

GLU

,LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PRO

PRO

PRO

PRO

PRO

PRO

PRO

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ARG

ARG

1464 1464 1464 1464 1464 1465 1465 1465 1465 1465 1465 1465 1465 1466 1466 1466 1466 1466 1466 1466 1467 1467 1467 1467 1467 1467 1467 1467 1467 1468 1468 1468 1468 1468 1468 1468 1468 1469 1469 1469 1469 1469 1469 1469 1470 1470 -13.576 -12.446 -11. 381 -11.845 -11.722 -11. 518 -10.950 -10.155 -8.630 -8.222 -8.017 -12.046 -13.139 11. 794 -10.612 -12.754 -12. 152 -10.684 -12.862 -11. 857 -14.064 -14.255 -15.722 -16.314 -17.789 -18.379 -18.369 -13.808 -13.922 -13.272 -12.839 -11.328 -10.885 -11.623 -9.777 -13.274 -12.570 -14.450 -15.396 -14.963 -16.255 -16.702 -14.012 -14.172 -13. 075 -12.108 17.066 17.198 18.127 15.833 15.504 15.023 13.699 13. 196 1-3.316 14.754 12.803 12.697 12.730 3.1.852 11.884 10.831 10.331 10. 518 9. 701 9 290 9175 8. 126 8. 054 9.365 9.252 8.170 10.250 6.777 6.529 5.929 4.592 4.515 3.207 2.199 3.187 3.627 3.405 3.019 3.175 2.079 1.586 2.776 0.925 0.285 0.642 -0.435 8.598 7.684 8.275 7.341 6.165 8.347 8.087 9.291 9.227 9.013 10.506 7.739 8.301 6.726 5.844 6.284 4.981 5.202 7.305 7.883 7.491 8.467 8.873 9.353 9.699 9.504 10.160 7.914 6.711 8.791 8.407 8.186 7.529 7.572 6.962 9.493 10.493 9.305 8.183 10.294 9.641 8.816 10.625 11 657 9.720 1.00 57.39 *1.00 55.83 1.00 56.73 1.00 55.07 1.00 59.74 1.00 50.12 1.0.0 44.43 1.00 43.28 1.00 43.70 1.00 47.59 1.00 42.63 1.00 40.93 1.00 39.13 1.00 40.49 1.00 39.07 1.00 40.14 1.00 40.90 1.00 41.39 1.00 40.06 1.00 40.71 1.00 38.65 1.00 39..24 1.00 45.06 1.00 50.91 1.00 53.51 1.00 54.15 1.00 53.10 1.00 36.09 1.00 38.58 1.00 30.71 1.00 28.23 1.0.0 25.51 1.00 27.68 1.00 26.01 1.00 28.87 1.00 27.74 1.00 25.83 1.00 25.88 1.00 24.25 1.00 26.69 1.00 28.81 1.00 24.20 1.00 27.51 1.00 27.60 1.00 26.49 9.935 1.00 27.60 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 380

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

CB ARG CG ARG CD ARG NE ARG CZ ARG NH1 ARG NH2 ARG C ARG 0 ARG N TRP CA TRP CB TRP CG TRP CD2 TRP CE2 TRP CE3 TRP CD1 TRP NEI TRP CZ2 TRP CZ3 TRP CH2 TRP C TRP O TRP N GLU CA GLU CB GLU CG GLU CD GLU OEI GLU OE2 GLU C GLU 0 GLU N LETJ CA LEU CB LEU CG LEU CDI LEU CD2 LEU C LEU 0 LEU N PRO CD PRO CA PRO CB PRO CG PRO C PRO 0 PRO N ARG CA ARG CB ARG CG ARG CD ARG 1470 1470 1470 1470 1470 1470 1470 1470 1470 1471 1471 1471 1471 1471 1471 1471 1471 1471 1471 1471 1471 1471 1471 1472 1472 1472.

1472 1472 1472 1472 1472 1472 1473 1473 1473 1473 1473 1473 1473 1473 1474 1474 1474 1474 1474 1474 1474 1475 1475 1475 1475 1475 -11.285 -12.073 -11.153 -10.462 -9.577 -9.249 -8.990 -11.116 -10.588 -10.871 -9.892 -8.642 -7.998 -7.110 -6.732 -6.589 -8.129 -7.369 -5.860 -5.722 -5.364 10.292 -9.551 -11.464 -11.909 13.168 -13.497 -12.611 -11.877 -12.658 -12.-179 -12.795 -11.689 -11.961 -10.707 -10.958 -11.553 -9.646 -12.478 -12.007 -13.529 -14.380 -14.124 -15.266 -15.701 -13.099 -12.310 -13.110 -12.181 -12.442 -12.082 -11.984 -0.691 8.668 1.00 26.08 -1.125 -1.257 0.001 0.167 -0.846 1.346 -0.163 -1.091 1.107 1.430 1.964 0.947 -0.104 -0.807 0.509 0.831 -0.220 -1.898 -1.589 2.265 2.384 2.544 2.975 3.959 4.674 6.026 7.180 7.038 8.247 3.421 2.373 4.121 3.740 3.311 3.090 1.696 3.199 5.008 6.101 4 .896 3 .704 6.051 5.406 4.307 6 .715 6.042 8.038 8 .810 10.292 10.729 12.228 7.439 6.213 5.915 4.941 4.144 4.779 11.069 11.673 11.363 12.375 11.671 10.795 11.205 10.041 12.438 9.446 8.980 10.083 12.473 11.306 13.478 14.452 13.364 14.341 13.821 14.498 14.042 13.042 14.683 15.735 15 .891 16 .745 18.129 18.890 20.392 20.627 21.157 18.752 18.405 19.585 19.737 20.267 21.062 20.158 21.178 21.850 21.178 21.973 21.791 20.413 20.247 1.00 30.77 1.00 31.66 1.00 30.94 1.00 33.30 1.00 32.78 1.00 27.16 1.00 28.73 1.00 27.30 1.00 27.98 1.00 26.33 1.00 23.87 1.00 24.61 1.00 23.32 1.0.0 24.34 1.00 21.39 1.00 25.07 1.00 26.82 1.00 23.12 1.00 21.02 1.00 21.74 1.00 26.93 1.00 26.37 1.00 26.40 1.00 27.12 1.00 28.25 1.00 27.47 1.00 24.64 1.00 24.60 1.00 23.70 1.00 25.89 1.00 27.74 1.00 25.95 1.00 27.45 1.00 24.99 1.00 21.80 1.00 20.63 1.00 22.34 1.00 29.33 1.00 27.56 1.00 30.07 1.00 29.18 1.00 29.03 1.00 26.83 1.0.0 26.35 1.00 31.01 1.00 33.14 1.00 31.33 1.00 32.99 1.00 35.87 1.00 43.88 1.00 44.84 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 381

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

AxOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

99 100 101 102 103 104 105 106 107 108 109 110 112 113 114 115 116 12.7 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150

NE

Cz NHl NH2

C

0

N

CA

CB

CG

ODI

OD2

C

0

N-

CA

CB

CG

CD

NE

Cz NHl NH2

C.

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

cGI CG2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

C

0

ARG

ARG

ARG

ARG

ARG

ARG

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

VAL

VAL

VAL

VAL

VAL

VAL

VAL

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

GLY

GLY

GLY

GLY

1475 1475 1475 1475 1475 1475 1476 1476 1476 1476 1476 1476 1476 1476 1477 1477 1477 1477 1477 1477 1477 1477 1477 1477 1477 1478 1478 1478 1478 1478 1478 1478 1478 1479 1479 1479 1479 1479 1479 1479 1480 1480 1480 1480 1480 1480 1480 1480 1481 1481 1481 1481 -11.665 -10.435 -9.400 -10.241 -12.175 -11.115 -13.347 -13.468 -14.940 -15.796 -15.288 -16.995 -12.858 -12.830 -12.441 -11.828 -12.2.17 -13.564 -14.234 -14.493 -14.818 -14.931 -15.005 -10.316 -9.616 -9.800 -8.370 -7.886 -6.400 -5.939 -6.159 -7.974 -8.193 -7.416 -6.974 -7.085 -6.728 -8.493 -5.529 -4.581 -5.381 -4.077 -4.241 -4.828 -4.762 -4.037 -3.144 -3.511 -1.912 -0.960 0.349 0.429 12.499 12.663 12.618 12.746 8.456 8.400 8.134 7.800 7.853 6.818 6.056 6.758 6.457 6.109 5.670 4.370 3.418 3.189 2.525 3.485 3.145 1.874 4.095 4.489 3.515 5.690 5.883 6.508 6.424 4.964 7.115 6.757 7.972 6.140 6.902 6.089 6.973 5.537 7.341 6.546 8.607 9.192 10.541 10.535 11.952 9.613 9.324 9.912 8.842 8.896 9.633 10.626 18.846 18.374 19.202 17.065 23.442 24.072 23.974 25.380 25.797 25.089 24.234 25.406 25.770 26.949 24.781 25.033 23.886 23.599 24.772 25.842 27.085 27.438 27.985 25.177 25. 461 25.002 25.080 23.771 23.431 23 .382 22. 102 26.265 26.251 27.305 28.468 29.757 30.926 29. 913 28.239 28 .350 27.867 27.569 26.855 25.435 24. 907 24.499 28 .768 29.784 28.610 29.700 29.474 28.744 1.00 1.00 1.00 1.00, 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 2 00 1.00 1.00 .00 I.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 48.59 46.00 46.56 44.18 35.47 37.44 35.04 34.30 36.89 38.67 41.19 48.08 33.67 36.57 32.72 29.68 25.53 23.83 26.80 27.24 27.41 29.00 25.85 30.44 32.78 30.-9 31.96 30.43 31.90 28.92 33.55 33.60 33.96 33.54 32.52 32.76 33.27 30.15 34.24 32.24 35.88 38.43 36.93 35.67 32.47 33.60 39.70 39.88 39.70 41.31 44.39 45.69 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 382 ATOM 151 N LYS 1482 1.389 9.122 30.124 1.00 44.73 ATOM 152 CA LYS 1482 2.728 9.700 30.069 1.00 46.91 ATOM 153 CB LYS 1482 3.649 8.934 31.023 1.00 51.20 ATOM 154 CG LYS 1482 5.135 9.056 30.744 1.00 57.10 ATOM 155 CD LYS 1482 5.878 7.826 31.248 1.00 60.81 ATOM 156 CE LYS 1482 5.430 6.567 30.515 1.00 61.24 ATOM 157 NZ LYS 1482 6.235 5.375 30.912 1.00 65.39 ATOM 158 C LYS 1482 3.370 9.782 28.681 1.00 46.09 ATOM 159 0 LYS 1482 3.440 8.782 27.944 1.00 42.98 ATOM 160 N PRO 1483 3.886 10.969 28.324 1.00 46.65 ATOM 161 CD PRO 1483 3.910 12.184 29.152 1.00 46.11 ATOM 162 CA PRO 1483 4.536 11.212 27.036 1.00 45.96 ATOM 163 CB PRO 1483 5.015 12.660 27.172 1.00 43.59 ATOM 164 CG PRO 1483 4.041 13.253 28.122 1.00 45.37 ATOM 165 C PRO 1483 5.739 10.279 26-912 1.00 46.43 ATOM 166 0 PRO 1483 6.506 10.139 27.861 1.00 44.77 ATOM 167 N LEU 1484 5.844 9.579 25.786 1.00 48.21 ATOM 168 CA LEU 1484 6.978 8.684 25.554 1.00 50.46 ATOM 169 CB LEU 1484 6.543 7.426 24.811 1.00 49.38 ATOM 170 CG LEU 1484 5.655 6.437 25.576 1.0.0 50.15 ATOM 171 CD1 LEU 1484 5.067 5.422 24.615 1.00 44.90 ATOM 172 CD2 LEU 1484 6.446 5.750. 26.669 1.00 44.60 ATOM 173 C LEt) 1484 .8.058 9.419 24.764 1.00 53.33 ATOM 174 0 LEU 1484 9.241 9.116 24.896 1.00 51.94 ATOM .175 N GLY 1485 7.643 10.376' 23.931 1.00 57.68 ATOM 176 CA GLY 1485 8.603 11.140 2.3.149 1.00 60.27 ATOM 177 C GLY 1485 7.997 11.946 22.016 1.00 62.66 ATOM 178 0 GLY 1485 6.774 12.090 21.924 1.00 64.91 ATOM 179 N GLN 1491 4:'704 14.425 18..904 1.00 47.86 ATOM 180 CA GLN 1491 4.339 13.868 20.206 1.00 44.42 ATOM 181 CB GLN 1491 3.373 14.829 20.918 1.00 44.31 ATOM 182 C GLN 1491 3.755 12.433 20.170 1.00 43.09 ATOM 183 0 GLN 1491 2.807 12.150 19.426 1.00 43.67 ATOM 184 N VAL 1492 4.338 11.542 20.974 1.00 40.40 ATOM 185 CA VAL 1492 3.903 10.143 21.101 1.00 39.95 ATOM 186 CB VAL 1492 4.962 9.119 20.673 1.00 37.64 ATOM 187 CG1 VAL 1492 4.416 7.721 20.897 1.00 34.94 ATOM 188 CG2 VAL 1492 5.336 9.296 19.233 1.00 40.26 ATOM 189 C VAL 1492 3.720 9.905 22.586 1.0.0 40.23 ATOM 190 0 VAL 1492 4.679 10.038 23.355 1.00 40.41 ATOM 191 N VAL 1493 2.516 9.518 22.993 1.00 38.15 ATOM 192 CA VAL 1493 2.250 9.291 24.405 1.00 37.11 ATOM 193 CB VAL 1493 1.131 10.245 24.924 1.00 37.83 ATOM 194 CG1 VAL 1493 1.3.86 11.656 24.422 1.00 36.45 ATOM 195 CG2 VAL 1493 -0.252 9.769 24.508 1.00 39.28 ATOM 196 C VAL 1493 1.854 7.844 24.701 1.00 36.02 ATOM 197 0 VAL 1493 1.450 7.118 23.797 1.00 37.17 ATOM 198 N LEU 1494 2.052 7.418 25.944 1.00 32.77 ATOM 199 CA LEU 1494 1.645 6.081 26.335 1.00 30.87 ATOM 200 -CB LEt) 1494 2.445 5.587 27.550 1.00 27.22 ATOM 201 CG LEt) 1494 1.970 4.250 28.141 1.00.28.67 ATOM 202 CD1 LEU 1494 2.124 3.132 27.129 1.00 27.40 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 383 ATOM 203 CD2 LEU 1494

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

204 20.5 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230.

231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD

OE1 OE2

C

0

N

CA

CB

C

0

N

CA

CB

CG2

CGI

CDI

C

0

N

CA

C

0

N

CA

CB

CG

CDI

CD2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

LEU

LEU

ALA

ALA

ALA

ALA

ALA

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ALA

ALA

ALA

ALA

ALA

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

GLY

GLY

GLY

GLY

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ASN

ASN

ASN

1494 1494 1495 1495 1495 1495 1495 1496 1496 1496 1496 1496 1496 1496 1496 1496 1497 1497 1497 1497 1497 1498 1498 1498 1498 1498 1498 1498 1498 1499 1499 1499 1499 1500 1500 1500 1500 1500 1500 1500 1500 1505 1505 1505 1505 1505 1505 1505 1506 1506 1506 2.736 3.904 0.173 6.256 -0.249 7.344 -0.626 5.223 -2.044 5.307 -2.815 5.999 -2.608 3.919 -1.926 2.915 -3.836 3.867 -4.5.4 2.603 -4.841 2.441 3.627 2.233 -3.9'50 2.405 -4.322 3.534 -3.835 1.4)7 -5.799 2.594 -6.593 3.54.3 -5.961 1.561 -7.139 1.426 -6.742 0.969 -8.068 0.418 -7.657 -0.702 -9.31j.3 0.823 -1.0.302 -0.064 -11.359 0.727 12.233 -0.246 -10.690 1.745 -11.663 2.730 3.1.023 -0.777 -11.644 -0 .134 -10.917 -2.095 -11.588 -2.822 -10.709 -3.193 -9.993 -4.205 -10.729 -2.370 -9.963 -2.613 -8.445 -2.677 -7.516 -1.463 -6.082 -1.946 -7.703 -0.783 -10.420 -3.891 -10.544 -4.966 -13.321 -5.777 -13.937 -7"111 -14.289 -4.776 -15.630 -5.503 -15.271 6.918 -14.010 -4.321 -14.001 -3.122 -13.712 -5.272 -13.430 -4.945 -14.302 -5.776 29.377 26 .701 27 .119 26.477 26.817 25.691 27.057 26.846 27.552 27.793 29.272 30.140 31.613 31.999 32.378 26.970 27.020 26.153 25.324 23.930 25.965 26.278 26.201 26.811 27.619 28.439 28.545 29.155 25.673 24.838 25.610 24.554 23.372 23.438 22.321 21.087 21.345 21.166 21.263 19.824 20.376 20.984 25.373 25.286 25.848 25.710 26.025 27.294 27.571 28.178 29.571 30.512 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1 00 1.00 1.00 1.00 1.0*0 1.00 1.00 1.0,0 1.00 1.00 1.00 1.00 1.00 1.00O 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00' 1.00 1.00 1.00 28.84 31.18 30.88 30.40 28.30 27.35 26.32 24 .54 28.11 29.22 31 .77 37.26 39.77 37: 54 41.52 29 .76 31.39 29.55 28.69 23.86 29.51 30.40 31.33 32.30 33.61 34.55 31.99 26.68 32.69 32.03 37.34 44.45 50.75 53.68 51.14 51.15 50.85 49.05 44.92 44.03 50.50 49.92 48.57 50.09 46.31 45.25 48.85 43.31 42.84 40.46 42.33- 43.55 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 384

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 28 2 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 CG ASN OD. ASN ND2 ASN C ASN 0 ASN N ARC CA ARC CB ARC CG ARC CD ARG NE ARC CZ ARC NHl ARG NH2 ARC C ARC 0 ARC N VAL CA VAL CB VAL CGI VAL CG2 VAL C VAL O VAL N THR CA THR CB THR OGi THR CG2 THR C THR 0 TUR N U~S CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS O LYS N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL 0 VAL N ALA CA ALA CB ALA C ALA 0 ALA N VAL 1506 1506 1506 1506 1506 1507 1507 1507 1507 1507 1507 1507 1507.

1507 1507 1507 1508 1508 1508 1508 1.508 1508 1508 1509 1509 1509 1509 1509 1509 1509 1510 1510 1510 1510 1510 1510 1510 1510 1510 1511 1511 1511 1511 1511 1511 1511 1512 1512 1512 1512 1512 1513 -15.760 -16.141 -16-.591 -11.962 11. 617 -11 .099 -9.661 -9.144 -9.407 -8.357 -8.566 -8.012 7.193 -8.338 8.982 -9.458 7. 927 7-190 -6.824 -8 .072 -5.948 5.912 -5.392 5'.427 -4.206 -4.492 -5,522 -3.255 3.323 774 -2 .092 -1.162 0 .092 117 1.191 1.065 0.318 -0.813 -0.521 -0.904 -0.625 -1.~951 -2.719 -2.829 0.150 0.274 0.679 1.408 2 .740 0 .535 0.033 0.351 -5.436 -4 .269 -6.461 -5.097 -5.221 -5.066 -5.186 -6.384 -7.728 8. 063 -9.401 -9.861 -9.093 .068 -3.940 -3 .354 -3.491 -2.335 -1.296 -0.723 -1.900 -2.869 -3.926 -2.152 -2.527 -3 .015 -4 .008 3.648 -1.300 -0.219 -1.432 -0.325 -0.595 -0.460 -0.614 -1.603 -1.067 -0.213 -1.218 1. 004 1.305 1.464 0.143 2.629 2 .626 3 .346 2.935 4.173 3.889 5 .012 4 .515 6.281 30.382 30 .316 30.323 29.957 31.137 28.949 29.145 28.353 28.992 30.038 30.574 31.691 32.406 32.134 28.611 27.642 29.279 28.782 29.883 30.498 30.938 28.155 28.555 27.154 26.476 25.031 25.066 24.411 26.419 26.039 26 .893 26.831 27.648 29.135 29.896 31.062 32.245 25.355 24.700 24.836 23.446 22 .636 22.615 23.223 23.365 24.360 22 .185 21.979 21.331 21.057 20.061 21.404 1.00 42.68 1.00 47.11 1.00 45.66 1.00 42.89 1.00 43.23 1.00 42.72 1.00 42.24 1.00 50.39 1.00 60.88 1.00 67.47 1.00 74.19 1.00 79.97 1.00 81.67 1.00 82.38 1.00 38.15 1.00 36.46 1.00 35.19 1.00 33.82 1.00 30.19 1.00 34.68 1.00 28.53 1.00 33.91 1.00O 34.02 1.00 31.32 1.00 30.47 1.00 30.88 1.0.0 33.90 1.00 24.49 1.00 '28 .74 1.00 27.29 1.00 29.17 1.00 30.55 1.00 27.23 1.00 34.33 1.00 40.49 1.00 48.28 1.00 51.03 1.00 29.64 1.00 28.00 1.00 30.10 1.00 30.13 1.00 31.39 1.00 30.42 1.00 28.08 1.00 30.51 1.00 31.09 1.00 28.30 1.00 25.23 1.00 23.82 1.00 25.50 1.00 27.06 1.00 29.37 SSSD/55034. V01 WO 98/07835 WO 9807835PCTIUS97/14885 385

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

307 308 309 310 311 312 313 314 315 316 317 318 31.9 320 321 322 323 324 325.

326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 CA VAL 1513 CB VAL 1513 CG1 VAL 1513 CG2 VAL 1513 C VAL O VAL N LYS CA LYS CS LYS CG LYS CD LYS CE LYS NZ LYS C LYS O LYS N MET CA MET CB MET CG MET SD MET CE MET C MET O MET N LEU CA LEU CS LEU CG LEU CD1 LEU CD2 LEU C LEU 0 LEU N LYS CA LYS CS LYS CG LYS CD LYS CE LYS NZ LYS C LYS O LYS N SER CA SER CB SER C SER 0 SER N ASP CA ASP CB ASP C ASP 0 ASP N ALA CA ALA 1513 1513 1514.

1514 1514 1514 1514 1514 1514 1514 1514 1515 1515 1515 1515 1515 1515 1515- 1515 1516 1516 1516 1516 1516 1516 1516 1516 1517 1517 1517 1517 1517 1517 1517 1517 1517 1518 1518 1518 1518 1518 1519 1519 1519 1519 1519 1520 1520 -0.477 -1.588 -2.453 -2.452 0 .347 1 .030 0.321 1. 022 1.541 2 .524 2 .725 3 .245 4-.408 0.020 -li 095 0.433 -0-.419 -1.162 -0.251 -1.271 -1.523 0 .397 1 .606 -0.288 0. 349 513 -0.757 -1.733 0 .555 0.549 -0.143 1 .500 1 .773 3 .220 4 .281 5 .666 6 .711 8 .020 0 .824 0.226 0.720 -0.167 -0.085 0.-124 -0.798 1.402 1.802 3 .162 1.861 2.432 1 .322 1.344 7.199 7.843 8 .775 6.776 8. 328 9 .064 8.423 9.466 8 .917 7.792 6 .998 7.860 8 .680 10.574 10 .305 11.812 12.981 13.299 13.641 13.763 12 .018 14 .197 14 .255 15 .182 16.423 17.129 16.463 17.298 16.329 17.391 17.326 18.299 19.315 19.813 18.810 19.197 18.118 18.410 20.474 20.557 21.391 22.543 23.439 23.382 23.843 23.530 24.326 24.973 23.548 24.035 22-.332 21.508 20.625 21.504 20.684 22.152 20.006 20 .719 18 .680 17. 929 16.606 16 .800 15 .535 14 .416 14 .844 17.653 17 .192 17. 908 17.713 18. 991 20.139 21.571.

21.959 17.321 17 .550 16 .747 16 .312 15.255 13 .904 13 .114 13 .163 17.473 18 .488 17.302 18. .313 18.222 18.663 18.130 18 .414 17 .751 18.037 16 .960 18.987 18.848 20.090 17 .609 16.938 17.280 16 .127 16.385 14 .817 13 .844 14 .798 13 .595 1 -QO 31.53 1.00 32.26 1.00 34.37 1.00 33.42 1.00 33.34 1.00 32.35 1.00 36.65 1.00 37.26 1.00 36.21 1.00 39.32 1.00 42.59 1.00 44.71 1.00 38.78 1.00 37.21 1.00 37.39 1.00 39.05 1.0.0 41.68 1.00 41.07 1.00 40.69 1.00 41.18 1.00 40.98 1.00 44.66 1.00 43.83 1.00 50.63 1.00 52.21 1.00 53.18 1.00 50.25 1.00 51.02 1.00 51.60 1.00 54.25 1.00 52.52 1.00 59.09 1.00 62.57 1.00 66.29 1.00 70.96 1.00 74.61 1.00 78.21 1.00 77.95 1.00 63.07 1.00 63.68 1.00 64.54 1.00 67.29 1.00 65.14 1.00 69.48 1.00 71.85 1.00 70.88 1.00 72.00 1.00 72.61 1.00 72.32 1.00 73.72 1.00 72.11 1.00 71.13 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885' 386 ATOM 359 CB ALA 1520 0.659 20.173 13.855 1.00 71.01 ATOM 360 C ALA 1520 0.666 22.242 12.440 1.00 69.96 ATOM 361 0 ALA 1520 -0.314 22.962 12.639 1.00 71.41 ATOM 362 N TER 1521 1.230 22.101 11.249 1.00 67.39 ATOM 363 CA TER 1521 0.676 22.726 10.064 1.00 66.23 ATOM 364 CB THR 1521 1.798 23.167 9.132 1.00 66.40 ATOM 365 OGi THR 1521 2.521 22.016 8.680 1.00 70.07 ATOM 366 CG2 THR 1521 2.741 24.070 9.867 1.00 66.67 ATOM 367 C THR 1521 -0.150 21.665 9.364 1.00 65.62 ATOM 368 0 THR 1521 -0.093 20.493 9.740 1.00 66.78 ATOM 369 N GLU 1522 -0.893 22.057 8.330 1.00 63.60 ATOM 370 CA GLU 1522 -1.698 21.0-95 7. 584 1.00 62.25 ATOM 371 CB GLU 1522 -2.560 21.802 6.531 1.00 64.02 ATOM 372 C GLU 1522 -0.768 20..051 6.942 1.00 60.41 ATOM 373 0 GLU 1522 -1.161 18.906 6.738 1.00 61.94 ATOM 374 N LYS 1523 0.475 20.441 6.662 1.00 56.47 ATOM 375 CA LYS 1523 1.449 19.529 6.080 1.00 54.53 ATOM 376 CE LYS 1523 2.739 20.273 5.713 1.00 57.44 ATOM 377 CG LYS 1523 3.897 19.381 5 219 1.00 61.49 A.TOM 378 CD LYS 1523 3.482 18.451 4.071 1.0.0 64.66 ATOM 379 CE LYS .1523 4.681 17.723 3.469 1.00 68.18 ATOM 380 NZ LYS 1523 4.2E2 16.704 2.458 1.00 73.23 ATOM 381 C LYS 1523 1.728 18.474. 7.135 1.00 52.30 ATOM 382 0 LYS 1523 1.757 17.280 6.832 1.00 54.59 ATOM 383 N ASP 1524.. 1.899 18.921 8.376 1.00 47.78 ATOM 384 CA ASP 1524 2.147 18.023 9.493 1.00 45.55 ATOM 385 CE ASP 1524 2.380 18.815 10.783 1.00 47.64 ATOM 386 CG ASP 1524 3.744 19.511 10.817 1.00 49.50 ATOM 387 ODi ASP -1524- 3.849 20.580 11.460 1..00 47.22 ATOM 388 0D2 ASP 1524 4.715 18.984. 10.230 1.00 52.84 ATOM 389 C ASP 1524 0.968 17.054 9.661 1.00 43.55 ATOM 390 0 ASP 1524 1.157 15.890 10.007 1.00 43.98 ATOM 391 N LET) 1525 -0.240 17.541 9.39. 1.00 40.77 ATOM 392 CA LET) 1525 -1.438 16.713 9.483 1.00 40.28 ATOM 393 CB LEU 1525 -2.701 17.592 9.411 1.00 40.54 ATOM 394 CG LEU 1525 -4.100 16.957 9.403 1.00 40.33 ATOM 395 CD1 LEU 1525 -4.289 15.933 10.514 1.00 42.75 ATOM 396 CD2 LEU 1525 -5.120 18.044 9.524 1.00 36.98 ATOM 397 C LET) 1525 -1.417 15.699 8.343 1.00 40.1i9 ATOM 398 0 LEU 1525 -1.682 14.525 8.557 1.00 41.90 ATOM 399 N SER 1526 -1.064 16.158 7.147 1.00 42.13 ATOM 400 CA SER 1526 -1.002 15.315 5.954 1.00 44.75 ATOM 401 CE SER 1526 -0.582 16.136 4.723 1.00 49.61 ATOM 402 OG SER 1526 -1.538 17.100 4-.352 1.00 59.95 ATOM 403 C SER 1526 -0.007 14.193 6.144 1.00 42.71 ATOM 404 0 SER 1526 -0.297 13.047 5.840 1.00 45.33 ATOM 405 N ASP 1527 1.167 14.527 6.655 1.00 40.97 ATOM 406 CA ASP 1527 2.210 13.546 6.867 1.00 41.03 ATOM 407 CE ASP 1527 3.497 14.235 7.316 1.00 45.30 ATOM 408 CG ASP 1527 4.083 15.147 6.235 1.00 47.84 ATOM 409 ODi ASP 1527 3.700 15.041 5.047 1.00 48.84 ATOM' 410 0D2 ASP 1527 4.957 15.966 6.600 1. 00 49.11 SSSD/55034. V01 WO 98/07835 PTU9/48 PCTIUS97/14885* 387

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

411 412 413 41.4 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447.

448 449 450 451 452 453 454 455 456 457 458 459 460 461 462

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

CD

OE 1 0E2

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N-

CA

ASP

ASP

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

SER

SER

S ER S ER

SER

SER

GLU

GLU

GLU

GLU

GL-U

GLU

GLU

GLU

GLU

MET

MET

MET

MET

MET

MET

MET

MET

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

MET

MET

1527 1527 1528 1528 1528 1528 1528 1528 1528 1528 1529 1529 1529 1529 1529 1529 1529 1529 1530 1530 1530 1530 1530 1530 1531 1531 1531 1531 1531 1531 1531 1531 1531 1532 1532 1532 1532 1532 1532 1532 1532 1533 1533 1533 1533 1533 1533 1533 1533 1533 1534 1534 1.782 2.021 1.094 0 .594 -0 .008 0.436 0.650 -0 .770 -0.453 -0 .442 1.311 -2.365 -3 .364 -4.311 -4.193 -5.024 -1.732 -2.148 -0.733 0.007 1.126 0 .605 0 .614 O0.494 1 .256 .1.865 2.629 3 .263 4 .094 4 .913 3 .940 0 .824 1 .118 0.377 -1.476 -2.608 -3.761 -5.095 -5.271 -2.002 -2.131 -2.257 -2.755 -2.987 -4 .117 -5.420 -5 .923 -5.939 -1.787 -2.197 -0-.500 0.606 12.485 11.298 12 .917 12 .004 12 .784 11 .961 10 .955 12 .877 11 .065 9.855 11 .614 10.839 11.732 10' 861 12 .579 13 .662 9 .825 8.667 10 .269 9 .414 10.197 11.332 8 .208 -1.083 8 .449 7 .369 7,.907 6 .812 7 .344 6 .561 8. 522 6 .351 5 .146 6 .832 5.966 6 .800 5.968 6 .973 8.228 5.145 3 .923 5 .824 5 .176 6.221 7 .154 6.405 5 .696 6 .518 4.120 3 .043 4.435 3 .571 7.858 7.651 8.909 9. 927 11.107 12.326 12 .692 13.499 9.309 9. 566 8.453 7.805 7 .012 6 .1.87 7. 983 7.335 6. 877 o6.860 6 .108 5.171 4.495 3 .835 5.868 5.376 7. 010 7.-766 8. 973 9.825 10.979 11. 495 11.378 8.215 8.259 8.553 8 .996 9.596 10.146 10.779 9.489 7.814 7.893 6. 70t 5.495 4.423 4.784 5.064 4 .166 6 .197 5.003 4.563 5.136 4.737 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1 .00 1.00 1.00 1. 00 1.00 1.00 1.00 1 00i 1.00 1.00 1.00 1.00 1.0,0 1 .00 1 .00 1 .00 1.00 1.00 1.00 1.00 1. 0.0 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 39.01 40.04 35.93 36 .48 36.51 40.56 42 .00 38.25 35.25 36 .37 33 32.32 31.17 32.01 31.35 32 .59 33.44 35.41 33 34 .34 38 .37 46 .02 30.41 30.50 27.40 28.90 28.45 29.33 31.14 33 .14 31.11 30.88 32.35 29.86 30.01 29.58 31.20 29.37 21.59 29.60 29.68 30.38 30.12 25.79 26 .67 29.90 29.93 29.10 30.32 32 .06 29.97 31.22 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 388

ATOM

ATOM

ATOM

ATOM

'ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

A4TOM

NTOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

463 464 465 466 467 468 469 470 471.

472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514

CB

CG

SD

CE

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

CD

CE

NZ

C

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

MET

MET

MET

MET

MET

MET

MET

MET

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

GLY

GLY

GLY

GLY

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

1534 1534 1.534 1534 1534 1534 1535 1535 1535 1535 1535 1535 1535 1535 1536 1536 1536 1536 1536 1536 1536 1536 1536 1537 1537 1537 1537 1537 1537 1537 1537 1538 1538 1538 1538 1538 1538 1538 1538 1539 1539 1539 1539 1540 1540 1540 1540 1540 1540 1540 1540 1540 1. 918 3 .118 3 .528 5.215 0. 565 0 .596 0.493 0.417 0. 325 1 .622 1.674 1.393 777 0.682 -1.885 -3.078 -4.237 4. 807 -5 92'5 6.402 -7.469 -2.813 -3.150 -2 .186 1 .890 -1.321 -2 .282 -3.740 -2.964 903 -1.102 0. 142 1,189 2 .381 3 .380 3 .097 4 .445 0.756 1.274 -0.200 -0.625 0.207 1.220 -0.195 0.461 -0.573 -1.530 -2.542 -3.568 -2.973 1 .577 1.536 4 .305 3 .487 3.627 4.257 2 .304 1 .193 2.485 1 .354 1 .829 2 .434 2 .633 4 .335 0 .460 -0 .7-14 1 .072 0. 315 1.253 1.947 2 .857 674 -1 .594 -0.5*13 -1.756 -0.0(JJ4 **0.783 0 .136 *1.208 0 .505 0.152.

-1.920 049 -1.626 -2.609 -1.948 2 .989 0.968 -0.465 -3.911 -4 .980 -3.849 -5.069 -5.369 -4.708 -6.396 -6.781 -7.350 6.346 -6.977 -5.942 -4.847 -7.796 -8.723 4. 985 4.675 2.982 3 .155 5.581 5.050 6.896 7.813 9.274 9. 803 11.595 1.1. 729 7.445 7.530 7 .029 6 .608 6.283 7.479 7.06.1 8.225 7. .796 5. 397 5 393 4.372 3 .Ui72 2.085 1.566 0. 744 -0.698 3.447 2 .996 4.223 4. 533 5.280 5. 745 4.345 4.874 5 .224 4.909 6.137 6.812 8.039 8.281 8.788 10.052 11.028 11.563 12.502 12 .994 13.836 9-974 9.176 1.00 33.86 1.00 40.40 1.00 48.27 1.00 42.49 1.00 30.90 1.00 33.24 1.00 29.07 1.00 28.82 1.00 28.87 1.00 28.16 1.00 30.96 1.00 27.69 1.00 28.59 1.0.0 30.37 1.00 26.53 1.00 27.60 25.88 1.00 23.80 1.0O'0.21.64 1.00O 21.83 1.00 26.27 1.00 27.49 1.00 29.24 1.00 27.89 1.0.0k 29.12 1. 00' 32.72 1.00 37.18 1.00 43.17 1.00 43.04 1.00 29.58 1.00 27.63 1.00 28.64 1.00 26.88 1.0.0 25.23 1.00 27.31 1.00 22.70 1.00 23.44 1.00 26.75 1.00 28.60 1.00 27.19 1.00 26.88 1.0.0 26.04 1.00 27.96 1.00 23.25 1.00 21.53 1.00 20.48 1.00 28.42 1.00 36.24 1.00 41.05 .1.00 41.25 1.00 19.96 1.00 21.51 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 389

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

515 516 517 518 51.9 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 N HIS CA HIS CB HIS CG HIS CD2 HIS ND1 HIS CEl HIS NE2 HIS C HIS O HIS N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS 0 LYS N ASN CA ASN CB ASN CG ASN ODi ASN ND2 ASN C ASN 0 ASN N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE O ILE N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE O ILE N ASN CA ASN CB ASN CG ASN ODI ASN ND2 ASN C ASN O ASN N LEU 1541 1541 1541 1541 1541 1541 1541 1541 1541 1541 1542 1542 1542 1542 1542 1542 1542 1542 1542 1543 1543 1543 1543 1543 1543 1543 1543 1544 1544 1544 1544 1544 1544 1544 1544 1545 1545 1545 1545 1545 1545 1545 1545 1546 1546 1546 1546 1546 1546 1546 1546 1547 2.514 -7.670 10.905 1.00 19.82 3.622 -8.613 4.704 -8.411 5.747 -9.490 5.810 -10.667 6.891 -9.428 7.609 -10.522 6.975 -11.293 4 198 4 .231 4 .587 5 .141 5. 578 6. 130 .6.380 6 995 7.457 6 .318 6 .462 7 .147 8 .333 9. 558' 9 .721 9. 501 10. 026 8 312 9:*353 7. 153 7-.037 6 .545 7 .436 5 .082 4.485 6 .044 5-.342 6-.103 5 .140 5 .586 4.399 6 .759 6 .450 3 .853 3 .809 2 .829 1. 528 0. 866 1-.690 1 .764 2 .324 0. 567 0. 709 -8.456 -7.352 -9.577 -9.610 -11..044 -11 .239 -12.719 -13 .414 -14 .831 8.674 -8.067 -8.546 -7..702 -8.482 -9.811 -10.883 -9.741 -6.268 -5.733 5.624 -4.226 4.029 -4.810 -4.447 -3.974 -3 .590 -4.309 -2.275 -1.608 -0.161 0.652 -0.178 -0.730 -1.555 -0.954 -2 .236 -2 .311 -3.697 -4.834 -4 .997 -5.606 -1.235 -0.682 11.040 9.972 9. 963 9.292 10.727 10.535 9.668 12.449 13.002 13 .045 14.396 14.742 16. 150 16.420 15. 18 3 15.421 14.608 15.676 13.576 13.689 12.217 13.945 13.372 .15.230 13.155 12. 776 13 I80 12.7~71 11.292 10.334 11.096 9. 760 13.757 14.466 13.943 14.826 15.198 15.718 16.193 17.579 14.010 12.920 14.514 13.853 14.060 13.481 12.274 14.343 14.325 15.426 1.00 21.35 1.00 21.39 1.00 17.07 1.00 18.04 1.00 19.05 1.00 19.63 1.00 18.32 1.00 23.61 1.00 25.66 1.00 24.32 1.00 27.04 1.00 30.70 1.00 40.75 1.00 48.24 1.00 56.89 1.0~ 60.99 1.00 24.59 1.00 23.35 1.00 22.05 1.00 21.40 1.0.0 20.89 1.00 20.37 1.00 24.97 1.00 21.56 1.00 20.38 .i.00 20.03 1.00 20. 02 1.00 21.14 1.00 22.97 1.00O 23.27 1.00 22.85 1.00 18.94 1.00 20.02 1.00 21.00 1.00 20.09 1.00 22.82 1.00 23.07 1.00 21.94 1.00 20.49 1.00 15.00 1.00 24.18 1.00 25.68 1.00 25.69 1.00 24.23 1.00 25.21 1.00 21.10 1.00 23.44 1.00 18.20 1.00 23.12 1.00 24.14 -0.382 -0.920 13.456 1.00 23.49 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 390

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

-ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618

CA

CB

CG

CD

CD

C

0

N

CA

CB

CG

CDJ

CD2

C

0

N

CA

C

0

N

CA

CB

C

0

N

CA

CB

SG

C

0

N

CA

CB

OGI

CG2

C

0

N

CA

CB

CG

CD

OE1 NE2

C

0

N

CA

CB

CG

ODI

OD2

LEU

LEU

LEU

1 LEU 2 LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

GLY

GLY

GLY

GLY

ALA

ALA

ALA

ALA

ALA

CYS

CYS

CYS

CYS

CYS

CYS

THR

THR

THR

THR

THR

THR

THR

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

ASP

ASP

ASP

ASP

ASP

ASP

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VO

WO 98/07835 WO 9807835PCTIUS97/14885 391.

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1554 1554 1555, 1555 1555 1555 1556 1556 1556 1556 1556 1556 1556 1557 1557 1557 1557 1557 1557 1557 1557 1558 1558 1558 1.558 1558 1558 1558 1558 1558 1558 1558 1558 1559 1559 1559 1559 1559 1559 1559 1560 1560 1560 1560 1560 1560 1560 1560 1561 1561 .1561 1561 -13.343 -13 .522 -12.182 -11.062 -9.728 -9.663 -8.635 -8.634 -7.271 -6.436 -7.269 -7.094 -7.574 -6.379 -6.112 -5.458 -4 .962 -6.080 -4.339 -5.190 -4.173 -5.606 -4.796 -5.529 -5 .588 -6.5 83 -6.678 -4.678 4.760 5.766 -5.868 -4.529 -5.467 -3.254 -2.855 -1.729 -1.456 -2.101 -2.358 -1.328 -3.146 -2.818 -4.112 -3.777 -5.063 -6.428 -1.954 -2.411 -0.720 0.238 1.445 0.952 15.563 15.375 15.966 16.185 15.891 15.567 15.987 16.266 15.740 15.947 16.842 14.314 13.377 14.153 12 .844 13.010 11. 77 4 10.763 12.22 9 12.057 12.578 10.841 9.993 10. 7S4 10. 793 11.957 11.805 12.878 12. 8 99 13.986 8-747 8.137 8.444 7.246 7.528 6.282 8.738 6.311 6.572 5.283 4.316 3.732 2.898 4.884 4.463 3.181 2.392 3.089 2.088 2.801 3.480 17.244 18 .452 16 .747 17.638 16. 994 15. 810 17. 759 19.208 17.294 18.549 19.389 16.806 17.444 15.699 15 .124 13 .741 12. 972 12.715 11.669 16 .060 16 .524 16 .396 17.237 18.534 :19.539 20.517 21.407 19.483 20.367 21. 324 22.164 16.436 35.924 16 .225 15.504 14.485 13.623 13.604 16.596 17.220 16. 889 17.928 18.552 19.788 18. 904 19.318 17.356 16.505 17.840 17.368 16.653 15.397 1.00 47.24 1.00 48.98 1.00 44.00 1.00 41.07 1.00 40.26 1.00 39.72 1.00 39.21 1.00 39.09 1.00 37.84 1.00 39.66 1.00 39.53 1.00 37.75 1.00 37.25 1.00 36.09 1.00 34.69 1.00 32.25 1.00 31.23 1.00 25.69 1.00 28.21 1.00 34.59 1.00 32.09 1.00 32.63 .1.00 29.66 1.00 33.14 1.00 32.87 1.00 34.58 1.00 34.65 1.00 35.69 1.00 37.01 1.00 37.52 1.00 40.19 1.00 28.08 1.00 30.12 1.00 25 89 1.00 23.70 1.00 23.78 1.00 20.75 1.00 22.54 1.00 23.47 1.00 26.84 1.00 23.58 1.00 23.75 1.00 22.67 1.c60 20.24 1.00 20.09 1.00 19.04 1.00 27.39 1.00 28.51 1.00 26.76 1.00 25.91 1.00 24.50 1.00 13.55 SSSD/55034. V0l WO 98/07835 PCTIUS97/1 4885 392 ATOM 671 CG2 VAL 1561 2.054 3.870 17.551 1.00 20.39 ATOM 672 C VAL 1561 0.693 1.151 18.519 1.00 24.80 ATOM 673 0 VAL 1561 0.397 1.417 19.696 1.00 25.26 ATOM 674 N GLU 1562 1.349 0.032 18.192 1.00 22.30 ATOM 675 CA GLU 1562 1.793 -0.901 19.230 1.00 21.49 ATOM 676 CB GLU 1562 2.369 -2.179 18.630 1.00 16.65 ATOM 677 CG GLU 1562 1.312 -3.115 18.092 1.00 19.71 ATOM 678 CD GLU 1562 1.895 -4.356 17.460 1.00 21.58 ATOM 679 OE1 GLU 1562 1.281 -5.432 17.572 1.00 24.28 ATOM 680 0E2 GLU 1562 2.956 -4.260 16.825 1.00 23.74 ATOM 681 C GLU 1562 2.802 -G.261 20.158 1.00 23.56 ATOM 682 0 GLU 1562 3.581 0.578 19.738 1.00 24.82 ATOM 683 N TYR 1563 2..787 -0.665 21.422 1.00 26.96 ATOM 684 CA TYR 1563 .3 .677 -0,132 22.442 1.00 28.98 ATOM 685 CB TYR 1563 2.907 0.035 23.744 1.00 30.34 ATOM 686 CG TYR 1563 3.744 0.456 24.929 1.00 33.86 ATOM 687 CD. TYR 156 3 4.457. 1.653 24.915 1.00 36.58 ATOM 688 CEl TYR 1563 5.195 2.069 26.021 1.00 36.89 ATOM 689 CD2 TYR 1563 3.787 -0.322 26.082 1. 00 34.25 ATOM 690 CE2 TYR 1563 4.522 0.080 27.186 1.0.0 34.47 ATOM 691 CZ TYR 1563 5.219 1 .273 27*.150 1.00 37.08 ATOM 692 OH TYR 1563 5.965 1.662 28.228 1.00 44.10 ATOM 693 C TYR 1563 4.884 -1.043 22.668 1.00 30.53 ATOM 694 0 TYR 1563 4.745 -2.269 22.751 1.00 30.66 ATOM 695 N ALA 1564 6..068 -0.440 22.779 1.00 31.09 ATOM 696 CA ALA 1564 7. 303 -1.192 22.998 1. 00 32.00 ATOM 697 CB ALA 1564 a.236 026 21.792 1.CO 30.82 ATOM 698 C ALA 1564 7.940 -0.663 24.283 1.0.0 25.32 ATOM 699 0 ALA 1564 8.703 0.309 24.274 1.00 32.26 ATOM 700 N SER 1565. 7.603 -1.303. 25.389 1. 0.0 29.55 ATOM 701 CA SER 1565 8zG59 -0.884 26.712 1.00 30.89 ATOM 702 CB SER 1565 '.392 -1.729 27.792 1.00 29.79 ATOM 703 OG SER 1565 7.704 -3.094 27.611 1.00 30.94 ATOM 704 C SER 1565 9.547 -0.840 26.986 1.00 31.39 ATOM 705 0 SER 1565 9. 978 -0.150 27.902 1.00 35.74 ATOM 706 N LYS 1566 10.340 -1.576 26.229 1.00 30.03 ATOM 707 CA LYS 1566 11.756 -1.560 26.495 1.00 28.80 ATOM 708 CE LYS 1566 12.322 -2.973 26.447 1.00 28.98 ATOM 709 CG LYS 1566 11.756 3.842 27.563 1.00 25.35 ATOM 710 CD LYS 1566 12.208 -5.279 27.459 1.00 30.93 ATOM 711 CE LYS 1566 11.875 -6.001 28.747 1.00 31.41 ATOM 712 NZ LYS 1566 12.315 -7.421 28.716 1.00 32.83 ATOM 713 C LYS 1566 12.529 -0.595 25.623 1.00 29.93 ATOM 714 0 LYS 1566 13.756 -0.672 25.544 1.00 30.89 ATOM 715 N GLY 1567 11.799 0.322 24.979 1.00 30.67 ATOM 716 CA GLY 1567 12.423 1.328 24.138 1.00 28.44 ATOM 717 C GLY 1567 13.136 0.874 22.875 1.00 27.19 ATOM 718 0 GLY 1567 12.919 -0.235 22.395 1.00 25.36 ATOM 719 N ASN 1568 14.011 1.731 22.352 1.00 28.39 ATOM 720 CA ASN 1568 14.735 1.421 21.130 1.00 28.41 ATOM 721 CE ASN 1568 15. 188 2.698 20.418 1.00 30.32 ATOM 722 CG ASN 1568 16.396 3.352 21.058 1.00 33.42 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 393 ATOM 723 ODi ASN 1568 17.418 2.720 21.317 1.00 35.16 ATOM 724 ND2 ASN 1568 16.328 4.661 21.203 1.00 36.23 ATOM 725 C ASN 1568 15.884 0.443 21.314 1.-00 28.34 ATOM 726 0 ASN 1568 16.478 0.373 22.388 1.00 30.67 ATOM 727 N LEU 1569 16.2-12 -0.270 20.244 1.00 27.65 ATOM 728 CA LEU 1569 17.269 -1.270' 20.247 l.00 29.10 ATOM 729 CB LEU 1569 17.311 -1.974 18.880 1.00 27.49 ATOM 730 CG LEU 1569 18.292 -3.130 18.657 1.00 28.82 ATOM 731 CD1 LEU 1569 18.236 -4.140 19.825 1.00 24.68 ATOM 732 CD2 LEU 1569 17.994 -3.791 17.316 1.00 22.26 ATOM 733 C LEU 1569 18.667 -0.790 20.676 1.00 29.37 ATOM 734 0 LEU 1569 19.389 -1.525 21.355 1.00 29.72 ATOM 735 N ARG 1570 19.058 0.425 20.303 1.00 30.89 ATOM 736 CA ARG 1570 20.374 0.943 20.689 1.00 33.01 ATOM 737 CB ARG 1570 20.591 2.353 20.121 1.00 30.95 ATOM 738 CG ARG 1570 21.896 2.983 20.584 1.00 38.85 ATOM 739 CD ARG 1570 21.968 4.472 20.303 1.00 43.03 ATOM 740 NE ARG 1570 .20.749 5.192 20.670 1.00 53.34 ATOM 741 CZ ARG 1570. 20.404 5.573 21.905 1.00 57.49 ATOM 742 NH1 ARG 1570 21.1.84 5.310 22.955 1.00 55.59 ATOM 743 NH2 ARG 1570 19.272 6.252 22.086 1.00 59.53 ATOM 744 C ARG 1570 20.475 0.947 22.229 1. 00 33.82 ATOM 745 0 ARG 1570 21.351 0.296 22.817 1.00 33.93 ATOM 746 N GLU 2.571 19. 52 8 1.639 22.865 1.00 33.91 ATOM 747 CA GLU 1571 19.4 3c 746 24. 317 1.00 32.59 ATOM 748 CB GLU 1571 18.2.77 2.524 24.676 1.00 36.4C ATOM 749 CG GLU 1571 18. 174 3.958 24.175 1.00 45.91 ATOM 750 CD GLU 1571 16.822 4.654 24.328 1.00 '52. ATOM 751 OE1 GLU 2571 15.793 :A.959 24.529 1.00 54.50 ATOM' 752 0E2 GLU 1571 16.792 5.905 24.222 1.00 55.17 ATOM 753 C GLU 1571 1-9.380 0.361 24.959 1.00 31.40 ATOM 754 0 GLU 1571 20.115 0.054 25.895 1.00 31.09 ATOM 755 N TYR 1572 .18.503 -0.477 24.433 1.00 29.24 ATOM 756 CA TYR 1572 18.334 -1.835 24.920 1.00 27.43 ATOM 757 CB TYR 1572 17.387 -2.590 23.991 1.00 26.41 ATOM 758 CG TYR 1572" 17.196 -4.045 24.311 1.00 23.13 ATOM 759 CD1 TYR 1572 16.224 -4.448 25.216 1.00 28.16 ATOM 760 CEl TYR 1572 15.983 -5.784 25.456 1.00 28.32 ATOM 761 CD2 TYR 1572 17.936 -5.024 *23.665 1.00 20.00 ATOM 762 CE2 TYR 1572 17.699 -6.361 23.899 1.00 22.28 ATOM 763 CZ TYR 1572 16.721 -6.731 24'.801 1.00 26.53 ATOM 764 OH TYR 1572 16.479 -8.058 25.055 1.00 30.25 ATOM 765 C TYR 1572 19.671 -2.564 24.960 1.00 30.90 ATOM 766 0, TYR 1572 1'9.953 -3.323 25.901 1.00 30.68 ATOM 767 N LEU 1573 20.487 -2.337 23.933 1.00 31.27 ATOM 768 CA LEU 1573 21.776 -2.995 23.841 1.00 33.33 ATOM 769 CB LEU 1573 22.287 -2.975 22.399 1.00 30.85 ATOM 770 CG LEU 1573 21.643 -3.908 21.370 1.00 26.92 ATOM 771 CD1 LEU 1573 22.144 -3.546 19.980 1.00 22.76 ATOM 772 CD2 LEU 1573 21.939 -5.372 21.695 1.00*25.82 ATOM 773 C LEU 1573 22.801 -2.390 24.791 1.00 36.07 ATOM 774 0 LEt? 1573 23.544 -3.117 25.457 1.00 36.40 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 394

ATOM

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1575 15.75 1575 1575 1576 1576 1576 1576 3.576 1576 1576 1576 1576 1576 1576 1577 1577 1577 1577 1577 1577 1577 1577 1577 1577 -1577 1578 1578 1578 1578 1578 1578 1578 1579 1579 1579 1579 1579 1579 1579 1592 1592 22.815 23 .763 23 .722 24.240 24.046 23.391 24.606 23.502 24.431 22.229 21.846 20.394 22.102 21.758 22.647 22.943 22.027 20. 599 19.649 18.308 17.590 18.086 16.337 24.405 24 .790 25.226 2 6.661 27.306 27:' 048 27.696 27.798 28.284 28.719 28.346 27.222 26.652 28.307 29.038 28.877 29.933 30.352 29. 490 29.814 29.604 29.208 30.169 30.175 28.997 31.575 32.481 19.097 20.535 -1.065 -0.391 1.119 1.529 3 .009 3.740 3 .452 -0.711 -0.988 -0.742 -1.021 -0.669 -2.473 -2.843 -3 .299 -4.687 -5.636 -5.481 -6 .146 -6.147 051 -3 .855 -5.160 -5.052 231 -4.*017 185 -2.855 -2.402 -1.042 -0.747 0.385 1.359 0 .539 -4.594 -4 .244 -5 .381 -6.041 -5.766 -6.809 -6 .391 -4 .493 -3 .538 -4.432 -5 .463 -3 .265 -3 .708 -4 .638 904 -3 .739 -5.342 -5.076 24.887 1.00 37.25 25.759 1.00 37.41 25.522 1.00 38.07 24.147 1.00 40.76 23.851 1.00 44.73 24.597 1.00 46.47 22.732 1.00 46.93 27.233 1.00 37.80 27.990 1.00 38.55 27.617 1.00 37.28 28.987 1.00 35.47 29.178 1.00 31.42 29.424 1.00 38.30 30.544 1.00 41.11 28.528 1.00 37.59 28.869 1.00 37.23 28.111 1.00 36.82 28.561 1.00 34.61 27.640 1.00 31.82 28.201 1.00 31.54 28.426 1.00 33.71 28.149 1.00 33.68 28.857 1.00 38.97 26.683 1.00 38.53 28.700 1.00 38.39 28.538 1.00 39.28 28.394 1.00 39.33 27.998 1.00 35.44 26.584 1.00 33.45 26.330 1.00 32.83 24.897 1.00 36.69 24.384 1.00 36.99 25.175 1.00 40.35 23.065 1.00 36.53 29.754 1.00 41.24 30.796 1.00 41.03 29.769 1.00 44.39 28.667 1.00 44.50 31-066 1.00 44.89 30.686 1.00 42.49 29.327 1.00 43.63 31.672 1.00 45.20 30.947 1.00 44.68 33.003 1.00 46.51 33.981 1.00 46.36 33.685 1.00 47.56 35.141 1.00 46.45 35.205. 1.00 47.51 33.200 1.00 50.19 33.196 1.00 53.53 32.478 1.00 60.30 32.445 1.00 59.47 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 395 ATOM 827 CB ALA 1592 20.975 -4.338 33.715 1.00 61.58 ATOM 828 C ALA 1592 21.367 -6.350 32.252 1.00 58.15 ATOM 829 0 ALA 1592 22.543 -6.285 31.879 1.00 59.09 ATOM 830 N ALA 1593 20.754 -7.510 32.479 1.00 55.79 ATOM 831 CA ALA 1593 21.457 -8.775 32.324 1.00 55.06 ATOM 832 CB ALA 1593 20. 519 -9.939 32.604 1.00 57.05 ATOM 833 C ALA 1593 22.053 -8.897 30.924 1.00 53.57 ATOM 834 0 ALA 1593 21.402 -8.598 29.926 1.00 53.85 ATOM 835 N 'GLN 1594 23.303 -9.336 30.862 1.00 53.22 ATOM 836 CA GLN 1594 24.004 -9.490 29.599 1.00 50.13 ATOM 837 CB GLN 1594 25.400 -10.082 29.832 1.00 50.73 ATOM 838 CG GLN 1594 26.308 -9.253 30.743 1.00 54.69 ATOM 839 CD GLN 1594 27.550 -10.019 31.217 1.00 57.79 ATOM 840 OE1 GLN 1594 28.075 -10.900 30.524 1.00 58.82 ATOM 841 NE2 GLN 1594 28.026 -9.673 32.407 1.00 59.53 ATOM 842 C GLN 1594 .23.210 -10.374 28.637 1.00 47.73 ATOM 843 0 GLN 1594 22.427 -11.241 29.054 1.00 47.09 ATOM 844 N LEU 1595 23.418 -10.133 27.350 1.00 45.64 ATOM 845 CA LEU 1595 22. 758 -10.880 26.292 1.00 42.00 ATOM 846 CB LEU 1595 22.405 -9.947 25.122 1.00 37.98 ATOM 847 CG LEU 1595 21.345 '-8.894 25.446 1.00 37.70 ATOM 848 CD1 LEU 1595 21.568 7.611 24.660 1.00 33.34 ATOM 849 CD2 LEU i595 19.971 -9.479 25.222 1.00 32.84 ATOM 850 C LEU 1595 23.729 -11.944 25.828 1.00 40.92 ATOM 851 0 LEU 1595 24.944 -11.745 25.855 1. 00 41.12 ATOM 852 14 SER 1596 23.201 -13.103 25.471 1.0.0 40.09 ATOM 853 CA SER 1596 24.044 -14.178 24.985 2.00 38.93 ATOM 854 CB SER 1596 23.388 -15.535 25.235 1.00 37.45 ATOM 855 OG SER 1596 22.158 -15.662 24.545 1.00 39.49 ATOM 856 C SER 1596 24.302 -13.987 23.499 1. 0.0 39.41 ATOM 857 0 SER 1596 23.634 -13.183 22.832 1.00 39.51 ATOM 858 N SER 1597 25.266 -14.738 22.977 1.00 39.17 ATOM 859 CA SER 1597 25.587 -14.667 21.563 1.00 40.23 ATOM 860 CB SER 1597 26.740 -15.611 21.230 1.00 39.96 ATOM 861 OG SEP 1597 27.865 -15.339 22.048 1.00 46.60 ATOM 862 SER 1597 24.347 -15.057 20.773 1.00 39.65 ATOM 863 0 SER 1597 24.066 -14.469 19.725 1.00 41.13 ATOM 864 N LYS 1598 23.590 -16.023 21.291 1.00 36.82 ATOM 865 CA LYS 1598 22.390 -16.467 20.611 1.00 36.17 ATOM 866 CB LYS 1598 21.827 -17.742 21.217 1.00 36.19 ATOM 867 CG LYS 1598 21.030 -18.562 20.180 1.00 39.59 ATOM 868 CD LYS 1598 20.150 -19.623 20.830 1.00 37.49 ATOM 869 CE LYS 1598 19.769 -20.719 19.855 1.00 39.64 ATOM -870 NZ LYS 1598 20.976 -21.437 19.380 1.00 41.43 ATOM 871 C LYS 1598 21.340 -15.381 20.649 1.00 37.72 ATOM 872 0 LYS 1598 20.604 -15.213 19.677 1.00 39.82 ATOM 873 N ASP 1599 21.291 -14.627 21.752 1.00 36.20 ATOM 874 CA ASP 1599 20.331 -13.530 21.907 1.00 33.96 ATOM 875 CB ASP 1599 20.456 -12.884 23.279 1.00 35.66 ATOM 876 CG ASP 1599 19.913 -13.744 24.394 1.00 36.18 ATOM .877 ODi ASP 1599 20.365 -13.565 25.544 1.00 39.14 ATOM 878 0D2 ASP 1599 19.036 -14.593 24.128 1.00 33.40 SSSD/55034. Vo1 WO 98/07835 WO 9807835PCTIUS97/14885 396

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879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 8.97 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 C ASP O ASP N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C ,LEU O LEU N VAL CA VAL CB VAL CG1 VAL CG2- VAL C VAL 0 VAL N SER CA SER CB SER OG SER C SER O SER N CYS CA CYS CB C YS.

SG CYS C CYS O CYS N ALA CA ALA CB ALA C ALA O ALA N TYR CA TYR CB TYR CG TYR CD1 TYR CEl TYR CD2 TYR CE2 TYR CZ TYR OH TYR C TYR O TYR N GLN CA GLN CB GLN CG GLN CD GLN OE1 GLN 1599 1599 1600 1600 1600 1600 1600 1600 1600 1600 1601 1.601 1601 1601 1601 1601 1601 1602 1602 1602 1602 1602 1602 1603 1603 1603 1603 1603 1603 1604 1604 1604 1604 1604 1605 1605 1605 1605 1605 1605 1605 1605 1605 1605 1605 1605 1606 1606 1606 1606 1606 1606 20.595 -12.471 19.660 -11.953 22.304 -11.121 23.804 -10.850 24.174 -10.153 25.660 -9.877 23.408 -8.857 21.964 -11.523 21.385 -10.734 22.271 -12.764 21.983 -13.268 22.648 -14.649 22.403 -15.104 24.156 -14.568 20.474 -13.353' 19.991 -13.147 19.733 -13.590 18.277 -134.671 17.731 -14.259 16.317 -14.306 17.669 -12.280 16.643 -12.141 18.289 -11.262 17.878 -9.871 18.797 -8.937 18.512 -7.186 17.994 -9.517 17.083 -8.932 19.138 -9.854 19.422 -9.592 20.851 -10.035 18.419 -10.302 17.894 -9.713 18.130 -11.557 17.175 -12.359 17.104 -13.751 15.997 -14.608 16.109 -15.244 15.069 -16.049 14.830 -14.797 13.801 -15.596 13.922 -16.212 12.855 -16.944 15.766 -11.735 15.180 -11.635 15.231 -11.319 13.907 -10.699 13.561 -10.383 13.329 -11.608 13.052 -11.243 12.087 -10.542 20.857 20.225 20.706 19.735 19.916 21.242 21.324 21.369 18 .291 17.541 17.930 16.597 16.345 14 .921 16.593 16.399 15.295 17.478 17.406 18 .694 18 .646 17.149 16.465 17.737 17. 561 18 .350 18 .059 16 .090 15.520 15.492 14 .073 13.741 13 .168 12.226 13 .488 12.730 13 .334 12.789 11.546 11.053 13 .520 13 .038 11.810 11.364 12.658 11.578 13 .807 13 .892 15.342 16.210 17.649 17.944 1.00 33.57 1.00 32.60 1.00 32.82 1.00 31.14 1.00 30.23 1.00 27.52 1.00 24.11 1.00 21.94 1.00 29.24 1.00 27.61 1.00 27.38 1.00 27.26 1.00 30.47 1.00 28.72 1.00 29.92 1.00 26.23 1.00 25.54 1.00 27.43 1.00 27.09 1.00 29.02 1.00 35.77 1.00 26.87 1.00 25.13 1.00 26.09 1.00 24.81 1.00 23.87 0.50 24.17 1.00 25.24 1.00 27.48 1.00 26.80 1.00 26.15 1.00 24.35 1.00 26.61 1.00 28.81 1.00 27.10 1.00 27.02 1.00 27.35 1.00 31.67 1.00 32.96 1.00 29.27 1.00 31.42 1.00 28.20 1.00 29.20 1.00 27.90 1.00 27.90 1.00 28.40 1.00 27.12 1.00 25.32 1.00 24.31 1.*00 25.05 1.00 26.35 1.00 26.11 SSSD/55034. V01 WO 98/07835 PC1TUS97/14885 397 ATOM 931 NE2 GLN 1606

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932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 C GLN O GLN N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL 0 VAL N ALA CA ALA CE ALA C ALA 0 ALA N ARG CA ARG CE ARG CG ARG CD ARG NE ARG CZ ARG NH1 ARG NH2 ARG C ARG 0 ARG N GLY CA GLY C GLY O GLY N MET CA MET CB MET CG MET SD MET CE MET C MET 0 MET N GLU CA GLU CE GLU CG GLU CD GLU OE1 GLU 0E2 GLU C GLU O GLU N TYR CA TYR CE TYR CG TYR CD1 TYR 1606 1606 1607 1607 1607 1607 1607 1607 1607 1608 1608 1608 1608 1608 1609 1609 1609 1609 1609 1609 1609 1609 1609 1609 1609 1610 1 610 1610 1610 1611 1611 1611 1611 1611 1611 1611 1611 1612 1612 1612 1612 1612 1612 1612 1612 1612 1613 1613 1613 1613 1613 13.917 -11.684 13.849 -9.415 12.825 -9.089 14.943 -8.662 15.053 -7.419 16.337 -6.661 16.545 -5.457 16.277 -6.224 15.035 -7.718 14.337 -7.046 15.795 -8.722 15.812 -9.079 16.823 -10.145 14.418 -9.558 14.033 -9.405 13.671 -10.169 12.314 -10.628 11.822 -11.577 12.278 -12.979 11.449 -13.885 10.771 -14.865 9.931 -15.778 9.674 -15.828 9.353 -16.649 11.318 -9.490 10.470 -9.542 11.375 -8.500 10.497 -7.353 10.732 -6.715 9.794 -6.455 12.011 -6.545 12.423 -5.970 13.925 -5.737 14.371 -4.547 13.449 -2.960 13.869 -2.525 12.024 -6.843 11.608 -6.332 12.141 -8.162 11.759 -9.059 11.980 -10.522 11.587 -11.468 11.735 -12.942 11.386 -13.316 12.190 -13.725 10.283 -8.821 9.916 -8.728 9.437 -8.700 8.003 -8.456 7.263 -8.526 -5.785 -8.218 4.880 -9.213 -18 .551 13 .078 12.455 13 .122 12 .359 12 .731 11. 800 14 .190 10.860 10.096 10.435 9. 027 8 .783 8 .600 7.432 9.530 9.246 10.326 10.114 10.939 10.115 10.594 11.898 9.776 9.065 8 .160 9. 948 .9.827 8 .464 7.693 8 .130 6 .851 6 .838 7 .694 7.422 5.757 5.670 4.613 5 .825 4.743 5.110 3.968 4.313 5.448 3.443 4.398 3 .226 5.422 5.212 6.549 6.449 6 .062 1.00 27.77 1.00 27.52 1.00 27.87 1.00 27.90 1.00 26.41 1.00 25.61 1.00 27.37 1.00 21.50 1.00 26.09 1.00 28.48 1.00 23.05 1.00 20.32 1.00 14.95 1.00 23.08 1.00 23.91 1.00 24.57 1.00 24.30 1.00 26.13 1.00 31.07 1.00 36.13 1.00 38.37 1.00 37.95 1.00 '35.31 1.00 37.85 1.00 22.34 1.00 24.57 1.00 20.52 1.00 19.33 1.00 20.04 1.00 19.10 1.00 18.21 1.00 20.32 1.00 19.20 1.00 20.83 1.00 25.39 1.00 18.67 1.00 23.98 1.00 24.13 1.00 25.76 1.00 25.49 1.00 26.09 1.00 26.56 1.00 29.26 1.00 29.10 1.00 31.11 1.00 26.29 1.00 28.46 1.00 24.78 1.00 23.07 1.00 23.75 1.00 20.80 1.00 20.97 SSSD/55034. V0l WO 98/07835 PCT/US97/14885 398 ATOM 983 CEI TYR 1613

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984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1002.

1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 CD2 TYR CE2 TYR CZ TYR OH TYR C TYR O TYR N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N ALA CA ALA CB ALA C ALA O ALA N SER CA SER CB SER OG SER C SER O SER N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS 0 LYS N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C L.YS O LYS N CYS CA CYS CB CYS SG CYS C CYS O CYS N ILE CA ILE 1613 1613 1613 1613 1613 1613 1614 1614 1614 1614 1614 1614 1614 1614 1615 1615 1615 1615 1615 1616 1616 1616 1616 1.616 1616 1617 1617 1617 1617 1617 1617 1617 1617 1617 1618 1618 1618 1618 1618 1618 1618 1618 1618 1619 1619 1619 1619 1619 1619 1620 1620 3.517 -8.944 5.289 -6.938 3.926 -6.661 3.046 -7.672 1.694 -7.420 7.766 -7.094 6.970 -6.979 8.436 -6.065 8.321 -4.713 9.169 -3.747 8.607 -3.395 9.504 -2.425 7.230 -2.795 8.729 -4.676 8.073 -4.038 9.819 -5.366 10.313 -5.435 11.625 -6.207 9.264 -6.098 8.945 -5.587 8.692 -7.205 7.660 -7.919 7.283 -9.217 6.415 -8.966 6.397 -7.062 5.650 -7.266_ 6.136 -6.135 4.997 -5.237 4.436 -4.881 3.709 -6.046 2.463 -6.448 1.691 -7.571 2.401 -8.852 5.346 -3.981 4.588 -3.007 6.496 -4.002 6.957 -2.883 5.871 -2.513 5.734 -3.465 5.557 -4.914 5.590 -5.850 4.373 -5.748 7.404 -1.610 7.533 -0.548 7.719 -1.744 8.103 -0.614 7.338 -0.690 7.916 0.427 9.586 -0.480 10.257 -1.435 10.110 0.717 11.532 1.046 5.958 6 .731 6 .628 6 .244 6.161 4 .550 3 .615 5.062 4.519 5.350 6 .733 7.470 6.558 3 .043 2 .211 2.729 1.355 1.292 0.491 -0.579 0.972 0.207 0 .912 2 .007 -0.018 -0.975 0.895 0.779 2.160 2.851 2.059 2.725 2.601 -0.017 -0.013 -0.679 -1.528 -2.555 -3.749 -3.328 -4.520 -5.354 -0.796 -1.402 0.489 1.312 2 .643 3.957 1.543 1. 958 1.288 1.474 1.00 20.03 1.00 19.72 1.00 21.87 1.00 24.87 1.00 24.37 1.00 21.68 1.00 20.20 1.00 21.72 1.00 20.42 1.00 17.68 1.00 18.47 1.00 16.59 1.00 14.07 1.00 21.70 1.00 22.25 1.00 21.55 1.00 20.52 1.00 19.78 1.00 19.98 1.00 20.14 1.00 20.65 1.00 19.59 1.00 15.96 1.00 16.62 1.00 22.05 1.00 23.62 1.00 23.39 1.00 23.02 1.00 21.50 1.00 24.94 1.00 26.57 1.00 31.05 1.00 38.73 1.00 24.01 1.00 28.15 1.00 23.84 1.00 24.05 1.00 25.74 1.00 28.34 1.00 32.45 1.00 30.41 1.00 31.84 1.00 23.84 1.00 20.60 1.00 25.11 1.00 21.68 1.00 20.84 1.00 26.69 1.00 23.16 1.00 25.60 1.00 23.91 1.00 26.01 SSSD/55034. V01 WO 98/1835 PCTIUS97/14885 399 ATOM 1035 CB ILE 1620 12.098 1.830 0.236 1.00 22.61 ATOM 1036 CG2 ILE 1620 13.551 2.259 0.471 1.00 16.86 ATOM -1037 CG1 ILE 1620 12.014 0.977 -1.026 1.00 22.72 ATOM 1038 CD1 ILE 1620 12.096 1.804 -2.316 1.00 23.62 ATOM 1039 C ILE 1620 11.566 1.934 2.729 1.00 26.83 ATOM 1040 0 ILE 1620 10.900 2.965 2.772 1.00 28.92 ATOM 1041 N HIS 1621 12.293 1.500 3.758 1.00 26.44 ATOM 1042 CA HIS 1621 12.386 2.245 5.007 1.00 23.61 ATOM 1043 CB HIS 1621 13.142 1.429 6.065 1.00 20.98 ATOM 1044 CG HIS 1621 12.940 1.917 7.463 1.00 21.57 ATOM 1045 CD2 HIS 1621 12.321 1.346 8.528 1.00 20.74 ATOM 1046 ND1 HIS 1621 13.382 3.151 7.897 1.00 21.08 ATOM 1047 CEl HIS 1621 13.035 3.321 9. 162 1.00 21.00 ATOM 1048 NE2 HIS 1621 12.396 2.237 9.572 1.00 21.97 ATOM 1049 C HIS 1621 13.054 3.582 4.841 1.00 24.83 ATOM 1050 0 HIS 1621 12.560 4.585 5.310 1.00 25.76 ATOM 1051 N ARG 1622 14.247 3.565 4.269 1.00 27.57 ATOM 1052 CA ARG 1622 15.056 4.776 4.066 1.00 26.47 ATOM 1053 CB ARG 1622 14.233 5.918 3.460 1.00 20.08 ATOM 1054 CG ARG 1622 13.762 5.634 2.077 1.00 15.87 ATOM 1055 CD ARG 1622 12.998 6.791 1.501 0.50 11.86 ATOM 1056 NE ARG 1622 12.613 6.458 0.144 0.50 12.46 ATOM 1057 CZ ARG 1622 11.537 5.748 -0.178 0.50 11.18 ATOM 1058 NH1 ARG 1622 10.711 5.304 0.767 0.50 7.16 ATOM. 1059 NH2 ARG 1622 11.340 5.398 -1.442 0.50 9.57 ATOM. 1060 C ARG 1622 15.813 5.250 5.325 1.00 26.18 ATOM 1061 0 ARG 1622 16.645 6.150 5.250 1.00 26.90 ATOM -1062 N ASP 1623 15.544 4.650 6.480 1.00 27.26 ATOM 1063 CA ASP 1623 16.268 5.042 7.684 1.00 29.80 ATOM 1064 CB ASP 1623 15.714 6.330 8.292 1.00 32.13 ATOM 1065 CG ASP 1623 16.690 6.940 9.298 1.00 37.87 ATOM 1066 ODi ASP 1623 16.237 7.671 10.202 1.00 42.95 ATOM 1067 0D2 ASP 1623 17.907 6.684 9.191 1.00 41.09 ATOM 1068 C ASP 1623 16.364 3.943 8.738 1.00 29.10 ATOM 1069 0 ASP 1623 16.164 4.168 9.939 1.00 27.69 ATOM 1070 N LEU 1624 16.723 2.755 8.270 1.00 28.23 ATOM 1071 CA LEU 1624 16.874 1.599 9.129 1.00 26.00 ATOM 1072 CB LEEJ 1624 16.944 0.351 8.245 1.00 22.14 ATOM 1073 CG LEtJ 1624 17.036 -0.998 8.941 1.00 22.32 ATOM 1074 CD1 LEU 1624 15.853 -1.196 9.932 1.00 17.01 ATOM 1075 CD2 LEU 1624. 17.068 -2.064 7.848 1.00 20.50 ATOM 1076 C LEIJ 1624 18.129 1.757 10.003 1.00 25.89 ATOM 1077 0 LEU 1624 19.247 1.917 9.499 1.00 26.11 ATOM 1078 N ALA 1625 17.936 1.706 11.316 1.00 25.58 ATOM 1079 CA ALA 1625 19.006 1.864 12.292 1.00 23.16 ATOM 1080 *CB ALA 1625 19.323 3.340 12.493 1.00 19.06 ATOM 1081 C ALA 1625 18.475 1.286 13.584 1.00 24.12 ATOM 1082 0 ALA 1625 17.269 1.083 13.721 1.00 27.40 ATOM 1083 N ALA 1626 19.357 1.041 14.543 1.00 24.67 ATOM 1084 CA ALA 1626 18.929 .0.491 15.827 1.00 25.07 ATOM 1085 CB ALA 1626 20.148 0.145 16.691 1.00 2-6.06 ATOM 1086 C ALA 1626 18.015 1.474 16.560 1.00 25.13 SSSD/55034. V0l WO 98/07835 PCT/US97/14885 400

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1087 0 ALA 1088 N ARG 1089 CA ARG 1090 CB ARG 1091 CG ARG 1092 CD ARG 1093 NE ARG 1094 CZ ARG 1095 NH1 ARG 1096 NH2 ARG 1097 C ARG 1098 0 ARG 1099 N ASN 1100 CA ASN 1101 CB ASN 1102 CG ASN 1103 ODI ASN 1104 ND2 ASN 1105 C ASN 1106 0 ASN 1107 N VAL 1108 CA VAL 1109 CB VAL 1110 CG1 VAL 1111 CG2 VAL 1112 C VAL 1113 0 VAL 1114 N LEU 1115 CA LEU 1116 CB LEU 1117 CG LEU 1118 CD1 LEU 1119 CD2 LEU 1120 C LEU 1121 0 LEU 1122 N VAL 1123 CA VAL 1124 CB VAL 1125 CG1 VAL 1126 CG2 VAL 1127 C VAL 1128 0 VAL 1129 N THR 1130 CA THR" 1131 CB THR 1132 OGI THR 1133 CG2 THR 1134 C THR 1135 0 THR .1136 N GLU 1137 CA GLU 1138 CB GLU 1626 1627 1627 1627 1627 1627 1627 1627 1627 1627 1627 1627 1628 1628 1628 1628 1628 1628 1628 1628 1629 1629 1629 1629 1629 1629 1629 1630 1630 1630 1630 1630 1630 1630 1630 1631 1631 1631 1631 1631 1631 1631 1632 1632 1632 1632 1632 1632 1632 1633 1633 1633 17.184 18.197 17.367 17.850 17.731 18.159 18.448 19.667 20.717 19.841 15. 926 15. 015 15. 722 14.382 14.351 14 .503 13.876 15.361 13.782 12.896 14.307 13.778 14.829 14.346 15.068 13.411 14.237 12.181 11.751 10.447 10.522 9.149 11.339 11.641 11.475 11.792 11.741 13.068 13 .113 14.240 10.560 10.419 9.703 8.530 7.476 7.948 7.186 8.882 9.950 7.946 8.165 6.881 1.069 2 770 3 784 5.187 5.501 6. 920 7. 085 7.006 6.752 7.201 3 .632 3 979 3 .093 2.934 3.407 4.918 5.686 5.348 1.524 1.161 0.733 -0.610 -1.727 -3.014 -1.962 -0.575 -0.204 -0.941 919 -0.129 1.293 1.870 2.196 -2.327 -3.320 -2.418 -3.694 -3.930 -5.345 -3.688 -3.758 -2.918 -4.756 -4.939 -5.800 152 -5.262 -5.603 -6.185 -5.589 -6.19-3 -6.114 17.366 16.308 16.939 16.565 15.078 14.740 13.310 12.784 13.561 11.492 16.482 17.216 15.286 14.723 13.269 13.143 13.863 12.220 14.833 14.056 15.763 16.036 15.823 16.462 14.341 17.520 18.357 17.850 19.239 19.359 18.758 18.601 19.618 19.835 19.108 21.153 21.866 22.624 23.222 21.680 22.836 23.738 22.641 23.487 22.793 22.708 21.414 24.809 24.946 25..751 27.062 27.899 1.00 26.38 1.00 23.08 1.00 24.05 1.00 28.05 1.00 37.58 1.00 42.10 1.00 42.67 1.00 43.58 1.00 46.17 1.00 43.78 1.00 23.04 1.00 22.27 1.00 24.49 1.00 23.80 1.00 27.82 1.00 30.25 1.00 32.33 1.00 31.50 1.00 23.93 1.00 23.64 1.00 24.10 1.00 22.59 1.00 21.16 1.00 17.53 1.00 14.48 1.00 24.81 1.00 24.09 1.00 24.34 1.00 26.53 1.00 26.19 1.00 24.33 1.00 20.51 1.00 19.77 1.00 28.14 1.00 28.31 1.00 28.21 1.00 26.96 1.00 25.71 1.00 20.40 1.00 19.88 1.00 29.84 1.00 32.46 1.00 30.90 1.00 31.16 1.00 29.58 1.00 29.17 1.00 22.23 1.00 32.23 1.00 33.23 .1.00 34.38 1.00 35.51 1.00 35.48 SSSD/55034. V01 WO 98/07935 WO 9807835PCT/US97/14885 401

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1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166.

1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 CG GLU CD GLU OE1 GLU 0E2 GLU C GLU 0 GLU N ASP CA ASP CB ASP CG ASP ODi ASP 0D2 ASP C ASP 0 ASP N ASN CA ASN CB ASN CG ASN ODi ASN ND2 ASN C ASN 0 ASN N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL 0 VAL N MET CA MET CB MET CG MET SD MET CE MET C MET O MET N LYS CA LYS CB LYS CG LYS CD LYS CE LYS N'Z LYS C LYS 0 LYS N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE 1633 1633 1633 1633 1633 1633 1634 1634 1634 1634 1634 1634 1634 1634 1635 1635 1635 1635 1635 1635 1635 1635 1636 1636 1636' 1636 1636 1636 1636 1637 1637 1637 1637 1637 1637 1637 1637 1638 1638 1638 1638 1638 1638 1638 1638 1638 1639 1639 1639 1639 1639 1639 7.004 -6.685 8.070 -5.999 8.174 -4.750 8.789 -6.723 8.624 -7.635 9.387 -8.119 8.204 -8.308 8.573 -9.709 7.435 -10.491 6.100 -10.315 5.885 -10.957 5.256 -9.544 9.842 -9.882 10.148 -10.988 10.582 11.833 12.893 13.335 13.496 13.525 11.641 12.431 10.557 10.260 8.743 8.451 8.289 10.725 10.432 11.567 12.107 13.325 14.446 15.051 15.163 11.033 10.479 10.758 9.745 8.495 7.723 6 .442 5.560 4.892 10.254 10.613 10.259 10.707 10.925 11.270 12.068 11.975 -8.787 -8 .763 692 244 -8.057 -10 .191 -9.073 -9.799 -8.541 -8.722 -8.945 -9.066 -10.220 -7.461 -6.355 -7.637 -6.539 -7.008.

-7.576 -6 .440 -7.542 -6 .108 -6 .951 -4 .805 -4.255 -3.883 -5.087 -4 .699 -5 .934 -6.414 -3 .034 -2 .041 -3 .101 -1.984 -2.439 -1.262 -3.454 -4.369 29.309 30.183 30. 163 30.919 26.930 27 .758 25.861 25.662 24.991 25.706 26.759 25.197 24.840 24.414 24.655 23.868 24.471 25 .840 26 .088 26 .743 22.372 21.754 21.819 20.415 20.177 18.678 20.884 19.721 20.179 18.707 17. 927 17.138 17.982 19.245 20.648 16.951 16.244 16.893 16.006 16.793 17.268 17.969 18.189 16.941 15.257 15.868 13 .934 13 .113 11.648 10.766 11.604 10.461 1.00 45.16 1.00 50.45 1.00 52.70 1.00 53.59 1.00 35.40 1.00 36.57 1.00 36.76 1.00 37.95 1.00 42.90 1.00 49.06 1.00 50.95 1.00 53.92 1.00 36.05 1.00 34.95 1.00 36.53 1.00 36.21 1.00 37.91 1.00 37.60 1.00 42.72 1.00 38.03 1.00 34.59 1.00 33.52 1.00 31.95 1.00 28.92 1.00 31.00 1.00 29.52 1.00 29.03 1.00 28.05 1.00 25.21 1.00 28.78 1.00 27.29 1.00 27.97 1.00 29.31 1.00 29.58 1.00 23.51 1.00 26.60 1.00 26.60 1.00 24.35 1.00 20.79 1.00 18.95 1.00 22.82 1.00 25.49 1.00 24.36 1.00 22.23 1.00 22.79 1.00 24.60 1.00 23.92 1.00 24.22 1.00 23.18 1.00 19.97 1.00 26.92 SSSD/55034. V01 WO 98/07835 WO 9807835PCTIUS97/14885 402

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 C ILE O ILE N ALA CA ALA CB ALA C ALA O ALA N ASP CA ASP CB ASP CG ASP ODi ASP 0D2 ASP C ASP O ASP N PHE CA PHE CB PHE CG PHE CD1 PHE CD2 PE CEl PE CE2 PHE CZ PE C PHE 0 PE N GLY CA GLY C GLY O GLY N LEU CA LEU CB LEU CG LEU CD1 LEIJ CD2 LEU C LEU O LEU N ALA CA ALA CB ALA C ALA O ALA N ALA CA ALA CB ALA C ALA O ALA N ASP CA ASP CB ASP CG ASP 1639 1639 1640 1640 1640 1640 1640 1641 1641 1641 1641 1641 1641 1641 1641 1642 1642 1642 1642 1642 1642 1642 1642 1642 1642 1642 1643 1643 1643 1643 1644 1644 1644 1644 1644 1644 1644 1644 1645 1645 1645 1645 1645 1646 1646 1646 1646 1646 1647 1647 1647 1647 9.686 8 .473 10.200 9.394 9. 623 9. 720 10. 765 8 .815 8. 952 10. 096 9. 713 10.475 8. 684 9. 088 9. 526 8. 611 8. 664 8.459 7. 167 6. 002 7. 119 4. 796 5. 926 4. 760 7. 686 7. 946 6 .600 5. 640 5.736 4. 896 6. 816 7. 077 8. 363 8. 321 7. 161 9.663 7.178 7.770 6 .553 6 .591 5.432 7. 935 8.254 8.727 10. 023 11. 108 10.446 10.430 10.811 11.280 10. 898 11.128 -0.846 -1.075 0.364 1.577 2.211 2 .595 2.522 3.551 4.631 5.581 6.551 7. 524 6.355 4.228 5.022 3.032 2.528 1.009 0.555 0. 547 0. 112 0.094 -0.341 -0,352 3 .242 3 .330 3.791 4.4.76 5.991 6.707 6 .471 7.890 8.058 9.137 8.827 9.186 8.708 8.267 9.881 10.786 11.762 11.545 12 .200 11.444 12.121 11.194 12.601 11.823 13.876 14.394 15.861 16.339 13.173 13.042 13.390 13.497 14.862 12.411 11.755 12.237 11.259 11.646 12.771 12.953 13.470 9.799 8.966 9.477 8 .114 8.100 8.697 7.942 10.007 8.485 10.559 9. 802 7 .163 5. 975 7 .693 6.845 6 .874 6.332 7.458 7.601 8.389 9.446 10.384 10.190 6.293 5.312 6.293 5.148 5.241 5.173 6.163 4.107 4.077 4.646 2.692 1.740 2.567 1.283 1.083 -0.356 1.00 25.63 1.00 26.20 1.00 27.31 1.00 27.45 1.00 27.20 1.00 27.87 1.00 26.95 1.00 29.66 1.00 31.25 1.00 33.40 1.00 33.86 1.00 37.57 1.00 29.83 1.00 30.77 1.00 29.52 1.00 30.38 1.00 .29.43 1.00 25.46 1.00 20.44 1.00 22.76 1.00 18.52 1.00 25.55 1.00 21.76 1.00 24.94 1.00 31.03 1.00 35.19 1.00 30.42 1.00 28.27 1.00 28.46 1.00 24.29 1.00 31.65 1.00 36.03 1.00 32.41 1.00 35.30 1.00 37.60 1.00 36.62 1.00 40.21 1.00 40.65 1.00 44.50 1.00 48.66 1.00 45.63 1.00 51.32 1.00 52.68 1.00 52.77 1.00 54.73 1.00 55.34 1.00 56.41 1.00 57.76 1.00 58.2.0 1.00 59.39 1.00 59.29 1.00 60.67 SSSD/55034. V01 WO 98/07935 WO 9807835PCTIUS97/14985 403 ATOM 1243a ODi ASP 1647 12.110 15.908 -1.009 1.00 61.21

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1244 0D2 1245 C 1246 0 1247 N 1248 CA 1249 CB 1250 CG2 1251 CG1 1252 CD1 1253 C 1254 0 1255 N 1256 CA 1257 CB 1258 CG 1259 CD2 1260 ND1 1261 CEI 1262 NE2 1263 C 1264 0 1265 N 1266 CA 1267 CB 1268 CG 1269 CD2 1270 ND1 1271 CEl 1272 NE2 1273 C 1274 0 1275 N 1276 CA 1277 CB 1278 CG2 1279 CGl 1280 CD1 1281 C 1282 0 1283 N 1284 CA 1285 CB 1286 CG 1287 OD1 1288 0D2 1289 C 1290 0 1291 N 1292 CA 1293 CB 1294 CG

ASP

ASP

ASP

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP-

TYR

TYR

TYR

TYR

1647 1647 1647 1648 1648 1648 1648 1648 1648 1648 1648 1649 1649 1649 1649 1649 1649 1649 1649 1649 1649 1650 1650 1650 1650 1650 1650 1650 1650 1650 1650 1651 1651 1651 1651 1651 1651 1651 1651 1652 1652 1652 1652 1652 1652 1652 -1652 1653 1 653 1653 1653 10.337 12 .793 13 .523 13.248 14 .658 14 .848 14.023 14 .429 15.005 15.470 16.633 14 .844 15.505 14.8959 15.142 16.253 14.210 14 .733 15.974 15.505 15.636 15.273 15.262 13.849 13.342 13.509 12.571 12.279 12.840 15.872 15.686 16 .599 17.234 17.660 18.463 16.426 16.747 18.463 19.326 18.529 19.678 19.272 20.456 21.463 20.369 20.771 20.709 21.778 .22.906 23.829 23.316 17.173 14 .236 15. 023 13.209 12.878 11.626 10.469 11.922 10.976 14.047 14.245 14.839 15. 992 16.358 15.388 14.686 15.064 14.216 13.966 17.200 18.341 16.963 18.026 18.551 19.448 20.772 18.984 19.983 21.080 17.580 18.241 16.464 15.937 14.472 13.966 13 .591 12.141 16 .769 17.022 17.197 17.976 18.878 19. 640 19.888 20.030 17.007 16.421 16.868 15 .978 15. 913 14 .993 -0.835 1.273 1.889 0.562 0 .439 -0.444 0.131 -1.883 -2.890 -0.127 0.233 -0.995 -1.589 -2 .934 -4 .038 -4 .355 -4 .999 -5.867 -5.494 -0.663 -1.116 0.629 1 .633 1.860 0 .765 0.537 -0.270 -1.076.

-0.609 2.965 3.977 2.949 4.143 3 .942 5.142 3 .752 4.523 3.688 5.784 6.235 7.411 7.982 7.287 9.170 6 .652 7 .735 5.808 6 .074 4.855 3 .771 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1. 00 1.00 1..00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1. 00 1.00 1.00 1. 00 61.34 60.16 58 .16 61.28 62.12 59.97 58.26 55.69 54 .38 65 .02 66.85 65.85 66.73 65.67 66.47 67.11 65.21 66.52 66.25 68.55 69.35 71.25 73 .53 76.79 83 .36 86.47 87. 02 88.66 88.34 73.11 73.23 72.64 72. 54 74.59 75.52 77.59 80.12 71.47 72.40 70.34 68.57 72.80 76. 79.62 80.36 66.01 64.75 64.05 63.55 63.81 65.65 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 404 ATOM 1295 CD. TYR 1653 24.082 14 710 2.643 1.00 65.32 ATOM 1296 CE. TYR 1653 23.638 13.810 1.674 1.00 68.40 ATOM 1297 CD2 TYR 1653 22.079 14.357 3.903 1.00 66.72 ATOM 1298 CE2 TYR 1653 21.626 13.451 2.940 1.00 69.93 ATOM 1299 CZ TYR 1653 22.409 13.182 1.833 1.00 70.13 ATOM 1300 OH TYR 1653 21.966 12.272 0.902 1.00 72.73 ATOM 1301 C TYR 1653 23.708 16.334 7.328 1.00 62.96 ATOM 1302 0 TYR 1653 24.342 15.473 7.938 1.00 63.3].

ATOM 1303 N TYR 1654 23.653 17.598 7.727 1.00 63.02 ATOM 1304 CA TYR 1654 24.379 18.065 8.902 1.00 63.89 ATOM 1305 CB TYR 1654 24.896 19.491 8.684 1.00 60.37 ATOM 1306 CG TYR 1654 26.012 19.565 7.669 1.00 59.33 ATOM 1307 CD. TYR 1654 25.735 19.673 6.313 1.00 59.29 ATOM 1308 CE]. TYR 1654 26.759 19.687 5.362 1.00 61.50 ATOM 1309 CD2 TYR 1654 27.349 19.480 8.061 1.00 60.05 ATOM 1310 CE2 TYR 1654 28.384 19.498 7.119 1.00 61.35 ATOM 1311 CZ TYR 1654 28.082 19.598 5.773 1.00 62.41 ATOM 1312 OH TYR 1654 29.098 19.589 4.842 1.00 60.57 ATOM 1313 C TYR 1654 23.586 17.984 10.192 1.00 65.65 ATOM 1314 0 TYR 1654 24.104 18.321 11.252 1.00 67.31 ATOM 1315 N LYS 1655 22.349 17.504 10.118 1.00 67.52 ATOM 1316 CA LYS 1655 21.499 17.390 11.303 1.00 69.54 ATOM 1317 CB LYS 1655 20.028 17.445 10.893 1.00 71.09 ATOM 1318 CG LYS 1655 19.057 17.518 12.049 1.00 73.08 ATOM 1319 CD LYS 1655 17.648 17.713 11.531 1.00 76.73 ATOM 1320 CE LYS 1655 16.624 17.320 12.568 1.00 81.94 ATOM 1321 NZ LYS 1655 15.232 17.521 12.072 1.00 84.53 ATOM 1322 C LYS 1655 21.783 16.102 12.076 1.00 70.33 ATOM 1323 0 LYS 1655 21.952 15.032 11.478 1.00 70.43 ATOM 1324 N LYS 1656 21.825 16.218 13.403 1.00 70.11 ATOM 1325 CA LYS 1656 22.093 15.079 14.274 1.00 70.03 ATOM 1326 CB LYS 1656 23.049 15.481 15.394 1.00 67.72 ATOM 1327 CG LYS 1656 24.473 15.716 14.947 1.00 66.34 ATOM 1328 CD LYS 1656 25.326 16.124 16.136 1.00 66.60 ATOM 1329 CE LYS 1656 26.801 15.839 15.905 1.00 64.71 ATOM 1330 NZ LYS 1656 27.612 16.059 17.138 1.00 62.24 ATOM 1331 C LYS 1656 20.823 14.480 14.881 1.00 70.67 ATOM 1332 0 LYS 1656 19.759 15.104 14.864 1.00 71.91 ATOM 1333 N THR 1657 20.941 13.265 15.412 1.00 69.38 ATOM 1334 CA THR 1657 19.818 12.586 16.035 1.00 68.30 ATOM 1335 CB THR 1657 20.052 11.051 16.101 1.00 69.30 ATOM 1336 OG. THR '1657 21.179 10.757 16.941 1.00 68.20 ATOM 1337 CG2 THR 1657 20.310 10.479 14.713 1.00 69.71 ATOM 1338 C THE 1657 19.706 13.145 17.445 1.00 67.60 ATOM 1339 0 THE 1657 20.521 13.971 17.846 1.00 67.40 ATOM 1340 N ALA 1658 18.715 12.694 18.206 1.00 67.83 ATOM 1341 CA ALA 1658 18.564 13.163 19.582 1.00 67.73 ATOM 1342 CB ALA 1658 17.345 12.503 20.234 1.00 68.87 ATOM 1343 C ALA 1658 19.833 12.820 20.364 1.00 66.59 ATOM 1344 0 ALA 1658 20.368 13.640 21.115 1.00 66-33 ATOM 1345 N ASN 1659 20.343 11.616 20.129 1.00 65.38 ATOM 1346 CA ASN 1659 21.545 11.143 20.801 1.00 62.65 SSSD/55034. V01 WO 98/07835 WO 9807835PCT1US97/14885 405 ATOM 1347 CB ASN 1659 21.702 9.638 20.616 1.00 63.61 ATOM 1348 CG ASN 1659 22.548 9.009 21.697 1.00 64.09 ATOM 1349 OD1 ASN 1659 -22.526 9.451 22.850 1.00 63.69 ATOM 1350 ND2 ASN 1659 23.279 7.959 21.345 1.00 64.10 ATOM 1351 C ASN 1659 22.808 11.844 20.321 1.00 60.46 ATOM 1352 0 ASN 1659 23.882 11.601 20.856 1.00 60.78 ATOM 1353 N GLY 1660 22.671 12.675 19.285 1.00 58.84 ATOM 1354 CA GLY 1660 23.803 13.407 18.735 1.00 56.69 ATOM 1355 C GLY 1660 24.570 12.721 17.616 1.00 56.40 ATOM 1356 0 GLY 1660 25.738 13.028 17.377 1.00 56.43 ATOM 1357 N ARG 1661 23.929 11.779 16.937 1.00 56.00 ATOM 1358 CA ARG 1661 24.585 11.048 15.849 1.00 53.80 ATOM 1359 CB ARG 1661 24.312 9.540 15.952 1.00 54.52 ATOM 1360 CG ARG 1661 24.876 8.879 17.218 1.00 55.28 ATOM 1361' CD ARG 1661 24.556 7.395 17.226 1.00 58.01 ATOM -1362 NE ARG 1661 25.051 6.670 18.396 1.00 58.41 ATOM 1363 CZ ARG 1661 24.918 5.355 18.559 1.00 59.08 ATOM 1364 NH1 ARG 1661 24.306 4.637 17.623 1.00 55.82 ATOM 1365 NH2 ARG 1661 25.394 4.762 19.652 1.00 57.53 ATOM 1366 C ARG 1661 24.139 11.581 14.491 1.00 51.03 ATOM 1367 0 ARG 1661 23.160 12.323 14.401 1.00 48.69 ATOM 1368 N LEU 1662 24.859 11.189 13.440 1.00 48.33 ATOM 1369 CA LEU 1662 24.565' 11.647 12.087 1.00 45.87 ATOM 1370 CB LEU 1662 25.839 12.199 11.426 1.00 46.18 ATOM 1371 CG LEU 1662 26.374 13.511 12.016 1.00 45.78 ATOM 1372 -CD1 LEU 1662 27.856 13.681 11.722 1.00 45.92 ATOM 1373 CD2 LEU 1662 25.576 14.698 11.489 1.00 44.92 ATOM 1374 C LEU 1662 23.961 10.542 11.230 1.00 43.02 ATOM 1375 0 LEU 1662 24.647 9.607 10.811 1.00 42.04 ATOM 1376 N PRO 1663 22.648 10.640 10.968 1.00 41.48 ATOM 1377 CD PRO 1663 21.769 11.718 11.468 1.00 40.54 ATOM 1378 CA PRO 1663 21.886 9.680 10.161 1.00 39.60 ATOM 1379 CB PRO 1663 20.582 10.424 9.889 1.00 38.77 ATOM 1380 CG PRO 1663 20.386 11.183 11.151 1.00 40.83 ATOM 1381 C PRO 1663 22.578 9.273 8.860 1.00 35.90 ATOM 1382 0 PRO 1663 22.448 8.124 8.427 1.00 36.85 ATOM 1383 N VAL 1664 23.356 10.180 8.276 1.00 33.16 ATOM 1384 CA VAL 1664 24.053 9.880 7.024 1.00 32.51 ATOM 1385 CB VAL 1664 24.851 11.106 6.439 1.00 32.44 ATOM 1386 CG1 VAL 1664 23.917 12.213 6.065 1.00 26.99 ATOM 1387 CG2 VAL 1664 25.897 11.607 7.421 1.00 29.84 ATOM 1388 C VAL 1664 24.989 8.675 7.158 1.00 30.30 ATOM 1389 0 VAL 1664 25.400 8.091 6.161 1.00 30. 16 ATOM 1390 N LYS 1665 25.278 8.276 8.393 1.00 27.72 ATOM 1391 CA LYS 1665 26.170 7.151 8.649 1.00 27.96 ATOM 1392 CB LYS 1665 26.808 7.276 10.025 1.00 26.42 ATOM 1393 CG LYS 1665 27.857 8.351 10.061 1.00 28.20 ATOM 1394 CD LYS 1665 28.221- 8.754 11.478 1.00 32.47 ATOM 1395 CE LYS 1665 29.398 9.720 11.468 1.00 32.33 ATOM 1396 NZ LYS 1665 29.713 10.231 12.819 1.00 30.38 ATOM 1397 C LYS 1665 25.522 5.794 8.486 1.00 25.81 ATOM 1398 0 LYS 1665 26.159 4.769 8.691 1.00 27.53 SSSD/55034. V01 WO 98/07835 PCT/US97/14889 406

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416 1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 .144 8 1449 1450 N TRP CA TRP CB TRP CG TRP CD2 TRP CE2 TRP CE3 TRP CD1 TRP NEl TRP CZ2 TRP CZ3 TRP CH2 TRP C TRP O TRP N MET CA MET CB MET CG MET SD MET CE MET C MET 0 MET N ALA CA ALA CB ALA C ALA O ALA N PRO CD PRO CA PRO CB PRO CG PRO C PRO 0 PRO N GLU CA GLU CB GLU CG GLU CD GLU OE1 GLU 0E2 GLU C GLU O GLU N ALA CA ALA CB ALA C ALA O. ALA N LEU CA LEU CB LEU CG LEU 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1666 1667 1667 1667 1667 1667 1667 1667 1667 1668 1668 1668 1668 1668 1669 1669 1669 1669 1669 1669 1669 1670 1670 1670 1670 1670 1670 1670 1670 1670 1671 1671 1671 1671 .1671 1672 1672 1672 1672 24.247 23.499 22.259 22.547 23.020 23.154 23.349 22.408 22 .777 23.606 23.795 23.920 23.092 22 .662 23 .350 22 .963 22.796 21.793 .21.778 21.011 23.938 25.139 23.406 24 .218 23 .342 24.800 24.163 26.011 26.935 26.614 27.855 28.259 25.687 25.576 24.971 24 .093 23 .613 22.545 23.089 22.248 24.325 22.931 22.477 22.452 21.337 20.729 21.860 .21 .234, *23 .011 23.647.

24.831 25.662 5 .793 4 .554 4. 537 4 .067 4.864 4 .009 6.225 2 .795 2 .751 4.453 6 .664 5. 782 4.444 3 .390 5-.508 5.568 7.018 7 .813 9.495 9.209 4. 942 5. 173 4 .195 3. 576.

2 .672 4. 706 5. 748 4. 511 3.374 5. 563 4.876 3.946 6. 048 7.250 5. 137 5. 553 4 .365 3.492 2.238 1.430 2. 040 6.407 7.281 6.163 6 .928 6.189 8.283 9.310 8.266 9.484 9.127 10.264 8.120 7.896 8.800 10.226 11.324 12.438 11.475 10.715 12.034 13 .684 12 .712 13.798 6.425 5.971 5.664 4.252 3.809 4. 564 3 .910 2 .387 3.279 3 .362 2.324 1.278 0.396 0.438 0.251 -0.101 0.066 -0.919 -1.482 -0.358 -2.030 -2.263 -2.685 -3.769 -4.614 -3.980 -3.310 -2.874 -3 .215 -3.301 -4.042 -2.084 -1.510 -0.319.

-1.065 -1.305 -0.406 0.074 0.952 1.527 1.00 26.13 1.00 25.88 1.00 26.15 1.00 28.12 1.00 26.14 1.00 24.97 1.00 25.14 1.00 26.09 1.00 22.55 1.00 25.32 1.00 21.72 1.00 23.77 1.00 24.79 1.00 25.26 1.00 24.21 1.00 23.79 1.00 25.08 1.00 32.58 1.00 41.43 1.00 40.85 1.00 22.52 1.00 23.63 1.00 22.77 1.00 24.91 1.00 24.41 1.00 26.66 1.00 24.54 1.00 26.97 1.00 26.23 1.00 26.05 1.00 24.03 1.00 26.27 1.00 26.44 1.00 27.72 1.00 27.16 1.00 27.63 1.00 29.35 1.00 29.16 1.00 28.03 1.00 24.12 1.00 26.07 1.00 25.52 1.00 24.12 1.00 27.74 1.00 27.65 1.00 23.18 1.00 28.22 1.00 28.51 1-.00 30.60 1.00 32.67 1.00 32.05 1.00 34.00 SSSD/55034. VOl WO 98/07835 WO 9807835PCTIUS97/14885 407

ATOM

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1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 147 4 1475 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 1501 1502 CD1 CD2

C

0

N

CA

CB

CG

CD1 CD2 CEl CE2 cz

C

0

N

CA

CB

CG

OD1 0D2

C

0

N

CA

CB

CG

CD

NE

cz NH1 NE2

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

CB

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CD1 CE1 CD2 CE2

CZ

OH

LEU

LEU

LEU

LEU

PE

PE

PHE

PE

PE

PE

PE

PE

PE

PE

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AS P AS P

ASP

ASP

ASP

ASP

AS P

ASP

ARC

ARG

ARG

ARG

ARC

ARG

ARG

ARG

ARG

ARC

ARC

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

1672 1672 1672 1672 1673 1673 1673 1673 1673 1673 1673 1673 1673 1673 1673 1674 1674 1674 1674 1674 1674 1674 1674 1675 1675 1675 1675 1675 1675 1675 1675 1675 1675 1675 1676 1676 1676 1676 1676 1676 1676 1676 1677 1677 1677 1677 1677 1677 1677 1677 1677 1677 24 .874 26 .910 24 .121 23.799 24 .905 25.403 26 .692 27.782 28.456 28 .143 29.467 29.156 29.819 24.406 24.276 23.693 22 .757 22 .957 24 .384 25.057 24 .822 21.263 20.427 20.923 19 .521 18 .890 19.480 19.407 20.025 19.652 18 .662 20.265 18 .674 17 .495 19.281 18 .576 19.378 18 .509 19.835 20.798 18.315 19.236 17 .056 16 .677 15.742 16 .442 16 .510 17.129 17.022 17.642 17.685 18.227 10.981 9.667 10.398 11.580 9.858 10.664 10.061 9.857 8.633 10.874 8 .421 10.678 9.444 10.890 11.997 9.844 9.931 8.736 8.617 9.663 7.470 9.999 10.079 9.899 9.944 11.300 12.449 13.727 14 .854 16 .123 16.439 17.085 8.825 9.005 7.658 6.514 5.825 4.850 6.868 6.348 5.541 4 .898 5.465 4.589 5.310 6 .367 7.693 8.665 6.048 7 .017 8.315 9.273 2 .577 2.149 067 -1.086 -1.997 -3 .102 -3 .667 -2 .644 -2.566 -1.762 -1.623 -0.816 -0.748 -4.245 -4.734 -4.651 -5.762 -6.700 -7.201 -7.333 -7.469 -5.418 -6.317 -4 .134 3 .706 -4.028 -3.252 -4 .0.68 -3.381 -3.539 -4.365 -2 .860 -4 .299 74 .588 -4.479 -5.012 -6.096 -6.797 -7.116 -8.145 -3.874 -3.364 -3.454 -2.350 -1.398 -0.580 -1.018 -0.250 0.644 1.414 0.968 1.783 1.00 1.00 1 .00 1 .00 1.00 1.00 1 .00 1 .00 1 .00 1 .00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 38.85 35.22 37.10 37.19 .37.60 37.11 35.24 33 .54 31.54 33.10 34.66 35.41 34.81 39.03 39.02 42.35 41.59 46.08 51.20 53. 97 50.65 42.89 41.95 42.82 42 .64 48.80 61.19 72.90 83.15 88.21 89.58 92 .07 38.05 38.87 34.44 30.11 29.58 30.72 34.29 41.15 26.90 22.06 28.17 26.80 26.05 26 .92 23 .98 23.90 26.99 24.87 ~26 .44 30.89 SSSD/55034. V0l WO 98/07835 PCTIUS97/14885 408

ATOM

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ATO M

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ATOM

1503 1504 1505 1506 1507 1508 1509 1510 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540 1541 1542 1543 1544 1545 1546 1547 1548 1549 -1550 1551 1552 1553 1554 C TYR 0 TYR N THR CA THR CB THR OGi THR CG2 THR C THR O THR N HIS CA HIS CB HIS CG HIS CD2 HIS ND1 HIS CEl HIS NE2 HIS C HIS 0 HIS N GLN CA GLN CB GLN CG GLN CD GLN OE1 GLN NE2 GLN C GLN O GLN N SER CA SER CB SER OG SER C SER O SER N ASP CA ASP CB ASP CG ASP ODi ASP 0D2 ASP C ASP 0 ASP N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL O VAL N. TRP CA TRP CE TRP 1677 1677 1678 1678 1678 1678 1678 1678 1678 1679 1679 1679 1679 1679 1679 1679 1679 1679 1679 1680 1680 1680 1680 1680 1680 1680 1680 1680 1681 1681 1681 1681 1681 1681 1682 1682 1682 1682 1682 1682 1682 1682 1683 1683 1683 1683 1683 -1683 1683 1684 1684 1684 16.006 15.080 16.489 15.973 16 .904 18.185 17 .068 15.987 16.476 15.500 15.496 14.747 13.297 12.552 12.423 11.206 11.255 16.976 17.358 17.799 19.248 19.860 19.896 19. 015 18.069 19.321 19.913 20.814 19.514 20.128 19.841 18.473 19.695 20.457 18.511 18.044 16.595 15.569 14.363 15.948 18.955 19.289 19.398 20 .307 20.515 21.587 19.187 21. 618 22.107 22 .172 23.375 23.685 3.350 3.445 2.197 0.918 0.336 0.095 1.305 -0.049 0.277 -1.260 -2.276 -3.520 -3.279 -3.476 -2.795 -2 .713 -3.116 -2.591 -2 .954 -2.382 -2.587 -2.400 -3.651 -3.559 -2.780 -4.356 -1.609 1.981 -0.350 0.606 2.065 2.290 0.292 0.542 -0.303 -0.662 -1.149 -0.016 -0.282 1.135 -1.756 -1.770 -2.649 -3.732 -4.740 -5.777 -5.437 -3.150 -3.577 -2.160 -1.489 -0.273 -2.894 -3.703 -2.458 -2.927 -3.994 -3.405 -5.174 -1.758 -0.693 -1.974 -0.933 -1.411 -1.695 -2.812 -0.741 -1.255 -2.515 -0.665 0.451 -1.695 -1.657 -3.038 -3.877 -5.096 -5.122 -6.113 -0.724 0 .021 -0.773 0.135 -0.248 -0.506 1.564 2.495 1.739 3.080 3.070 3 .198 3.017 3.498 3 .611 4.799 2 .727 3.122 1.965 2.315 1.662 666 4.705 2.970 3.449 2.566 1.00 26.30 1.00 28.12 1.00 25.46 1.00 26.27 1.00 28.43 1.00 30.59 1.00 26.56 1.00 24.60 1.00 27.15 1.00 23.23 1.00 21.51 1.00 20.84 1.00 21.48 1.00 22.71 1.00 27.21 1.00 22.60 1.00 23.66 1.00 20.81 1.00 22.50 1.00 19.58 1.00 20.89 1.00 23.76 1.00 34.08 1.00 37.77 1.00. 43.23 1-.00 37.02 1.00 20.72 1.00 21.53 1.00 21.01 1.00 23.86 1.00 21.10 1.00 23.18 1.00 23.91 1.00 26.70 1.00 21.71 1.00 21.28 1.00 23.22 1.00 23.08 1.00 21.99 1.00 24.42 1.00 20.86 1.00 21.62 1.00 21.60 1.00 22.27 1.00 22.22 1.00 21.52 1.00 20.89 1.00 21.96 1.00 24.39 1.00 22.01 1.00 23.06 1.00 20.25 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 409

ATOM

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ATOM

ATOM

1555 1556 1557 1558 1559 1560 1561 1562 1563 1564 1565 1566 1567 1568 1569 1570 1571 1572 1573 1574 1575 1576 1577 1578 1579 1580 1581 1582 1583 1584 1585 1586 1587 1588 1589 1590 1591 1592 1593 1594 1595 1596 1597 1598 1599 1600 1601 1602 1603 1604 1605 1606

CG

CD2 CE2 CE3

CDI

NEl CZ2 CZ3 CH2

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

CD1 CD2

CEI

CE2 Cz

C

0

N

CA

C

0

N

CA

CB

CG1 CG2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD1

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

SER

SER

SER

SER

SER

SER

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

GLY

GLY

GLY

GLY

VAL

VAL

VAL

VAL

VAL

VAL

VAL

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

1684 1684 1684 1684 1684 1684 1684 1684 1684 1684 1684 1685 1685 1685 1685 1685 1685 1686 1686 1686 1686 1686 1686 1686 1686 1686 1686 1686 1687 1687 1687 1687 1688 1688 1688 1688 1688 1688 1688 1689 1689 1689 1689 1689 1689 1689 1689 1690 1690 .1690 1690 1690 24.808 26.118 26.879 26.728 24.825 26.066 28.216 28.059 28.785 23.105 23.889 21.992 21.615 20.266 20.276 21.516 21.865 21.041 20.915 20.153 19.965 19.142 20.669 19.023 20.554 19.732 22.304 22.473 23.294 24.653 25.185 25.857 24.893 25.296 24. 974 25.440 25.681 24.547 25.126 23.264 22.465 21.008 19.933 18.572 19.885 23.080 23.203 23.487 24.111 24.556 23.594 24.385 0.549 0.644 1.500 0. 091 1.346 1. 915 1.815 0.405 1.257 -1.025 -1.308 -0.332 0. 144 0.870 1.950 -1.011 -0.850 -2.168 -3.340 -4.457 -5.683 -5.641 -6.853 -6.743 -7.965 -7.908 -3.845 -4.378 -3.691 -4.079 -3.211 -3 .714 -1.906 -0.937 0.548 1.493 0.923 -1.297 -1.271 -1.648 -2.058 -2.316 -2.392 -2.053 -3.768 -3.330 -3.426 -4.287 -5.520 -6.446 -7.390 -8.132 3.069 2.503 3.334 1.370 4.193 4.355 3.061 1.095 1.942 4.903 5.815 5.118 6.447 6.376 5.452 7.457 8.638 6.998 7.854 7.129 7.971 9.108 7.688 9.947 8.514 9.653 8.316 9.436 7.436 7.769 8.899 9.808 8.829 9.860 9.467 10.564 8.186 11.142 12.225 11.021 12.187 11.776 12.874 12.272 13 .543 12.797 14 .016 11. 956 12.457 11.315 10.589 9.538 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 22.35 24.14 23.68 25.09 22.52 21.48 20.56 23.92 23.18 23.96 25.98 24.68 22.75 21.11 21.98 23.06 22.55 21.83 21.92 18.02 20.86 18.76 18.96 19.29 19.27 21.91 22.11 21.35 20.48 20.41 19.03 20.27 20.57 21.14 20.78 21.51 19.70 23.16 24.14 24.50 25.93 25.42 26.29 23.43 25.66 28.01 30.06 27.19 25.29 24.98 24.85 24.22 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 410 ATOM 1607 CD2 LEU 1690

ATOM

ATOM

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ATOM

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ATOM

1608 1609 1610 1611 1612 1613 1614 1615 1616 1617 1618 1619 1620 1621 1622 1623 1624 1625 1626 1627 1628 1629 1630 1631 1632 1633 1634 1635 1636 1637 1638 1639 1640 1641 1642 1643 1644 1645 1646 1647 1648 1649 1650 1651 1652 1653 1654 1655 1656 1657 1658 C LEU -0 LEU N TRP CA TRP CB TRP CG TRP CD2 TRP CE2 TRP CE3 TRP CDI TRP NEl TRP CZ2 TRP CZ3 TRP CH2 TRP C TRP O TRP N GLU CA GLU CB GLU CG GLU CD GLU OEI GLU OE2 GLU C GLU O GLU N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE O ILE N PHE CA PHE CB PHE CG PHE CD1 PHE CD2 PHE CEI PHE CE2 PHE CZ PHE C PHE O PHE N THR CA THR CB THR OGI THR CG2 THR C THR O THR 1690 1690 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1691 1692 1692 1692 1692 1692 1692 1692 1692 1692 1693 1693 1693 1693 1693 1693 1693 1693 1694 1694 1694 1694 1694 1694 1694 1694 1694 1694 1694 1695 1695 1695 1695 1695 1695 1695 22.960 -8.434 25.326 -5.123 25.521 -5.624 26.117 -4.197 27.316 -3.693 27.998 -2.621 29.331 -2.173 29.565 -1.082 30.966 -0.996 28.726 -0.167 30.570 -2.702 31.550 -1.995 31.543 -0.022 29.300 0.799 30.700 0.862 26.998 -3.131 27.772 -3.301 25.865 -2.448 25.452 -1.869 24.257 -0.933 24.365 0.091 23.111 0.935 22.303 0.722 22.919 1.819 25.072 -2.963 25.278 -2.818 24.484 -4.046 24.080 -5.164 23.177 -6.203 22.966 -7.465 21.820 -5.569 20.964 -6.395 25.322 -5.843 25.401 -6.126 26.329 -6.051 27.503 -6.709 28.122 -7.623 27.142 -8.649 26.522 -8.486 26..751 -9.709 25.525 -9.355 25.751 -10.586 25.136 -10.408 28.495 -5.821 29.485 -6.305 28.217 -4.516 29.044 -3.598 29.540 -2.379 28.422 -1.628 30.457 -2.816 28.198 -3.126 28.620 -2.268 11.512 13.291 14.408 12.747 13.425 12.567 13.105 14.004 14.208 14.652 12.811 13.471 15.034 15.484 15.665 14.823 15.750 14.956 16.238 16.068 14.962 14.880 13.962 15.738 17.225 18.422 16.720 17.565 16.787 17.637 16.416 15.435 18.133 19.324 17.304 17.827 16.771 16 .263 15. 034 17.074 14.625 16.674 15.453 18.578 19.126 18.635 19.419 18.627 18.137 17.508 20.604 21.386 1.00 19.10 1.00 24.70 1.00 23.57 1.00 23.68 1.00 24.83 1.00 20.94 1.00 24.80 1.00 23.71 1.00 23.81 1.00 22.20 1.00 24.44 1.00 25.38 1.00 24.39 1.00 21.99 1.00 25.57 1.00 25.87- 1.00 27.39 1.00 26.45 1.00 25.13 1.00 23.56 1.00 18.73 1.00 23.79 1.00 22.70 1.00 25.63 1.00 25.28 1.00 27.65 1.00 26.23 1.00 23.81 1.00 22.99 1.00 21.67 1.00 20.23 1.00 13.67 1.00 24.77 1.00 24.94 1.00 27.59 1.00 29.42 1.00 29.37 1.00 27.99 1.00 28.43 1.00 27.86 1.00 30.12 1.00 25.78 1.00 26.17 1.00 29.83 1.00 32.81 1.00 28.35 1.00 25.39 1.00 21.81 1.00 21.54 1.00 16.93 1.00 26.16 1.00 26.77 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 411 ATOM 1659 N LEU 1696.

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ATOM

1660 1661 1662 1663 1664 1665 1666 1667 1668 1669 1670 1671 1672 1673 1674 1675 1676 1677 1678 1679 1680.

1681 1682 1683 1684 1685 1686 1687 1688 1689 1690 1691 1692 1693 1694 1695 1696 1697 1698 1699 1700 1701 1702 1703 1704 1705 1706 1707 1708 1709- 1710 CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N GLY CA GLY C GLY 0 GLY N GLY CA GLY C GLY O GLY N SER CA SER CB SER OG SER C SER O SER N PRO CD PRO CA PRO CE PRO CG PRO C PRO O PRO N TYR CA TYR CB TYR CG TYR CD1 TYR CEl TYR CD2 TYR CE2 TYR CZ 'TYR OH TYR C TYR 0 TYR N PRO CD PRO CA PRO CB PRO CG PRO C PRO O PRO N GLY CA -GLY.

C GLY O GLY 1696 1696 1696 1696 1696 1696 1696 1697 1697 1697 1697 1698 1698 1698 1698 1699 1699 1699 1699 1699 1699 1700 1700 1700 1700 1700 1700 1700 1701 1701 1701 1701 1701 1701 1701 1701 1701 1701 1701 1701 1702 1702 1702 1702 1702 1702 1702 1703 1703 1703 1703 27 .023 26 .069 26 .572 26.-903 27.448 25 .658 25. 727 25.824 25 .265 24 .899 26 .040 26 .055 27.008 28 .150 27.795 26 .896 28 .520 28.304 28 .622 28.578 2.203 30 .408 28.629 27 .204 29.427 28 .358 27.101 30 .258 29. 792 31.487 32.372 32.039 32. 088 30. 936 30.977 33 .293 33.351 32.190 32.251 32 .377 32.066 32 .753 33 .288 32.775 33 .321 33 .063 33. 736 34 .875 33.275 34.101 34.232 34.904 -3.747 20.747 -3.446 21.813 -3.977 23.156 -5.456 23.182 -5.821 24.546 -6.234 22.882 -1.984 21.946 -1.410 23.025 -1.395 20.857 0.007 20.859 0.900 20.452 2.090 20.760 0.330 19.748 1.110 19.314 2.186 18. 310 2.028 17.496 3.295 18.375 4.420 17.491 5.714 18.246 6.863 17.407 4.269 16.268 4.073 16.403 4.324 15.062 4.482 14.745 4.192 13.837 4.096 12.736 3.713 13.461 5.456 13.651 6.550 13.983 5.306 13.170 6.441 12.910 7.055 11.537 6.092 10.378 5.807 9.638 4.955 8.535 5.495 9.990 4.646 8.886 4.382 8.160 3.572 7.039 7.559 13.970 8.711 13.679 7.229 15.215 5.946 15.695 8.258 16.270 7.499 17.482 6.061 17.166 9.388 15.919 9.145 15.522 10.625 16.089 11.792 .15.802 12.166 14.339 13.146 14.005 1.00 26.87 1.00 27.64 1.00 30.54 1.00 29.75 1.00 32.53 1.00 33.79 1.00 25.51 1.00 27.90 1.00 26.48 1.00 25.81 1.00 26.40 1.00 29.69 1.00 27.65 1.00 28.38 1.00 30.13 1.00 32.55 1.00 30.56 1.00 32.11 1.00 33.58 1.00 38.87 1.00 32.10 1.00 31.12 1.00 32.70 1.00 34.35 1.00 32.25 1.00 32.85 1.00 35.54 1.00 31.84 1.00 31.56 1.00 31.07 1.00 32.41 1.00 32.39 1.00 35.63 1.00 37.94 1.00 40.79 1.00 37.49 1.00 41.82 1.00 45.96 1.00 55.61 1.00 32.85 1.00 32.41 1.00 34.48 1.00 35.64 1.00 33.68 1.00 32.52 1.00 38.81 1.00 33.47 1.00 34.66 1.00 35.31 1.00 32.51 1.00 33.68 1.00 31.22 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 412

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM,

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1711 1712 1713 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 1724 1725 1726 1727 1728 1729 1730 1731 1732 1733 1734 1735 1736 1737 1738 1739 1740 1741 1742 1743 1744 1745 1746 1747 1748 1749 1750 1751 1752 1753 1754 1755 1756 1757 1758 1759 1760 1761 1762

N

CA

CB

CG,

CG:

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG 2 CG2

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD1 CD2 CEl CE2

CZ

VAL.

VAL.

VAL.

1 VAL.

2 VAL.

VAL

VAL.

PRO

PRO

PRO

PRO

PRO

PRO

PRO

VAL.

VAL.

VAL.

VAL.

VAL.

VAL

VAL.

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PEE-

PHE

PE

PE

PE

PE

PHE

PE

PE

1704 1704 1704 1704 1704 1704 1704 1705 1705 1705 1705 1705 1705 1705 1706 1706 1706 1706 1706 1706 1706 1707 1707 1707 1707 1707 1708 1708 1708 1708 1708 1708 1708 1708 1708 1709 1709 1709 1709 1709 1709 1709 1709 1710 1710 1710 1710 1710 1710 1710 1710 1710 33 .583 33 .641 33 .679 33.825 34.825 32.475 31 .316 32.787 34.133 31.801 32.539 33.950 31.388 32.125 30.240 29.675 28.607 28 .011 27.494 30 .696 30.796 31.479 32 .500 33 .181 33 .567 34 .036 33 .964 34. 987 35 .567 36.189 37.444 38 .059 37.830 34 .365 35.013 33-.094 32.378 30.973 30.136 30.662 28.705 32.306 32.489 32 .043 31.945 31.680 30.310 29.337 29.984 28. 054 28.698 27. 733 11.404 11.658 10.335 10.605 9.477 12 .529 12 .151 13 .735 14 .333 14.685 16 .020 15 .625 14.375 13 .695 14 .912 14 .704 15.791 15.586 15.739 14 .632 13 .618 15.695 15.819 17.184 14 .731 14.311 14 .280 13 .249 13 .204 14-.508 14 .923 14 .082 16.115 11.906 11.041 11.749 10.522 10.548 9.357 8 .059 556 10.317 9.202 11.399 11.366 12 .768 13 .261 .12.393 14 .596 12.834 '-15 .053 14.169 13.462 12. 026 11.241 9. 766 11.727 11. 533 11.643 11.032 11.086 10.512 10.617 10.339 9. 074 8.355 8 .649 7. 303 6 .984 5.586 8. 028 6.155 5.463 6.020 4.987 5.083 4 .982 3 .923 6.160 6.249 7.664 8 .144 7.383 6.681 7.517 5.889 5.294 6 .245 5. 961 6.565 6.081 6.679 6.437 4.454 3. 970 3.727 2.279 1.737 2.020 2 .495 1.838 .2.787 2.130 2.605 1.00 35.00 1.00 33.25 1.00 31.04 1.00 32.72 1.00 26.97 1.00 34.75 1.00 36.79 1.00 35.01 1.00 35.61 1.00 35.33 1.00 35.59 1.00 37.23 1.00 36.33 1.00 38.44 1.00 34.93 1.00 35.19 1.00 36.19 1.00 36.30 1.00 *32. 74 1.00 36.20 1.00 38.16 1.00 34.38 1.00 33.75 1.00 35.79 1.00 31.97 1.00 32.84 1.00 29.57 1.00 31.32 1.00 36.11 1.00 44.10 1.00 55.58 1.00 61.47 1.00 60.54 1.00 32.20 1.00 32.39 1.00 31.43 1.00 31.71 1.00 28.84 1.00 28.28 1.00 27.34 1.00 29.71 1.00 30.55 1.00 31.79 1.00 30.99 1.00 32.80 1.00 34.22 1.00 37.65 1.00 43.43 1.00 42.87 1.00 46.00 1.00 46.30 1.00 46.49 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 413 ATOM 1763 C PHE 1710 33.196 10.802 1.667 1.00 34.25 ATOM 1764 0 PEE 1710 33.133 9.948 0.785 1.00 36.09 ATOM 1765 N LYS 1711 34.324 11.249 2.209 1.00 34.37 ATOM 1766 CA LYS 1711 35.664 10.840 1.789 1.00 34.11 ATOM 1767 CB LYS 1711 36.672 11.768 2.476 1.00 37.74 ATOM 1768 CG LYS 1711 38.114 11.567 2.119 1.00 43.59 ATOM 1769 CD LYS 1711 38.978 12.573 2.857 1.00 46.97 ATOM 1770 CE LYS 1711 40.386 12.575 2.304 1.00 51.53 ATOM 1771 NZ LYS 1711 41.074 11.291 2.603 1.00 58.84 ATOM 1772 C LYS 1711 35.948 9.354 2.103 1.00 33.25 ATOM 1773 0 LYS 1711 36.512 8.641 1.274 1.00 32.22 ATOM 1774 N LEU 1712 35.537 8.894 3.285 1.00 32.62 ATOM 1775 CA LEU 1712 35.718 7.496 3.667 1.00 31.41 ATOM 1776 CB LEU 1712 35.223 7.237 5.106 1.00 29.80 ATOM 1777 CG LEU 17-12 36.020 7.889 6.244 1.00 29.22 ATOM 1778 CD1 LEU 1712 35.385 7.643 7.608 1.00 24.09 ATOM 1779 CD2 LEU 1712 37.437 7.356 6.234 1.00 28.36 ATOM 1780 C LEU 1712 34.939 6.638 2.674 1.00 31.88 ATOM 1781 0 LEU 1712 35.452 5.654 2.143 1.00 34.08 ATOM 1782 N LEU 1713 33.700 7.029 2.413 1.00 32.28 ATOM 1783 CA LEU 1713 32.850 6.305 1.482 1.00 35.36 ATOM 1784 CB LEU 1713 31.433 6.887 1.485 1.00 38.97 ATOM 1785 CG LEU 1713 30.629 6.494 2.730 1.00 39.56 ATOM 1786 CD1 LEU 1713 29.308 7.228 2.768 1.00 37.14 ATOM 1787 CD2 LEU 1713 30.424 4.988 2.748 1.00 37.73 ATOM 1788 C LEU 1713 33.430 6.296 0.070 1.00 36.47 ATOM 1789 0 LEU 1713 33.502 5.244 -0.563 1.00 39.32 ATOM 1790 N LYS 1714 33.855 7.455 -0.413 1.00 35.21 ATOM 1791 CA LYS 1714 34.437 7.544 -1.743 1.00 34.55 ATOM 1792 CB LYS 1714 34.812 8.984 -2.075 1.00 34.81 ATOM 1793 CG LYS 1714 33.624 9.903 -2.290 1.00 36.55 ATOM 1794 CD LYS 1714 32.681 9.372 -3.353 1.00 40.68 ATOM 1795 CE LYS 1714 31.488 10.310 -3.577 1.00 44.87 ATOM 1796 NZ LYS 1714 30.611 9.853 -4.701 1.00 50.99 ATOM 1797 C LYS 1714 35.671 6.649 -1.856 1.00 35.97 ATOM 1798 0 LYS 17 14 35.948 6.084 -2.920 1.00 38.11 ATOM 1799 N GLU 1715 36.385 6.490 -0.749 1.00 33.65 ATOM 1800 CA GLU 1715 37.582 5.663 -0.729 1.00 34.34 ATOM 1801 CE GLU 1715 38.574 6.221 0.288 1.00 34.90 ATOM 1802 CG GLU 1715 39.032 7.613 -0.110 1.00 42.07 ATOM 1803 CD GLU 1715 39.729 8.405 0.989 1.00 47.94 ATOM 1804 OE1 GLU 1715 39.977 7.870 2.098 1.00 45.03 ATOM 1805 0E2 GLU 1715 40.026 9.596 0.709 1.00 51.48 ATOM 1806 C GLU 1715 37.285 4.191 -0.466 1.00 34.76 ATOM 1807 0 GLU 1715 38.205 3.384 -0.411 1.00 37.36 ATOM 1808 N GLY 1716 36.002 3.848 -0.347 1.00 32.00 ATOM 1809 CA GLY 1716 35.604 2.474 -0.122 1.00 30.49 ATOM 1810 C GLY 1716 .35.932 1.937 1.251 1.00 31.32 ATOM 1811 0 GLY 1716 36.134 0.738 1.430 1.00 31.83 ATOM 1812 N HIS 1717 35.957 2.822 2.233 1.00 31.55 ATOM 1813 CA HIS 1717 36.265 2.416 3.595 1.00 33.20 ATOM 1814 CB HIS 1717 36.494 3.661 4.452 1.00 37.67 SSSD/55034. V01 WO 98/07835 PCT/US97/14885s 414 ATOM 1815 CG HIS 1717 -36.786 3.360 5.895 1.00 42.42 ATOM 1816 CD2 HIS 1717 37.957 3.259 6.567 1.00 40.97 ATOM 1817 ND1 HIS 1717 35.789 3.142 6.825 1.00 45.02 ATOM 1818 CEl HIS 1717 36.333 2.914 8.004 1.00 44.06 ATOM 1819 NE2 HIS 1717 37.645 2.976 7.873 1.00 43.67 ATOM 1820 C HIS 1717 35.149 1.567 4.201 1.00 31.72 ATOM 1821 0 HIS 1717 33.975 1.816 3.952 1.00 32.12 ATOM 1822 N ARG 1718 35.529 0.582 5.009 1.00 31.09 ATOM 1823 CA ARG 1718 34.586 -0.288 5.696 1.00 32.10 ATOM 1824 CB ARG 1718 34.531 -1.664 5.024 1.00 31.61 ATOM 1825 CG ARG 1718 34.048 -1.651 3.577 1.00 31.32 ATOM 1826 CD ARG 1718 32.579 -1.263 3.495 1.00 29.60 ATOM 1827 NE ARG 1718 32.036 -1.320 2.129 1.00 24.72 ATOM 1828 CZ ARG 1718 3.2.103 -0.324 1.243 1.00 22.01 ATOM 1829 NH1 ARG 1718 32.709 0.819 1.554 1. 00 19.00 ATOM 1830 NH2 ARG 1718 31.463 -0.444 0.083 1.00 14.18 ATOM 1831 C ARG 1718 35.042 -0.438 7.164 1.00 33.81 ATOM 1832 0 ARG 1718 36.234 -0.596 7.446 1.00 34.62 ATOM 1833 N MET 1719 34.084 -0.372 8.085 1.00 33.99 ATOM 1834 CA MET 1719 34.382 -0.466 9.508 1.00 32.51 ATOM 1835 CB MET 1719 33.110 -0.246 10.342 1.00 33.51 ATOM 1836 CG MET 1719 32.513 1.155 10.200 1.00 33.69 ATOM 1837 SD MET 1719 31.082 1.526 11.251 1.00 37.49 ATOM 1838 CE MET 1719 29.906 0.373 10.618 1.00 37.62 ATOM 1839 C MET 1719 35.033 -1.799 9.844 1.00 32.92 ATOM 1840 0 MET 1719 34.900 -2.772 9.098 1.00 33.67 ATOM 1841 N ASP 1720 35.776 -1.825 10.945 1.00 35.49 ATOM 1842 CA ASP 1720 36.466 -3.038 11.388 1.00 36.87 ATOM 1843 CB ASP 1720 37.585 -2.694 12.376 1.00 41.64 ATOM 1844 CG ASP 1720 38.688 -1.859 11.754 1.00 46.44 ATOM 1845 001 ASP 1720 38.507 -1.410 10.604 1.00 52.86 ATOM 1846 002 ASP 1720 39.740 -1.650 12.422 1.00 46.76 ATOM 1847 C ASP 1720 35.516 -4.005 12.053 1.00 34.70 ATOM 1848 0 ASP 1720 34.459 -3.603 12.548 1.00 34.31 ATOM 1849 N LYS 1721 35.937 -5.265 12.132 1.00 33.39 ATOM 1850 CA LYS 1721 35.119 -6.297 12.755 1.00 32.68 ATOM 1851 CB LYS 1721 35.692 -7.690 12.500 1.00 33.55 ATOM 1852 CG LYS 1721 34.834 -8.791 13.119 1.00 33.62 ATOM 1853 CD LYS 1721 35.336 -10.158 12.771 1.00 35.77 ATOM 1854 CE LYS 1721 36.082 -10.747 13.931 1.00 38.73 ATOM 1855 NZ LYS 1721 36.325 -12.190 13.711 1.00 43.86 ATOM 1856 C LYS 1721 35.034 -6.107 14.240 1.00 34.61 ATOM 1857 0 LYS 1721 36.057 -5.944 14.905 1.00 37.05 ATOM 1858 N PRO 1722 33.808 -6.092 14.781 1.00 36.16 ATOM 1859 CD PRO 1722 32.518 -6.062 14.066 1.00 34.73 ATOM 1860 CA PRO 1722 33.611 -5.926 16.222 1.00 37.84 ATOM 1861 CB PRO 1722 32.095 -6.017 16.360 1.00 37.19 ATOM 1862 CG PRO 1722 31.607 -5.448 -15.073 1.00 36.00 ATOM 1863 C PRO 1722 34.266 -7.109 16.950 1.00 39.95 ATOM .1864 0 PRO 1722 34.340 -8..218 16.406 -1.00 38.82 ATOM 1865 N -SER 1723 34.783 -6.884 18.150 1.00 42.36 ATOM 1866 CA SER 1723 35.359 -7.995 18.890 1.00 45.70 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 415

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1867 1868 1869 1870 1871 1872 1873 1874 1875 1876 1877 1878 1879 1880 1881 1882 1883 1884 1885 1886 1887 1888 1889 1890 1891 1892 1893 1894 1895 1896 1897 1898 1899 1900 1901 1902 1903 1904 1905 1906 1907 1908 1909 1910 1911 1912 1913 1914 1915 1916 1917 1918

CB

OG

C

0

N

CA

CB

CG

ODI

ND2

C

0

N

CA

CB

SG

C

0

N

CA

CB

OGI

CG2

C

0

N

CA

CB

CG

ODI

ND2

C

0

N

CA

CB

CG

CD

OE1 OE2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

SER

SER

SER

SER

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

CYS

CYS

CYS

CYS

CYS

CYS

THR

THR

THR

THR

THR

THR

THR

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

TYR

TYR

1723 1723 1723 1723 1724 1724 1724 1724 1724 1724 1724 1724 1725 1725 1725 1725 1725 1725 1726 1726 1726 1726 1726 1726 1726 1727 1727 1727 1727 1727 1727 1727 1727 1728 1728 1728 1728 1728 1728 1728 1728 1728 1729 1729 1729 1729 1729 1729 1729 1729 1730 1730 36.170 35.341 34 .136 33 .037 34.296 33 .174 32 .620 33.732 34 .565 33 .763 32 .101 30.925 32.564 31.719 31.603 30. 605 32.421 33.639 31.677 32 .268 31.308 30.074 31.017 32 .678 32 .180 33 .596 34 .009 35 .167 36 .464 37.019 36 .961 32.825 32.726 31.916 30.707 30.010 28.811 28.251 28.415 27.632 29.749 29.231 29.520 28.645 28.215 27.198 27.013 .25.865 29.269 28.548 30.594 31.281 -7.511 -6.964 -8.784 -8.224 -10.081 -10.900 -10.361 -10.088 -10.955 -8.867 -10.916 -10.617 -11.193 -11.295 -9.929 -9.929 -12.308 -12.236 -13 .289 -14.313 -15.500 -15.042 -16.160 -13 .770 12 729 -14 .450 -14. 024 -14 .872 -14.591 -13.495 -15.585 -14.147 -13.405 -15.065 -15.310 -16.580 -17.034 -18.369 -18.694 -19.086 -14.119 -13.679 -13.610 -12.462 -12.343 -13.410 -13.377 -13.161 -11.161 -10.255 -11.069 -9.881 20.093 21.100 19.346 19.477 19.559 19.992 21.330 22.365 22.646 22.912 18.873 19.089 17 .663 16.478 15.788 14.272 15.5"70 15.397 15 .064 14.202 13.993 13.406 15.306 12.845 12.415 12.175 10.842 10,.308 11.026 10.933 11.749 9.905 8.929 10.224 9.418 9.917 9.094 9.577 10.777 8.758 9.468 8.438 10.672 10.849 12.310 12.721 14.226 .12.010 10.335 9.914 10.363 9.844 1.00 47.50 1.00 55.28 1.00 46.70 1.00 47.27 1.00 47.84 1.00 51.26 1.00 57.15 1.00 61.53 1.00 64.13 1.00 61.69 1.00 50.72 1.00 52.63 1.00 48.01 1.00 45.16 1.00 44.77 1.00 40.74 1.00 41.51 1.00 42.47 1.00 37.54 1.00 35.03 1.00 31.87 1.00 32.84 1.00 29.78 1.00 34.76 1.00 38.22 1.00 32.47 1.00 34.75 1.00 39.77 1.00 46.09 1.00 49.54 1.00 50.04 1.00 33.38 1.00 34.10 1.00 32.01 1.00 30.41 1.00 32.27 1.00 31.55 1.00 36.38 1.00 38.35 1.00 36.34 1.00 29.40 1.00 26.23 1.00 29.19 1.00 30.26 1.00 30.74 1.00 31.27 1.00 33.65 1.00 26.16 1.00 28.79 1.00 30.60 1.00 26.64 1.00 26.47 SSSD/55034. V01 WO 98/07835 PCTIUS97I14S85 416 ATOM 1919 CB TYR 1730 32.742 -9.869 10.298 1.00 24.31 ATOM 1920 CG TYR 1730 33.512 -8.670 9.805 1.00 25.61 ATOM 1921 CD1 TYR 1730 33.029 -7.373 10.016 1.00 25.68 ATOM 1922 CEl TYR 1730. 33.691 -6.264 9.496 1.00 23.70 ATOM 1923 CD2 TYR 1730 34.688 -8.826 9.067 1.00 24.48 ATOM 1924 CE2 TYR 1730 35.361 -7.719 8.537 1.00 22.61 ATOM 1925 CZ TYR 1730 34.856 -6.445 8.748 1.00 24.41 ATOM 1926 OH TYR 1730 35.476 -5.354 8.176 1.00 24.37 ATOM 1927 C TYR 1730 31.186 -9.902 8.301 1.00 26.06 ATOM 1928 0 TYR 1730 30.981 -8.881 7.651 1.00 23.68 ATOM 1929 N MET 1731 31.347 -11.084 7.727 1.00 26.60 ATOM 1930 CA MET 1731 31.247 -11.270 6.299 1.00 29.90 ATOM 1931 CB MET 1731 31.475 -12.740 5.968 1.00 38.39 ATOM 1932 CG MET 1731 31.076 -13.157 4.577 1.00 52.98 ATOM 1933 SD MET 1731 -31.612 -14.831 4.216 1.00 69.59 ATOM 1934 CE MET 1731 32.659 -14.506 2.727 1.00 66.05 ATOM 1935 C MET 1731 29.864 -10.819 5.840 1.00 29.05 ATOM 1936 0 MET 1731 29.720 -10.194 4.791 1.00 30.94 ATOM 1937 N MET 1732 28.845 -11.134 6. 633 1.00 29.40 ATOM 1938 CA MET 1732 27.475 -10.743 6.328 1.00 26.97 ATOM 1939 CB MET 1732 26.537 -11.293 7.398 1.00 25.73 ATOM 1940 CG MET 1732 25.068 -10.984 7.156 1.00 26.01 ATOM 1941 SD MET 1732 23.980 -11.637 8.407 1.00 26.97 ATOM 1942 CE MET 1732 23.773 -13.354 7.798 1.00 21.23 ATOM 1943 C MET 1732 27.387 -9.220 6.271 1.00 27.49 ATOM 1944 0 MET 1732 26.778 -8.661 5.361 1.00 29.17 ATOM 1945 N MET 1733 27.982 -e.550 7.259 1.00 27.79 ATOM 1946 CA MET 1733 28.001 -7.090 7. 293' 1.00 27.41 ATOM 1947 CE MET 1733 28.797 -6.587 8.484 1.00 28.84 ATOM 1948 CG MET 1733 28.153 -6.761 9.829 1.00 32.18 ATOM 1949 SD MET 1733 29.300 -6.248 11.127 1.00 32.77 ATOM 1950 CE MET 1733 28.850 -7.423 12.399 1.00 33.03 ATOM 1951 C MET 1733 28.711 -6.599 6.035 1.00 28.54 ATOM 1952 0 MET 1733 28.250 -5.680 5.357 1.00 30.69 ATOM 1953 N ARG 1734 29.865 -7.194 5.751 1.00 28.59 ATOM 1954 CA ARG 1734 30.650 -6.831 4.571 1.00 29.53 ATOM 1955 CE ARG 1734 31.970 -7.609 4.531 1.00 28.74 ATOM 1956 CG ARG 1734 32.944 -7.245 5.638. 1.00 26.75 ATOM 1957 CD ARG 1734 33.158 -5.755 5.702 1.00 26.58 ATOM 1958 NE ARG 1734 33.825 -5.288 4.499 1.00 34.72 ATOM 1959 CZ ARG 1734 35.139 5.360 4.306 1.00 37.67 ATOM 1960 NH1 ARG 1734 35.927 -5.867 5.251 1.00 40.46 ATOM 1961 NH2 ARG 1734 35.663 -4.986 3.147 1.00 38.11 ATOM 1962 C ARG 1734 29.855 -7.051 3.294 1.00 28.03 ATOM 1963 0 ARG 1734 29.958 -6.260 2.359 1.00 27.22 ATOM 1964 N ASP 1735 29.071 -8.130 3.260 1.00 27.81 ATOM 1965 CA ASP 1735 28.212 -8.436 2.103 1.00 27.27 ATOM 1.966 CB ASP 1735 27.608 -9.835 2.216 1.00 28.62 ATOM 1967 CG ASP 1735 28.638 -10.932 2.075 1.00 30.15 ATOM 1968 ODI ASP 1735 29.745 -10.663 1.553 1.00 31.23 ATOM 1969 0D2 ASP 1735 28.354 -12.070 2.501 1.00 32.00 ATOM 1970 C ASP 1735 27.099 -7.400 1.971 1.00 24.78 SSSD/55034. V01 WO 98/07835 WO 9807835PCIUS97/14885 417 ATOM 1971 0 ASP 1735

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022

N

CA

CB

SG

C

0

N

CA

CB

CG

CD2 CE2 CE3 CD1 NEl CZ2 CZ3 CH2

C

0

N

CA

CB

CG

CD2 NDl CEl NE2

C

0

N

CA

CB

C

0

N

CA

CB

CG1 CG2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CYS

CYS

CYS

CYS

CYS

CYS

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ALA

ALA

ALA

ALA

ALA

VAL

VAL

VAL

VAL

VAL

VAL

VAL

PRO

PRO

PRO

PRO

PRO

PRO

PRO

SER

SER

1736 1736 1736 1736 1736 1736 1737 1737 1737 1737 1737 1737 1737 1737 1737 1737 1737 1737 1737 1737 1738 1738 1738 1738 1738 1738 1738 1738 1738 1738 1739 1739 1739 1739 1739 1740 1740 1740 1740 1740 1740 1740 1741 1741 1741 1741 1741 1741 1741 1742 1742 26.714 -7.068 26.590 -6.908 25.530 -5.871 24.965 -5.679 23.898 -7.030 26.042 -4.520 25.276 -3.718 27.348 -4.303 27.988 -3.072 29.026 -2.631 *28.485 -2.418 29.194 -2.609 28.329 -2.213 30.478 -3.083 27.248 -1.932 27.147 -1.805 28.705 -2.270 30.857 -3.134 29.972 -2.728 28.673 -3.226 29.648 -2.519 28.203 -4.170 28.808 -4.341 28.163 -5.497 29.017 -6.013 29.550 5.380 29.492 -7.308 30.286 -7.445 30.341 -6.288 28.670 -3.024 27.615 -2.381 29.752 -2.608 29.762 -1.378 31.079 -1.234 28.645 -1.391 27.955 -0.391 28.507 -2.521 27.481 -2.700 27.966 -3.698 27.013 -3.757 29.308 -3.260 26.170 -3.209 26.126 -4.347 25.090 -2.397 25.074 -1.093 23.763 -2.695 22.891 -1.554 23.866 -0.419 23.189 -4.074 22.700 4.788 23.335 -4.473 22.826 -5.754 0.852 3 .104 3.140 4.569 5.143 2 .611 2 .070 2 .743 2 .302 3 .314 4 .686 5 .913 6 .959 6.238 5 .022 6.383 8.319 7 .583 8.604 0. 956 0.670 0 .136 -1.172 -1.928 -3.051 -4.129 -3.104 -4.156 -4.794 -1.958 -1.933 -2.607 -3.385 -4 .076 -4.416 -4.606 -5.102 -6.121 -7.206 -8.360 -7.720 -5.481 -4 .978 -5.545 -6.237 -4.980 -5.526 -5.647 -5.343 -4.462 -6.615 -7.119 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00o 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 24 .52 24.10 25.20 23.85 18.77 23.39 21.76 23 .53 21.57 18.82 19.89 22.39 21.78 23 .52 19.40 21.52 21.85 25.30 26.17 24.49 25.09 25.12 22. 23.14 23.26 23.78 24. 91 25.29 26.99 22. 92 20.27 24.30 23. 25.24 25.37 27.86 23.97 24.64 26.39 22.65 27.43 23.97 24 .14 22.77 17.82 23.22 18.19 15.09 23.26 22.42 23.49 23.17 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 418

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 2051 2052 2053 2054 2055 2056 2057 2058 2059 2060 2061 2062 2063 2064 2065 2066 2067 2068 2069 2070 2071 2072 2073 2074 CB SER 1742 OG SER C SER O SER N GLN CA GLN CB GLN CG GLN CD GLN OE1 GLN NE2 GLN C GLN O GLN N ARG CA ARG CB ARQ CG ARG CD ARG NE ARG CZ ARG NHI ARG NH2 ARG C ARG O ARG N PRO CD PRO CA PRO CB PRO CG PRO C PRO 0 PRO N THR CA THR CB THR OGI THR CG2 THR C THR O THR N PHE CA PHE CB PHE CG PHE CD1 PHE CD2 PHE CEI PHE CE2 PHE CZ PHE C PHE O PHE N LYS CA LYS CB LYS 1742 1742 1742 1743 1743 1743 1743 1743 1743 1743 1743 1743 1744 1744 1744 1744 1744 1744 1744 1744 1744 1744 1744 1745 1745 1745 1745 1745 1745 1745 1746 1746 1746 1746 1746 1746 1746 1747 1747 1747 1747 1747 1747 1747 1747 1747 1747 1747 1748 1748 1748 22.956 -5.808 24.324 -5.891 23.524 -6.984 22.993 -8.104 24.719 -6.782 25.466 -7.895 26.953 -7.754 27.255 -7.828 26.684 -9.076 27.176 -10.178 25.647 -8.907 25.227 -8.121 25.744 -9.083 24.458 -7.240 24.155 -7.395 23.635 -6.087 24.623 -4.962 24.013 -3.656 24.869 -2.563 24.461 -1.322 23.184 -0.972 25.337 -0.438 23.095 -8.470 22.363 -8.772 23.065 -9.139 24.025 -9.114 22.057 -10.175 22.532 -10.879 23.240 -9.777 20.726 -9.485 20.80 -8.281 19.646 -10.236 18.335 -9.689 17.307 -10.334 17.299 -11.763 17.668 -10.002 17.961 -9.975 18.676 -10.711 16.884 -9.381 16.456 -9.678 15.353 -8.720 15.872 -7.368 16.627 -7.207 15.611 -6.248 17.124 -5.944 16.111 -4.991 16.862 -4.846 15.992 -11.133 16.189 -11.796 15.430 -11.632 14.971 -13.014 14.344 -13.327 -8.641 -9.023 -6.545 -6.603 -5.997 -5.416 -5.702 -7.170 -7.810 -7.584 -8.625 -3.927 -3.366 -3.290 -1.868 -1.277 -1.342 -0.863 -1.318 -1.564 -1.378 034 -1.712 -2.654 -0.559 0.563 -0.362 0.919 1.676 -0.146 0.128 -0.297 -0.085 -1.045 -0.886 -2.479 1.367 2.058 1.855 3.224 3.686 4.082 5.237 3.293 5.598 3.646 4.801 3.295 4.304 2. 199 2.140 0.782 1.00 23.67 1.00 26.64 1.00 23.09 1.00 21.90 1.00 23.62 1.00 23.26 1.00 24.32 1.00 23.04 1.00 24.83 1.00 21.07 1.00 22.66 1.00 23.85 1.00 25.36 1.00 22.69 1.00 21.65 1.00 21.22 1.00 21.63 1.00 19.06 1.00 24.44 1.00, 22.49 1.00 18.95 1.00 22.19 1.00 22.45 1.00 25.62 1.00 21.78 1.00 21.02 1.00 20.99 1.00 21.12 1.00 19.86 1.00 22.18 1.00 23.04 1.00 19.31 1.00 19.12 1.00 19.86 1.00 22.54 1.00 22.97 1.00 19.91 1.00 19.93 1.00 21.80 1.00 23.46 1.00 21.84 1.00 24.84 1.00 22.23 1.00 22.97 1.00 19.42 1.00 17.14 1.00 18.02 1.00 22.28 1.00 23.76 1.00 23.46 1.00 25.84 1.00 26.89 SSSD/55034. V01 WO 98/07835 WO 9807835PCTIUS97/14885 419 ATOM 2075 CG LYS 1748 14.061 -14.793 0.583 1.00 31.07 ATOM 2076 CD LYS 1748 13.714 -15.064 -0.861 1.00 37.82 ATOM 2077 CE LYS 1748 13.231 -16.493 -1.068 1.00 44.36 ATOM 2078 NZ LYS 1748 12.027 -16.782 -0.235 1.00 50.16 ATOM 2079 C LYS 1748 16.160 -13.949 2.393 1.00 27.27 ATOM 2080 0 LYS 1748 16.067 -14.877 3.202 1.00 27.87, ATOM 2081 N GLN 1749 17.288 -13.674 1.730 1.00 25.64 ATOM 2082 CA GLN 1749 18.507 -14.457 1.903 1.00 24.32 ATOM 2083 CB GLN 1749 19.608 -13.938 0.983 1.00 28.87 ATOM 2084 CG GLN 1749 19.343 -14.049 -0.496 1.00 36.24 ATOM 2085 CD GLN 1749 20.437 -13.374 -1.318 1.00 41.30 ATOM 2086 OE1 GLN 1749 20.173 -12.422 -2.044 1.00 38.35 ATOM 2087 NE2 GLN 1749 21.683 -13.861 -1.190 1.00 45.38 ATOM 2088 C GLN 1749 19.002 -14.310 3.346 1.00 22.89 ATOM 2089 0 GLN 1749 19.302 -15.305 4.008 1.00 22.55 ATOM 2090 N LEU 1750 19.114 -13.064 3.813 1.00 20.89 ATOM 2091 CA LEU 1750 19.570 -12.776 5.167 1.00 21.44 ATOM 2092 CB LEU 1750 19.471 -11.282 5.462 1.00 19.53 ATOM 2093 CG LEU 1750 20.432 -10.400 4.663 1.00 19.14 ATOM 2094 CD1 LEU 1750 20.069 -8.919 4.816 1.00 14.53 ATOM 2095 CD2 LEU 1750 21.863 -10.685 5.106 1.00 16.18 ATOM 2096 C LEU 1750 18.776 -13.538 6.208 1.00 22.98 ATOM 2097 0 LEU 1750 19.335 -14.057 7.183 1.00 23.12 ATOM 2098 N VAL 1751 17.465 -13.586 6.020 1.00 23.48 ATOM 2099 CA VAL 1751 16.610 -14.292 6.945 1.00 23.21 ATOM 2100 CB VAL 1751 15.132 -14.075 6.590 1.00 20.94 ATOM 2101 CG1 VAL 1751 14.268 -15.008 7.375 .1.00 21.67 ATOM 2102 CG2 VAL 1751 14.730 -12.649 6.929 1.00 20.32 ATOM 2103 C VAL 1751 16.974 -15.774 6.990 1.00 26.13 ATOM 2104 0 VAL 1751 17.030 -16.379 8.058 1.00 26.35 ATOM 2105 N GLU 1752 17.260 -16.348 5.831 1.00 30.05 ATOM 2106 CA GLU 1752 17.632 -17.747 5.778 1.00 32.54 ATOM 2107 CB GLTJ 1752 17.695 -18.221 4.338 1.00 38.54 ATOM 2108 CG GLU 1752 16.322 -18.226 3.673 1.00 50.06 ATOM 2109 CD GLU 1752 16.333 -18.759 2.247 1.00 56.55 ATOM 2110 OE1 GLU 1752 15.365 -18.480 1.507 1.00 61.63 ATOM 2111 0E2 GLU 1752 17.303 -19.466 1.875 1.00 59.57 ATOM 2112 C GLU 1752 18.974 -17.965 6.486 1.00 31.62 ATOM 2113 0 GLU 1752 19.113 -18.858 7.322 1.00 29.63 ATOM 2114 N ASP 1753 19.938 -17.103 6.193 1.00 30.74 ATOM 2115 CA ASP 1753 21.246 -17.211 6.807 1.00 31.00 ATOM 2116 CE ASP 1753 22.209 -16.181 6.203 1.00 31.47 ATOM 2117 CG ASP 1753 22.445 -16.390 4.710 1.00 35.82 ATOM 2118 ODi ASP 1753 22.396 -17.549 4.248 1.00 36.78 ATOM 2119 0D2 ASP 1753 22.671 -15.396 3.992 1.00 41.04 ATOM 2120 C ASP 1753 21.158 -17.058 8.314 1.00 28.94 ATOM 2121 0 ASP 1753 21.597 -17.933 9.059 1.00 29.91 ATOM 2122 N LEU 1754 20.526 15.984 8.764 1.00 28.33 ATOM 2123 CA LEU 1754 20.386 -15.731 10.199 1.00 26.88 ATOM 2124 CB LEU .1754 .19.724 -14.372 10.457 1.00 19.82 ATOM 2125 CG LEU 1754 20.737 -13.269 10.154 1.00 20.90 ATOM 2126 CD1 LEU 1754 20.074 -11.886 9.995 1.00 14.83 SSSD/55034. V01 WO 98/07835 PCT[EUS97/14885 420

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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ATOM

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ATOM

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ATOM

2127 2128 2129 2130 2131 2132 2133 2134 2135 2136 2137 2138 2139 2140 2141 2142 2143 2144 2145 2146 2147 2148 2149 2150 2151 2152 2153 2154 2155 2156 2157 2158 2159 2160 2161 2162 2163 2164 2165 2166 2167 2168 2169 2170 2171 2172 2173 2174 2175 2176 2177 2178 CD2 LEU C LEU O LEU N ASP CA ASP CB ASP CG ASP ODi ASP 0D2 ASP C ASP O ASP N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NH1 ARG NH2 ARG C ARG O ARG N ILE CA ILE CB ILE CG2 ILE.

CG1 ILE CD1 ILE C ILE O ILE N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL O VAL N ALA CA ALA CB ALA C ALA 0 ALA N LEU CA LEtI CB LEU CG LEU CD1 LEU CD2 LEU C LEU 0 LEU N THR CA THR 1754 1754 1754 1755 1755 1755 1755 1755 1755 1755 1755 1756 1756 1756 1756 1756 1756 1756 1756 1756 1756 1756 1757 1757 1757 1757 1757 1757 1757 1757 1758 1758 1758 1758 1758 1758 1758 1759 1759 1759 1759 1759 1760 1760.

1760 1760 1760 1760 1760 1760 1761 1761 21.831 19.645 20.030 18.638 17.892 16. 723 15.876 15.410 15. 685 18.801 18.665 19.738 20.700 2.1.417 22.522 23 .181 23 .676 24.795 25.556 25.165 21.719 22 .000 *22.244 23.242 23 .847 24. 915 24.481 24 .812 22.673 23.283 21.489 20.854 19.378 18.715 19.309 20.885 21.403 20.370 20.325 19.653 21.693.

21.780 22.750 24.095 24.899 24.279 25.016 24.327 24 .811 25.935 24.181 -13.308 -16.861 -17.262 -17.421 -18.517 -18.900 -19.997 -19.844 -21.031 -19.713 -20.428 -19.907 -21.004 -21.125 -22.181 -22.223 -20.917 -20.338 -20.937 -19.163 -20.754 -21.632 -19.536 -19.153 -17.753 -17.401 -17. 757 -16.387 -19.182 -19.764 -18.608 -18.589 -18.104 -18.183 -16.670 -19.986 -20.182 -20.957 -22.354 -23.197 -22.953 -23 .872 -22.465 -22.949 -22.900 -23.645 -23.279 -25.136 -22.118 -22.432 -21.031 11.240 10.896 11.986 10.238 10. 822 9.928 10.533 11.677 9.878 11.034 12 .025 10.107 10.169 8.825 8 .759 7.376 6 .916 7.349 8.266 6.853 11.275 12 .088 11.314 12.302 11. 984 12 .995 10.586 10 .032 13 .716 14.601 13. 917 15.243 15.165 16.530 14.651 15.850 16 .954 15.098 15.528 14.460 15.890 16.697 15.255 15.514 14.225 13.053 11.778 13.313 16.578 16 .986 17.004 1.00 16.39 1.00 29.18 1.00 30.55 1.00 31.65 1. 00 '31.78 1.00 34.57 1.00 38.29 1.00 45.68 1.00 43.09 1.00 33.50 1.00 34.39 1.00 35.51 1.00 35.33 1.00 38.41 1.00 40.99 1.00 44.60 1.00 49.55 1.00 53.56 1.00 53.25 1.00 55.72 1.00 35.01 1.00 34.86 1.00 35.06 1.00 35.25 1.00 34.59 1.00 32.98 1.00 33.64 1..00 28.79 1.00 36.74 1.00 36.60 1.00 39.16 1.00 41.06 1.00 38.77 1.00 38.72 1.00 39.49 1.00 43.92 1.00 46.90 1.00 43.96 1.00 43.47 1.00 42.26 1.00 44.02 1.00 45.94 1.00 45.07 1.00 46.72 1.00 48.22 1.00 51.98 1.00 56.19 .1.00 52.82 1.00 47.59 1.00 44.63 24.791 -20.166 17.987 1.00 50.15 SSSD/55034. V01 WO 98/07835 PTU9148 PCTfUS97/14885 421 ATOM 2179 CB .THR 1761

ATOM

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ATOM

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ATOM

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ATOM

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ATOM

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ATOM

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ATOM

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ATOM

2180 2181 2182 2183 2184 2185 2186 2187 2188 2189 2190 2191 2192 2193 2194 2195 2196 2197 2198 2199 2200 2201 2202 2203 2204 2205 2206 2207 2208 2209 2210 2211 2212 2213 2214 2215 2216 2217 2218 2219 2220 2222.

2222 2223 2224 2225 2226 2227 .2228 2229 2230 OGi THR CG2 THR C THR O THR N SER CA SER CB SER OG SER C SER O SER N ALA CA ALA CB ALA C ALA O ALA N ALA CA ALA CB ALA C ALA O ALA N TYR CA TYR CB TYR CG TYR CD1 TYR CEl TYR CD2 TYR CE2 TYR CZ TYR OH TYR C TYR 0 TYR N GLU CA GLU CB GLU CG GLU CD GLU 0E1 GLU 0E2 GLU C GLU O GLU N LEU CA LEU CE LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N PRO CD PRO 1761 1761 1761 1761 1762' 1762 1762 1762 1762 1762 461 461 461 461 461 462 462 462 462 462 463 463 463 463 463 463 463 463 463 463 463 463 464 464 464 464 464 464 464 464 464 465 465 465 465 465 465 465 465 466 466 24.309 -18.707 24.650 -18.262 24.997 -17.793 24.643 -20.655 23.565 -21.064 25.761 -20.622 25.835 -21.042 27.301 -21.039 27.502 -21.759 25.033 -20.081 25.193 -18.856 79.680 25.808 79.609 24.651 78.307 23.875 79.707 25.105 79.739 24.289 79.814 26.417 79.919 27.014 80.034 28.532 81.074 26.461- 80.869 26.036 82.279 26.449 83.477 25.959 84.615 26.968 84.372 28.176 84.071 29.422 83.783 30.518 84.384 28.064 84.096 29.154 83.796 30.372 83.491 31.442 83.988 24.579 84.605 23.947 83.761 24.109 84.224 22.769 85.725 22.790 86.123 23.764 87.619 24.009 88.013 24.922 88.400 23.311 83.517 22.294 83.252 23.106 83.193 21.003 82.527 20.449 81.520 19.348 80.488 19.538 79.356 18.544 79.983 20.981 83.572 19.862 84.70.7 19.573 83.215 19.684 81.929 20.073 17.811 16.489 18.809 19.426 19.866 20.143 21.533 21.969 23.173 22.403 22.301 14 .502 13.610 13 .860 12.151 11. 243 11.957 10.634 10.750 9.806 8 .673 10.383 9.686 9.765 8.894 9.456 8.652 7.501 6.690 7.271 6.476 10.024 9.175 11.244 11.630 11.901 12 .991 13.075 13.835 12.383 12.875 13.763 12.939 14.12 1 13 .762 12.651 12 .911 12.596 15.058 14.642 16.338 16.942 1.00 49.78 1.00 49.83 1.00 4-9.37 1.00 51.84 1.00 51.38 1.00 53.45 1.00 53.79 1.00 58.33 1.00 63.27 1.00 50.43 1.00 48.42 1.00 57.40 1.00 53.47 1.00 54.34 1.00 49.53 1.00 48.04 1.00 46.57 1.00 43.66 1.00 43.87 1.00 39.75 1.00 36.18 1.00 37.82 1.00 36.88 1.00 39.12 1.00 45.68 1.00 46.07 1.00 48.07 1.00 47.80 1.00 45.55 1.00 47.44 1.00 49.77 1.00 34.97 1.00 35.48 1.00 34.33 1.00 36.96 1.00 41.01 1.00 45.91 1.00 53.97 1.00 58.84 1.00 56.78 1.00 34.98 1.00 35.30 1.00 33.52 1.00 35.65 1.00 32.97 1.00 33.16 1.00 27.30 1.00 29.96 1.00 38.14 1.00 35.58 1.00 39.91 1.00 42.38 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 422 ATOM 2231 CA PRO 466 84.118 19.126 17.348 1.00 40.82 ATOM 2232 CB PRO 4 66 83.264 19.131 18.611 1.00 41.62 ATOM 2233 CG PRO 466 82.327 20.294 18.380 1.00 45.42 ATOM 2234 C PRO 466 84.475 17.707 16.976 1.00 41.29 ATOM 2235 0 PRO 466 83.681 16.996 16.361 1.00 40.64 ATOM 2236 N GLU 467 85.664 17.292 17.370 1.00 43.54 ATOM 2237 CA GLU 467 86.106 15.950 17.065 1.00 47.01 ATOM 2238 CB GLU 467 87.569 15.955 16.627 1.00 50.95 ATOM 2239 CG GLU 467 88.000 14.641 15.990 1.00 59.47 ATOM 2240 CD GLU 467 89.372 14.700 15.334 1.00 63.95 ATOM 2241 OE1 GLU 467 90.123 15.688 15.538 1.00 62.08 ATOM 2242 0E2 GLU 467 89.697 13.736 14.606 1.00 66.76 ATOM 2243 C GLU 467 85.892 14.993 18.233 1.00 44.81 ATOM 2244 0 GLU 467 85.988 15.386 19.397 1.00 45.53 ATOM 2245 N ASP 468 85.572 13.751 17.906 1.00 43.85 ATOM 2246 CA ASP 468 85.357 12.708 18.903 1.00 43.44 ATOM 2247 CB3 ASP 468 83.872 12.582 19.247 1.00 43.33 ATOM 2248 CG ASP 468 83.611 11.659 20.420 1.00 44.52 ATOM 2249 ODi ASP 468 82.452 11.613 20.888 .1.00 48.19 ATOM 2250 0D2 ASP 468 84.557 10.985 20.877 1.00 42.43 ATOM 2251 C ASP 468 85.887 11.411 18.299 1.00 42.37 ATOM 2252 0 ASP 468 85.158 10.644 17.669 1.00 43.22 ATOM 2253 N PRO 469 87.194 11.182 18.433 1.00 40.72 ATOM 2254 CD PRO 469 88.167 12.102 19.045 1.00 40.30 ATOM 2255 CA PRO 469 87.861 9.992 17.909 1.00 39.00 ATOM 2256 CB PRO 469 89.228 10.078 18.570 1.00 39.03 ATOM 2257 CG PRO 469 89.484 11.564 18.551 1.00 38.11 ATOM 2258 C PRO 469 87.173 8.663 18.229 1.00 39.37 ATOM 2259 0 PRO 469 87.235 7.718 17.442 1.00 39.27 ATOM 2260 N ARG 470 86.497 8.596 19.371 1.00 39.93 ATOM 2261 CA ARG 470 85.814 7.374 19.770 1.00 42.32 ATOM 2262 CB ARC 470 85.030* 7.614 21.062 1.00 46.12 ATOM 2263 CG ARG 470 85.766 8.370 22.149 1.00 50.76 ATOM 2264 CD ARG 470 84.839 8.592 23.344 1.00 52.76 ATOM 2265 NE ARG 470 83.649 9.362 22.991 1.00 54.47 ATOM 2266 CZ ARC 470 82.770 9.823 23.873 1.00 59.36 ATOM 2267 NH1 ARG 470 82.945 9.597 25.169 1.00 61.19 ATOM 2268 NH2 ARG 470 81.712 10.508 23.455 1.00O 62.88 ATOM 2269 C ARG 470 84.814 6.896 18.721 1.00 42.79 ATOM 2270 0 ARG 470 84.670 5.700 18.504 1.00 45.63 ATOM 2271 N TRP 471 84.139 7.844 18.078 1.00 41.98 ATOM 2272 CA TRP 471 83.100 7.542 17.093 1.00 38.34 ATOM 2273 CB TRP 471 81.844 8.307 17.451 1.00 35.68 ATOM 2274 CG TRP 471 81.195 7.794 18.670 1.00 37.42 ATOM 2275 CD2 TRP 471 80.388 6.614 18.772 1.00 37.19 ATOM 2276 CE2 TRP 471 79.961 6.513 20.112 1.00 36.99 ATOM 2277 CE3 TRP 471 79.987 5.626 17.855 1.00 37.80 ATOM 2278 CD1 TRP 471 81.223 8.350 19.923 1.00 33.34 ATOM 2279 NEl TRP 471 80.486 7.583 20.794 1.00 34.46 ATOM 2280 CZ2 TRP 471 79.150 -5.464 20.559 1.00 38.31 ATOM 2281 CZ3 TRP 471 79.180 4.578 18.303 1.00 36.97 ATOM 2282 CH2 TRP 471 78.772 4.506 19.638 1.00 36.14 SSSD/55034. VOl WO 98/07835 WO 9807835PCTAUS97/14885 423

ATOM

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2283 2284 2285 2286 2287 2288 2289 2290 2291 2292 2293 2294 2295 2296 2297 2298 2299 2300 2301 2302 2303 2304 2305 2306 2307 2308 2309 2310 2311 2312 2313 2314 2315 2316 2317 2318 2319 2320 2321 2322 2323 2324 2325 2326 2327 2328 2329 2330 2331 233.2 2333 2334

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

Ca CD1 CD2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

CD

NE

CZ

NHl NH2

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD

NE

CZ

TRP

TRP

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ASP

AS P AS P

ASP

AS P

ASP

ASP

ASP

ARG

ARG

ARG

ARG

ARG

ARG

ARG

471 471 472 472 472 472 472 472 472 472 472 473 473 473 473 473 473 473 473 474 474 474 474 474 474 474 475 475 475 475 475 475 475 475 475 475 475 476 476 476 476 476 476 476 476 477 477 477 477 477 477 477 83.409 82.655 84 .478 84.839 86 .014 86 .146 84.930 84.361 84.568 85.135 85.872 84 .535 84 .775 83.505 83 .805 84 .365 82.556 85.283 84 .696 86 .412 87 .292 87 .010 88.233 88 .620 86.036 85.536 85.793 84 .846 84.743 84.311 84.282 83 .850 82 .585 81.630 82.286 85.101 84.160 86.359 86.690 88.197 88 .988 89.299 89.294 86.210 86.204 85.852 85.357 85 .909 87.325 88.043 87 .394 87 .810 7.830 7.430 8 .569 8 .951 9. 924 10.835 11.728 12.301 11.879 7.806 6.875 7.884 6 .893 6 .112 4 .910 3 .748 4.452 7.623 8 .631 7 .156 6 .107 7 .753 6 .865 6.477 7.663 6 .578 8 .784 8 .802 10.206 11.271 12 .691 13 .658 13 .859 13.181 14.639 7.745 7.212 7.381 6 .384 6 .371 5.925 4 .718 6 .779 4 .988 4 .074 4 .814 3 .525 3 .252 2 .723 -2 .898 2.213 2.297 15.641 14.749 15.397 14 .041 14 .087 12.871 12 .625 13 .571 11.445 13 .069 13.386 11.883 10.848 10.511 9.599 10.406 8.859 9.601 9.187 9. 025 9.568 7.824 7.587 8 .967 6.660 6.362.

5. 981 4 .863 4.258 5.267 4.679 5.679 6.011 5.402 7.047 3 .791 3 .204 3 .594 2.583 2.319 3.521 3.613 4.376.

2.973 2.145 4.241 4.732 6.126 6.088 7.406 8 .517 9.776 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00, 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 38.26 38. 72 37.71 38.43 37. 56 37.26 39.02 40.26 39.35 38.32 38. 11 38.44 37.19 35.38 .36.49 34. 47 37.55 38.21' 38. 52 37. 74 36.38 36. 91 34.65 32 .99 38. 38.24 38. 41.23 38.36 35.30 35.23 27.27 25.77 25.09 25.24 42.43 44. 06 44.69 48.37 52 .12 56.56 59. 72 61.19 49.50 51.61 48.26 47.16 49. 76 53 .26 58 .02 61.16 63.35 SSSD/55034. VOl WO 98/07835 PCTIUS97/14885 424 ATOM 2335 NH1 ARG .477 88.875 3.032 10.081 1.00 64.92 ATOM 2336 NH2 ARG 477 87.139 1.675 10.738 1.00 66.00 ATOM 2337 C ARG 477 83.822 3.445 4.740 1.00 45.38 ATOM 2338 0 ARG 477 83.239 2.540 5.336 1.00 43.67 ATOM 2339 N LET) 478 83.175 4.364 4.026 1.00 42.09 ATOM 2340 CA LET) 478 81.721 4.410 3.951 1.00 37.74 ATOM 2341 CB LEU 478 81.198 5.539 4.849 1.00 32.19 ATOM 2342 CG LEU 478 79.673 5.638 4.973 1.00 30.21 ATOM 2343 CD1 LEU 478 79.146 4.635 5.983 1.00 22.82 ATOM 2344 CD2 LET) 478 79.313 7.035 5.422 1.00 34.82 ATOM 2345 C LET) 478 81.329 4.702 2.514 1.00 38.75 ATOM 2346 0 LET) 478 81.818 5.669 1.935 1.00 40.60 ATOM 2347 N VAL 479 80.477 3.863 1.925 1.00 38.78 ATOM 2348 CA VAL 479 80.020 4.058 0.544 1.00 37.97 ATOM 2349 CB VAL 479 80.353 2.845 -0.360 1.00 36.36 ATOM 2350 CG1 VAL 479 79.837 3.090 -1.759 1.00 33.55 ATOM 2351 CG2 VAL 479 81.868 2.626 -0.405 1.00 33.76 ATOM 2352 C VAL 479 78.523 4.298 0.562 1.00 37.83 ATOM 2353 0 VAL 479 77.750 3.383 0.820 1.00 37.70 ATOM 2354 N LEU 480 78.127 5.542 0.305 1.00 39.32 ATOM 2355 CA LET) 480 76.723 5.942 0.333 1.OC 38.41 ATOM 2356 CB LET) 480 76.630 7.458 0.224 1.00 38.29 ATOM 2357 CG LEU 480 77.287 8.226 1.377 1.00 37.99 ATOM 2358 CD1 LEU 480 77. 098 9.730 1.159 1.00 34.00 ATOM 2359 CD2 LEU 480 76.666 7.785 2.703 1.00 32.79 ATOM 2360 C LET) 480 75.893 5.287 -0.753 1.00 38.24 ATOM 2361 0 LEU 480 76.315 5.205 -1.903 1.00 39.11 ATOM 2362 N GLY 481 74.672 4.896 -0.394 1L. 00 36.70 ATOM 2363 CA GLY 481 73.811 4.223 -1.357 1.00 36.53 ATOM 2364 C GLY 481 72.417 4.782 -1.524 1.00 37.61 ATOM 2365 0 GLY 481 72.159 5.961 -1.277 1.00 40.02 ATOM 2366 N LYS 482 71.484 3.913 -1.911 1.00 37.52 ATOM 2367 CA LYS 482 70.099 4.313 -2.153 1.00 39.89 ATOM 2368 CB LYS 482 69.243 3.104 -2.551 1.00 42.44 ATOM 2369 C LYS 482 69.447 5.028 -0.984 1.00 41.25 ATOM 2370 0 LYS 482 69.538 4.589 0.163 1.00 42.22 ATOM 2371 N PRO 483 68.779 6.156 -1.263 1.00 41.71 ATOM 2372 CD PRO 483 68.643 6.876 -2.537 1.00 41.01 ATOM 2373 CA PRO 483 68.118 6.889 -0.193 1.00 42.72 ATOM 2374 CB PRO 483 67.606 8.146 -0.906 1.00 41.26 ATOM 2375 CG PRO 483 67.425 7.713 -2.290 1.00 40.16 ATOM 2376 C PRO 483 66.999 6.061 0.429 1.00 44.69 ATOM 2377 0 PRO 483 66.306 5.314 -0.262 1.00 45.26 ATOM 2378 N LET) 484 66.883 6.163 1.751 1.00 45.34 ATOM 2379 CA LET) 484 65.872 5.450 2 512 1.00 47.34 ATOM 2380 CB LET) 484 66.494 4.793 3.746 1.00 42.40 ATOM 2381 CG LEU 484 67.517 *3.668 3.535 1.00 39.50 ATOM 2382 CD1 LEU 484 68.208 3.337 4.828 1.00 33.64 ATOM 2383 CD2 LET) 484 66.861 2.419 3.003 1.00 33.44 ATOM 2384 .C LET) 484 64.733 6.391 2.927 1.00 52.14 ATOM 2385 0 LEU 484 63.611 5.941 3.142 1.00 53.64 ATOM 2386 N GLY 485 65.013 7.697 3.025 1.00 55.25 SSSD/55034. V01 WO 98/07835 WO 9807835PCTIUS97/14885 425

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2387 CA GLY 2388 C GLY 238-9 0 GLY 2390 N ALA 2391 CA ALA 2392 CB ALA 2393 C ALA 2394 0 ALA 2395 N GLY 2396 CA GLY 2397 C GLY 2398 0 GLY 2399 N ALA 2400 CA ALA 2401 CE ALA 2402 C ALA 2403 0 ALA 2404 N PE 2405 CA PHE 2406 CE PHE 2407 C PHE 2408 0 PE 2409 N GLY 2410 CA GLY 2411 C GLY 2412 0 GLY 2413 N GLN 2414 CA GLN 2415 CE GLN 2416 CG GLN 2417 CD GLN 2418 OE1 GLN 2419 NE2 GLN 2420 C GLN 2421 0 GLN 2422 N VAL 2423 CA VAL 2424 CB VAL 2425 CG1 VAL 2426 CG2 VAL 2427 C VAL 2428 0 VAL 2429 N VAL 2430 CA VAL 2431 CB VAL 2432 CG1 VAL 2433 CG2 VAL 2434 C VAL 2435 0 VAL 2436 N LEU 2437 CA LEU 2438 CB LEU 485 485 485 486 486 486 486 486 487 487 487 487 488 488 488 488 488 489 489 489 489 489 490 490 490 490 491 491 491 491 491 491 491 491 491 492 492 492 492 492 492 492 493 493 493 493 493 493 493 494 494 494 63.982 8.653 64.441 10.104 65.640 10.376 63.490 11.032 63.791 12.458 63.847 13.035 62.730 13.179 61.655 12.633 63.022 14.404 62.054 15.158 62.431 16.617 63-.071 17.154 62.023 17.259 62.317 18.666 61.647 19.132 63.828 18.844 64.432 18.547 64.430 19.228 65.875 19.457 66.244 20.775 66.773 18.296 67.942 18.502 66.234 17.075 66.974 15.901 66.858 14.821 65.825 14.703 67.899 14.006 67.966 12.934 68.823 13.445 68.979 12.529 69.945 13.115 70.283 14.292 70.411 12.284 68.597 11.673 69.507 11.758 68.112 10.503 68.624 9.245 67.583 8.528 68.117 7.168 67.226 9.399 68.911 8.348 68.025 8.114 70.141 7. 862 70.481 6.994 71.471 7.674 71.128 9.137 72.929 7.498 71.071 5.6.78 71.645 5.599 70.899 4.637 71.460 3.345 70.748 2.241 3.427 1.00 58.76 3.503 1.00 60.58 3.600 1.00 61.49 3.489 1.00 61.46 3.545 1.00 63.24 2.126 1.00 64.42 4.355 1.00 63.86 4.599 1.00 65.24 4.768 1.00 63.89 5.538 1.00 64.30 5.623 1.00 65.34 4.718 1.00 65.98 6.711 1.00 66.16 6.934 1.00 66.71 8.219 1.00 70.05 7.027 1.00 66.55 8.063 1.00 65.59 5.904 1.00 65.54 5.807 1.00 65.40 6.498 1.00 67.06 6.311 1.00 64.01 6.651 1.00 62.51 6.288 1.00 61.41 6.724 1.00 55.89 5.667 1.00 53.58 5.000 1.0.0 54.22 5.543 1.00 51.23 4.556 1.00 47.90 3.387 1.00 50.09 2.183 1.00 56.77 1.161 1.00 60.83 1.218 1.00 65.11 0.232 1.00 63.81 5.190 1.00 45.27 6.014 1.00 45.41 4.805 1.00 41.69 5.325 1.00 39.95 6.230 1.00 41.77 6.701 1 .00 39.86 7.421 1.00 42.87 4.126 1.00 38.86 3.301 1.00 37.55 4.010 1.00 36.01 2.895 1.00 37.55 1.889 1.00 38.65 1.709 1.00 37.08 2.318 1.00 39.03 3.371. 1.00 38.61 4.456 1.00 39.75 2.572 1.00 39.68 2.910 1.00 40.98- 2.123 1.00 42.14 SSSD/55034. V01 WO 98/07835 PTU9148 PCTIUS97/14885 426 ATOM 2439 CG LEU 494

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2440 2441 2442 2443 2444 2445 2446 2447 2448 2449 2450 2451 2452 2453 2454 2455 2456 2457 2458 2459 2460 2461 2462 2463 2464 2465 2466 2467 2468 2469 2470 2471 2472 2473 2474 2475 2476 2477 2478 2479 2480 2481 2482 2483 2484 2485 2486 2487 2488 2489 2490 CD1 CD2

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

C

0

N

CA

CB

CG2 CG1 CD1

C

0

N

CA

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CD

CA

CB

CG

C

0

N

LEU

LEU

LEU

LEU

ALA

ALA

ALA

ALA

ALA

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ALA

ALA

ALA

ALA

ALA

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

GLY

GLY

GLY

GLY

LETJ

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ASN

494 494 494 494 495 495 495 495 495 496 496 496 496 496 496 496 496 496 497 497 497 497 497 498 498 498 498 498 498 498 498 499 499 499 499 500 500 500 500 500 500 500 500 505 505 505 505 505 505 506 71.250 0.808 71.186 0.425 70.411 -0.117 72.918 3.432 73.249 4.163 73.798 2.725 75.202 2.768 75.858 3.999 75.887 1.497 75.271 0.668 77.140 1.314 77.910 0.154 78.282 -0.722 77.062 -1.206 77.316 -2.476 76.448 -3.378 78.371 -2.575 79.151 0.658 79.957 1.366 79.232 0.385 80.374 0.799 79.910 1.182 81.381 -0.351 80.997 -1.512 82.666 -0.025 83.709 -1.042 84.611 -0.977 85.681 -2.'054 83.780 -1.150 83.073 0.112 84.572 -0.878 85.055 0.219 84.713 -1.964 85.526 -1.958 85.061 -1.111 85.885 -0.545 83.747 -1.058 83.167 -0.275 81.663 -0.556 80.764 -0.090 79.331 -0.536 80.845 1.426 83.849 -0.565 84.226 -1.710 87.501 -6.102 88.578 -6.722 87.860 -4.730 89.257 -4.557 89.782 -5.960 87.850 -4.508 88.038 -3.391 87.632 -5.584 2.305 3 .765 1.459 2.483 1 .552 3 .169 2.820 3.468 3 .289 3 .946 2.880 3.297 2.106 1 .346 0. 567 0.634 -0.103 3 .987 .1.387 5.282 6.086 7.471 6 .150 6.107 6 .206 6.262 5.014 5.082 3.741 3 .255 7.510 7.801 8.270 9.480 10.661 11.393 10.878 11. 974 12.086 10.937 11.168 10.799 13.306 13.576 10.460 11. 248 10.077 10.686 10.770 ,8.567 *8.087 7.826 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1 .00 1 .00 1.00 1.00 1 .00 1 .00 1 .00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1. 00 1. 00 1.00 1. 0 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1 .00 1. 00 40.33 39.62 40.75 40.66 40.05 39.74 42 .06 42 .91 43 .34 43 .81 44.40 45.12 48 .62 56.98 60.32 62.17 60.48 43.27 44.49 43 .29 44 .01 42.35 45.60 43 48.78 49.43 50.66 51 50.27 54 .24 50.32 49.08 51.88 55.86 59.72 61.66 59.88 58 .62 57.41 55.24 51.91 54 .93 58.51 60.71 82.25 82 .69 80.47 80.88 81.84 77.40 76.83 74 .91 SSSD/55034. V01 WO 98/07835 WO 987835PTIUS97/14885 427

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2491 CA ASN 2492 CB ASN 2493 C ASN 2494 0 ASN 2495 N ARG 2496 CA ARG 2497 CB ARG 2498 C ARG 2499 0 ARG 2500 N VAL 2501 CA VAL 2502 CB VAL 2503 CG1 VAL 2504 CG2 VAL 2505 C VAL 2506 0 VAL 2507 N THR 2508 CA THR 2509 CB THR 2510 OGi THR 2511 CG2 THR 2512 C THR 2513 0 THR 2514 N LYS 2515 CA LYS 2516 CB LYS 2517 CG LYS 2518 CD LYS 2519 CE LYS 2520 NZ LYS 2521 C LYS 2522 0 LYS 2523 N VAL 2524 CA VAL 2525 CB VAL 2526 CG1 VAL 2527 CG2 VAL 2528 C VAL 2529 0 VAL 2530 N ALA 2531 CA ALA 2532 CB ALA 2533 C -ALA 2534 0 ALA 2535 N VAL 2536 CA VAL 2537 CB VAL 2538 CG1 VAL 2539 CG2 VAi 2540 C VAL 2541 0 VAL 2542 N LYS 506 506 506 506 507 507 507 507 507 508 508 508 508 508' 508 508 509 509 509 509 509 509 509 510 510 510 510 510 510 510 510 511 511 511 511 511 511 511 512 512 512 512 512 513 513 513 513 513 513 513 514 87.572 88 .632 86 .180 85. 918 85.294 83 .924 83 .369 83 .048 83 .225 82.126 81.217 80.905 82 .163 80.184 79.928 79.483 79.345 78 .107 78.329 79.476 77.123 77.140 77.485 75.958 74 .975 73 .861 73 .008 73 .463 72.846 73 .112 74.'430 74 .053 74 .443 73.975 75.161 75.922 76.098 73 .116 72 .962 72 .542 71.724 70.382 72.487 72 .996 72 .556 73 .286 74.439 75.213 75.353 72.383 71.745 72.304 -5.502 -6.406 -5.938 -6 .094 124 534 -7.329 -5.321 -4.291 -5.429 -4.334 -4.178 952 -5.390 -4.614 -5.759 -3.555 -3.652 192 -3.851 -3.524 -2.705 558 191 333 -3.175 -2.420 -2.645 917 150 -1.470 006 149 0.757 1.399 0.340 2.100 1.873 1.984 2.687 3.818 3 .774 5.075 5.151 6. 057 7.290 7.503 8. 730 6.308 8.526 -8.799 9.228 6.375 1.00 73.04 5.749 1.00 73.39 5.929 1.00 71.75 4.739 1.00 71.33 6.905 1.00 69.66 6.638 1.00 66.59 7.819 1.00 69.86 6.409 1.00 63.59 7.070 1.00 64.09 5.462 1.00 59.52 5.187 1.00 57.28 3.686 1.00 55.73 2.922 1.00 57.01 3.149 1.00 58.06 5.935 1.00 57.10 6.018 1.00 57.35 6.482 1.00 55.31 7.227 1.00 50.14 8.686 1.00 50.91 9.227 1.00 49.20 9.559 1.00 51.96 6.528 1.00 47.53 6.242 1.00 47.22 6.191 1.00 45.64 5.551 1.00 44.44 4.948 1.00 46.74 3.950 1.00 54.51 2.513 1.00 54.97 1.934 1.00 58.25 2.740 1.00 58.33 6.696 1.00 42.75 7.742 1.00 43.14 6.531 1.00 38.63 7.576 1.00 34.16 8.333 1.00 35.66 9.100 1.00 31.46 7.357 1.00 35.08 7.024 1.00 31.58 5.818 1.00 33.18 7.906 1.00 30.77 7.484 1.00 28.58 8.145 1.00 26.09 7.905 1.00 29.94 9.031 1.00 29.90 7.012 1.00 28.68 7.280 1.00 28.26 6.269 1.00 26.92 6.618 1.00 25.26 6.238 1.00 25.10 7.230 1.00 29.54 6.200 1.00 28.56 8.359 1.00 28.94 SSSD/55034. V01 WO 98/07835 WO 9807835PCTIUS97/14885 428

ATOM

ATOM

ATOM

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ATOM

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ATOM

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ATOM

ATOM

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ATOM

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ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2543 2544 2545 2546 2547 2548 2549 2550 2551 2552 2553 2554 2555 2556 2557 2558 2559 2560 2561 2562 2563 2564 2565 2566 2567 2568 2569 2570 2571 2572 2573 2574 2575 2576 2577 2578 2579 2580 2581 2582 2583 2584 2585 2586 2587 2588 2589 2590 2591 2592 2593 2594

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA.

CB

CG

CD

CE

NZ

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

C

0

LYS

LYS

-LYS

LYS

LYS

LYS

LYS

LYS

MET

MET

MET

MET

MET

MET

MET

MET

LEU

LEU

LEU

LEU

LEU

LEU

LETJ

LEU

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

SER

SER

SER

SER

SER

SER

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ALA

ALA

ALA

ALA

ALA

514 514 514 514 514 514 514 514 515 515 515 515 515 515 515 515 516 516 516 516 516 516 516 516 517 517 517 517 517 517 517 517 517 518 518 518 518 518 518 519 519 519 519 519 519 519 519 520 520 520 520 520 71.519 70. 942 69.988 69.454 68.484 67.198 72 .430 73 .544 71.928 72 .676 73.425 72.502 73.377 73.949 71.683 70.472 72 .202 71.383 72 .110 72.455 73.210 71.217 71.092 71.763 70.069 69.755 68.246 67.432 66.172 65 .088 63 .902 70.520 70 .917 70.744 71.486 71.611 70.375 70.896 71.580 69.624 68.943 67.529 66.668 67.150 65.478 68.881 68.266 69.551 69.561 70.253 70.242 71.014 10.450 10.611 9.542 9.922 8 .892 8.861 11.636 11.714 12.576 13.762 13.487 13.026 12.418 10.803 14.880 14.685 16.056 17.220 18. 512 18.767 20.057 18. 844 17.274 16.636 18.018 18.187 18.363 17.182 16.940 17. 984 17 .740 19.455 20.21-/ 19.672 20.840 20. 772 20. 407 22.189 23.214 22.193 23.422 23.480 22.258 21.309 22 .250 23.645 24.602 22.784 22.895 21.687 24. 163 24.778 8.481 9. 893 10.328 11.690 12.222 11.475 8 .196 8. 722 7.407 7.008 5.693 4.556 3 .113 3 .715 6. 779 6.889 6.466 6 .180 6 .593 8 .067 8.190 8. 900 4 .674 3 .873 4.293 2 .890 2 .699 3.192 2 .356 2.581 1 .704 2 .507 3.383 1.213 0.714 -0.809 -1.396 1.110 1.058 1.485 1.885 1.268 1.608 2 .253 1.220 3.395 3.860 4.150 5.605 6.207 6 .076 5.331 1.00 28.60 1.00 31.19 1.00 31.41 1.00 40.14 1.00 48.93 1.00 57.07 1.00 25.53 1.00 20.42 1.00 26.63 1.00 27.59 1.00 28.22 1.00 28.70 1.00 32.30 1.00 24.88 1.00 28.41 1.00 32.15 1.00 29.12 1.00 29.98 1.00 25.32 1.00 26.60 1.00 24.56 1.00 22.75 1.00 31.50 1.00 32.97 1.00 33.29 1.00 32.20 1.00 36.34 1.00 43.49 1.00 53.91 1.00 58.71 1.00 59.37 1.00 31.31 1.00 28.74 1.*00 32.48 1.00 33.52 1.00 32.98 1.00 36.75 1.00 34. 62 1.00 34.57 1.*00 35.47 1.00 36.10 1.00 38.11 1.00 41.64 1.00 41.70 1.00 49.25 1.00 34.66 1.00 33.39 .1.00 33.52 1.00 32.12 1.00 32.08 1.00 30.91 1.00 30.57 SSSD/55034. V01 WO 98/07935 WO 9807835PCTIUS97/14885 429 ATOM 2595 N THR 521 -69.943 24.555 7.311 1.00 30.80 ATOM 2596 CA THR 521 70.546 25.738 7.921 1.00 32.33 ATOM 2597 CB TER 521 69.493 26.763 8.440 1.00 34.30 ATOM 2598 OGi TER 521 68.817 26.242 9.598 1.00 35.14 ATOM 2599 CG2 THR 521 68.484 27.109 7.366 1.00 37.70 ATOM 2600 C THR 521 71.418 25.312 9.098 1.00 33.11 ATOM 2601 0 THR 521 71.518 24.125 9.426 1.00 31.39 ATOM 2602 N GLU 522 72.022 26.293 9.753 1.00 34.91 ATOM 2603 CA GLU 522 72.882 26.048 10.901 1.00 39.44 ATOM 2604 CB GLU 522 73.516 27.357 11.360 1.00 46.96 ATOM 2605 CG GLU 522 74.550 27.220 12.488 1.00 59.20 ATOM 2606 CD GLU 522 75.919 26.740 12.011 1.00 64.70 ATOM 2607 OE1 GLU 522 76.910 27.478 12.219 1.00 63.87 ATOM 2608 0E2 GLU 522 76.006 25.627 11.445 1.00 71.55 ATOM 2609 C GLU 522 72.083 25.428 12.044 1.00 39.61 ATOM 2610 0 GLU 522 72.587 24.554 12.757 1.00 36.74 ATOM 2611 N LYS 523 70.827 25.849 12.193 1.00 38.60 ATOM 2612 CA LYS 523 69.970 25.327 13.252 1.00 37.77 ATOM 2613 CB LYS 523' 68.628 26.053 13.273 1.00 44.52 ATOM 2614 CG LYS 523 67.665 25.562 14.355 1.00 51.14 ATOM 2615 CD LYS 523 66.380 24.982 13.756 1.00 57.39 ATOM 2616 CE LYS 523 65.499 24.376 14.852 1.00 59.17 ATOM 2617 NZ LYS 523 64.365 23.553 14.327 1.00 62.68 ATOM 2618 C LYS 523 69.751 23.849 13.002 1.00 34.63 ATOM 2619 0 LYS 523 69.817 23.041 13.931 1.00 35.00 ATOM 2620 N ASP 524 69.496 23.495 11.746 1.00 31.60 ATOM 2621 CA ASP 524 69.293 22.100 11.367 1.00 29.05 ATOM 2622 CB ASP 524 69.002 21.975 9.871 1.00 29.60 ATOM 2623 CG ASP 524 67.695 22.626 9.472 1.00 31.90 ATOM 2624 ODi ASP 524 66.666 22.368 10.130 1.00 38.83 ATOM 2625 0D2 ASP 524 67.687 23.383 8.485 1.00 29.79 ATOM 2626 C ASP 524 70.558 21.317 11.696 1.00 28.02 ATOM 2627 0 ASP 524 70.494' 20.201 12.212 1.00 28.12 ATOM 2628 N LEU 525 71.709 21.899 11.378 1.00 28.32 ATOM 2629 CA LEU 525 72.971 21.231 11.677 1.00 27.71 ATOM 2630 CB LEU 525 74.173 22.085 11.257 .1.00 22.53 ATOM 2631 CG LEU 525 75.548 21.490 11.602 1.00 22.13 ATOM 2632 CD1 LEU 525 75.677 20.082 11.019 1.00 19.92 ATOM 2633 CD2 LEU 525 76.673 22.401 11.147 1.00 18.60 ATOM 2634 C LEU 525 73.007 20.952 13.162 1.00 27.44 ATOM 2635 0 LEU 525 73.227 19.817 13.577 1.00 29.73 ATOM 2636 N SER 526 72.689 21.976 13.947 1.00 29.09 ATOM 2637 CA SER 526 72.672 21.891 15.412 1.00 30.83 ATOM 2638 CB SER 526 72.222 23.230 16.006 1.00 34.25 ATOM 2639 OG' SER 526 71.966 23.147 17.397 1.00 40.67 ATOM 2640 C SER 526 71.765 20.777 15.931 1.00 29.32 ATOM 2641 0 SER 526 72.055 20.133 16.954 1.00 28.94 ATOM 2642 N ASP 527 70.644 20.587 15.242 1.00 26.54 ATOM 2643 CA ASP 527 69.681 19.558 15.601 1.00 27.00 ATOM 2644 CB. ASP. 527 68.392 19.798 14,829 1.00 25.91 ATOM 2645 CG ASP 527 67.640 21.052 15. 290 1.00 29..22 ATOM 2646 ODi ASP 527 68.016 21.662 16.320 1.00 26.80 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 430 ATOM 2647 0D2 ASP 527 66.660 21.425 14.605 1.00 33.85 ATOM 2648 C ASP 527 70.231 18.155 15.325 1.00 28.34 ATOM 2649 0 ASP 527 70.058 17.240 16.130 1.00 28.36 ATOM 2650 N LEU 528 70.884 17.982 14.177 1.00 29.50 ATOM 2651 CA LEU 528 71.448 16.680 13.830 1.00 30.48 ATOM 2652 CE LEU 528 71.915 16.651 12.366 1.00 27.89 ATOM 2653 CG LEU 528 72.443 15.305 11.832 1.00 26.48 ATOM 2654 CD1 LEU 528 .71.468 14.154 12.148 1.00 21.52 ATOM 2655 CD2 LET) 528 72.722 15.383 10.333 1.00 20.23 ATOM 2656 C LET) 528 72.583 16.308 14.804 1.00 31.69 ATOM 2657 0 LEU 528 72.688 15.145 15.222 1.00 30.09 ATOM 2658 N ILE 529 73.397 17.298 15.195 1.00 30.79 ATOM 2659 CA ILE 529 74.503 17.082 16.140 1.00 28.88 ATOM 2660 CB ILE 529 75.398 18.310 16.278 1.00 25.69 ATOM 2661 CG2 ILE 529 76.541 18.007 17.217 1.00 20.54 ATOM 2662 CG1 ILE 529 75.960 18.727 14.941 1.00 23.71 ATOM 2663 CD1 ILE 529 76.981 19.831 15.035 1.00 24.21 ATOM 2664 C ILE 529 73.951 16.767 17.533 1.00 31.52 ATOM 2665 0 ILE 529 74.439 15.850 18.213 1.00 30.66 ATOM 2666 N SER 530 72.917 17.500 17.947 1.00 29.79 ATOM 2667 CA SER 530 72.315 17.257 19.244 1.00 32.03 ATOM 2668 CB SER 530 71.176 18.239 19.492 1.00 38.91 ATOM 2669 OG SER 530 70.266 18.231 18.412 1.00 49.86 ATOM 2670 C SER 530 71.795 15.819 19.316 1.00 30.10 ATOM 2671 0 SER 530 71.921 15.154 20.353 1.00 31.31 ATOM 267.2 N GLU 531 71.185 15.350 18.231 1.00 27.18 ATOM 2673 CA GLU 531 70.671 13.989 18.180 1.00 27.89 ATOM 2674 CE GLU 531 69.923. 13.744 16.881 1.00 31.29 ATOM 2675 CG GLU 531 69.434 12.324 1E;.769 1.00 30.43 ATOM 2676 CD GLU 531 68.717 12.040 15.486 1.00 30.67 ATOM 2677 OE1 GLU 531 68.293 10.892 15.317 1.00 37.79 ATOM 2678 0E2 GLU 531 68.571 12.941 14.643 1.00 34.20 ATOM 2679 C GLU 531 71.765 12.929 18.348 1.00 26.67 ATOM 2680 0 GLU 531 71.604 11.986 29.119 1.00 24.33 ATOM 2681 N MET 532 72.851 13.074 17.595 1.00 28.93 ATOM 2682 CA MET 532 74.000 12.156 17.644 1.00 28.35 ATOM 2683 CE MET 532 75.073 12.637 16.659 1.00 29.48 ATOM 2684 CG MET 532 76.458 12.034 16.827 1.00 25.84 ATOM 2685 SD MET 532 77.650 12.692 15.582 1.00 30.60 ATOM 2686 CE MET 532 77.831 14.373 16.151 1.00 20.10 ATOM 2687 C MET 532 74.571 12.120 19.057 1.00 29.06 ATOM 2688 0 MET 532 74.876 11.053 19.589 1.00 28.22 ATOM 2689 N GLU 533 74.640 13 .289 19.688 1.00 28.61 ATOM 2690 CA GLU 533 75.150 13.388 21.041 1.00 28.40 ATOM 2691 CE GLU 533 75.340 14.846 21.429 1.00 29.34 ATOM 2692 CG GLU 533 76.449 15.534 20.640 1.00 31.87 ATOM 2693 CD GLU 533 77.822 14.923 20.892 1.00 35.10 ATOM 2694. QOE GLU. 533 78.242. 14.831 22.067 1.00 37.36 ATOM 2695 0E2 GLU 533 78.490 14.543 19.913 1.00 37.71 ATOM 2696 C GLU 533 74.211 12.684 22.023 1.00 31.03 ATOM 2697 0 GLU 533 74.651 11.936 -22.906 1.00 30.76 ATOM 2698 N MET 534 72.909 12.902 21.860 1.00 31.71 SSSD/55034. V0l WO 98/07835 WO 9807835PCT/US97/14885 431 ATOM 2699 CA MET 534 71.940 12.256 22.727 1.00 30.58 ATOM 2700 CB MET 534 70.510 12.620 22.315 1.00 33.53 ATOM 2701 CG MET 534 69.538 12.624 -23.509 0.50 3 2. ATOM 2702 SD MET 534 67.778 12.682 23.150 0.50 30.95 ATOM 2703 CE MET 534 67.523 14.422 22.895 0.50 30.50 ATOM 2704 C MET 534 72.158 10.752 22.616 1.00 28.44 ATOM 2705 0 MET 534 72.304 10.077 23.614 1.00 27.63 ATOM 2706 N MET 535 72.216 10.232 21.395 1.00 30.00 ATOM 2707 CA MET 535 72.448 8.800 21.176 1.00 29.38 ATOM 2708 CB MET 535 72.626 8.483 19.690 1.00 25.41 ATOM 2709 CG MET 535 71.395 8.753 18.893 1.00 25.06 ATOM 2710 SD MET 535 71.468 7.917 17.344 1.00 27.17 ATOM 2711 CE MET 535 71.439 9.227 16.247 1.00 33.'70 ATOM 2712 C MET 535 73.675 8.345 21.938 1.00 30.77 ATOM 2713 0 MET 535 73.681 7.254 22.534 1.00 27.49 ATOM 2714 N LYS 536 74.710 9.183 21.916 1.00 32.72 ATOM 2715 CA LYS 536 75.937 8.889 22.649 1.00 34.05 ATOM 2716 CB LYS 536 76.995 9.964 22.401 1.00 32.69 ATOM 2717 CG LYS 536 77.719 9.838 21.073 1.00 28.00 ATOM 2718 CD LYS 536 78.732 10.956 20.941 1.00 29.61 ATOM 2719 CE LYS 536 79.242 11.124 19.514 1.00 26.58 ATOM 2720 NZ LYS 536 80.020 12.389 19.460 1.00 22.22 ATOM 2721 C LYS 536 75.652 8.769 24.145 1.00 34.80 ATOM 2722 0 LYS 536 76.004 7.763 24.750 1.00 34.44 ATOM 2723 N MET 537 74.958 9.749 24.716 1.00 34.66 ATOM 2724 CA MET 537 74.634 9.724 26.131 1.00 37.25 ATOM 2725 CB MET 537 73.951 11.034 26.549 1.00 46.08 ATOM 2726 CG MET 537 74.862 12.272 26.619 1.00 57.95 ATOM 2727 SD MET 537 76.159 12.203 27.919 1.00 66.50 ATOM 2728 CE MET 537 75.287 12.873 29.377 1.00 64.52 ATOM 2729 C MET 537 73.749 8.537 26.523 1.00 36.05 ATOM 2730 0 MET 537 74.021 7.865 27.514 1.00 36.71 ATOM 2731 N ILE 538 72.730 8.255 25.719 1.00 33.77 ATOM 2732 CA ILE 538 71.804 7.160 26.007 1.00 30.52 ATOM 2733 CE ILE 538 70.616 7.172 25.012 1.00 28.15 ATOM 2734 CG2 ILE 538 69.780 5.899 25.122 1.00 26.08 ATOM 2735 CG1 ILE 538 69.729 8.377 25.289 1.00 26.24 ATOM 2736 CD1 ILE 538 68.644 8.558 24.256 1.00 26.87 ATOM 2737 C ILE 538 72.399 5.750 26.100 1.00 30.05 ATOM 2738 0 ILE 538 71.984 4.950 26.941 1.00 31.57 ATOM 2739 N GLY 539 73.320 5.424 25.211 1.00 30.34 ATOM 2740 CA GLY 539 73.910 4.103 25.249 1.00 28.22 ATOM 2741 C GLY 539 73.158 3.094 24.408 1.00 31.25 ATOM 2742 0 GLY 539 72.050 3.359 23.935 1.00 32.88 ATOM 2743 N LYS 540 73.781 1.933 24.221 1.00 31.96 ATOM 2744 CA LYS 540 73.222 0.845 23.416 1.00 33.40 ATOM 2745 CE LYS 540 74.342 -0.023 22.878 1.00 31.53 ATOM 2746 CG LYS 540 75.177- 0.645 21.846 1.00 37.05 ATOM 2747 CD LYS -540 76.273 -0.266 21.361 1.00 40.15 ATOM 2748 CE LYS 540 77.143 0.480 20.363 1.00 46.84 ATOM 2749 NZ LYS 540 76.374 0.920 19.152 1.00 48.60 ATOM 2750 C LYS 540 72.183 -0.090 24.023 1.00 36.22 SSSD/55034. V01 WO 98/07835 WO 9807835PCT/US97/14885 432

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2751 2752 2753 2754 2755 2756 2757 2758 2759 2760 2761 2762 2763 2764 2765 2766 2767 2768 2769 2770 2771 2772 2773 2774 2775 2776 2777 2778 2779 2780 2781 2782 2783 2784 2785 2786 2787 2788 2789 2790 2791 2792 2793 2794 2795 2796 2797 2798 2799 2800 2801 2802 O LYS N HIS CA HIS CB HIS CG HIS CD2 HIS ND1 HIS CEl HIS NE2 HIS C HIS O HIS N LYS CA LYS CB LYS C LYS O LYS N ASN CA ASN CB ASN CG ASN ODi ASN ND2 ASN C ASN O ASN N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE O ILE N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE O ILE N ASN CA ASN CB ASN CG ASN ODI ASN Nfl2 ASN C ASN O ASN N LEU CA LEU CB LEI CG LEU 540 541 541 541 541 541 541 541 541 541 541 542 542 542 542 542 543 543 543 543 543 543 543 543 544 544 544 544 544 544 544 544 545 545 545 545 545 545 545 545 .546 546 546 546 546 546 '546 546 547 .547 .547 547 72 .237 71.254 70.223 69.064 68.127 68 .127 67.086 66.489 67.096 69.720 69.648 69.348 68.908 68.715 67.652 67.474 66.778 65.529 64 .372 64.387 64.732 64 .053 65.426 64 .342 66 .546 66.582 67.052 66.338 68.568 69.105 67.582 68.388 67 .449 68.376 67.824 68 .920 66 .625 66 .988 69.631 69.586 70.740 72 .004 72 .709 71.956 71.793 71.472 72 .982 73 .045 73 .774 74 .828 75 .297 76 .367 -0.430 521 -1.486 -0.860 -1.862 -2.482 -2.411 -3.329 -3.384 -2.206 614 -3.478 311 -5.766 -3.848 -4.058 -3.2 12 754 -3.241 -4.739 -5.242 -5.462 -1.257 -0.679 -0.635 0.794 1.72 1 1.353 1.614 2.531 0.901 -0.008 1.940 2.163 3.164 3.556 2.568 1.326 2.718 3.7 52 2.011 2.382 1.122 0.463 1.031 -0.74 0 3.124 .2-894 3.982 -4.750 5.898 6.828 25.215 23.175 23.535 24.293 24.890 26 .093 24.177 24.911 26.081 22.275 21.200 22.430 21.306 21.753 20.614 19.417 21.369 20.803 21.660 21.840 22 .909 20.787 20.529 20.647 20.168 19. 833 21.019 22.306 21.234 22.332 18.680 18.480 17.849 16.745 15.709 14.731 14.955 14.117 17.401 18.068 17.221 17 .822 18.345 19.470 20.540 19.235 16.941 15.732 17.579 16.925 17.837 17.267 1.00 40.10 1.00 34.86 1.00 33.96 1.00 31.57 1.00 32.28 1.00 32.39 1.00 30.10 1.00 33.35 1.00 30.46 1.00 35.33 1.00 34.87 1.00 35.42 1.00 32.02 1.00 30.96 1.00 30.02 1.00 29.10 1.00 28.54 1.00 28.20 1.00 29.73 1.00 30.74 1.00 32.96 1.00 29.58 1.00 28.06 1.00 28.86 1.00 26.70 1.00 2-6.81 1.00 24.75 1.00 20.02 1.00 23.73 1.00 21.64 1.00 27.95 1.00 26.80 1.00 29.22 1.00 27.14 1.00 26.10 1.00 .24.70 1.00 23.78 1.00 22.15 1.00 28.14 1.00 28.21 1.00 28.40 1.00 28.49 1.00 27.05 1.00 27.29 1.00 29.92 1.00 24.63 1.00 28.39 1.00 .29.62 1.00 29.91 -1.00 30.68 1.00 25.28 1.00 24.81 SSSD/55034. V01 WO 98/07835 WO 980785PCTIUS97/14885 433 ATOM 2803 CD1 LEU 547 75.868 7.524 15.990 1.00 22.25 ATOM 2804 CD2 LEU 547 76.716 7.853 18.313 1.00 24.17 ATOM 2805 C LEU -547 76.016 3.812 16.629 1.00 31.67 ATOM 2806 0 LEU 547 76.481 3.090 17.509 1.00 31.34 ATOM 2807 N LEU 548 76.475 3.823 15.380 1.00 30.60 ATOM 2808 CA LET) 548 77.594 2.995 14.955 1.00 29.31 ATOM 2809 CB LEU 548 77.197 2.165 13.729 1.00 25.94 ATOM 2810 CG LEU 548 75.968 1.247 13.883 1.00 28.78 ATOM 2811 CD1 LEU 548 75.848 0.360 12.659 1.00 27.14 ATOM- 2812 CD2 LET) 548 76.049 0.392 15.149 1.00 23.72 ATOM 2813 C LEU 548 78.850 3.821 14.644 1.00 31.60 ATOM 2814 0 LEU 548 79.967 3.330 14.753 1.00 32.65 ATOM 2815 N GLY 549 78.665 5.076 14.248 1.00 32.22 ATOM 2816 CA GLY 549 79.795 5.928 13.937 1.00 31.40 ATOM 2817 C GLY 549 79.344 7.267 13.391 1.00 30.78 ATOM 2818 0 GLY 549 78.140 7.536 13.291 1.00 29.84 ATOM 2819 N ALA 550 80.320 8.099 13.045 1.00 31.88 ATOM 2820 CA ALA 550 80.073 9.416 12.485 1.00 30.14 ATOM 2821 CB ALA 550 79.634 10.382 13.590 1.00 31.08 ATOM 2822 C ALA 550 81.291 9.978 11.742 1.00 28.78 ATOM 2823 0 ALA 550 82.447 .9.705 12.102 1.00 26.39 ATOM 2824 N CYS 551 81.011 10.690 10.651 1.00 28.48 ATOM 2825 CA CYS 551 82.012 11.391 9~.846 1.00 23.69 ATOM 2826 CB CYS 551 81.825 11.128 8.352 1.00 24.18 ATOM 2827 SG CYS 551 81.870 9.3.95 7.840 1.00 28.40 ATOM 2828 C CYS 551 81.612 12.847 10.127 1.00 20.99 ATOM 2829 0 CYS 551 80.561 13.282 9.684 1.00 22.11 ATOM 2830 N THR 552 82.357 13.524 10.996 1.00 20.18 ATOM 2831 CA THR 552 82.073 14.914 11.349 1.00 22.79 ATOM 2832 CB THR 552 82.090 15.080 12.874 1.00 23.16 ATOM 2833 OGi THR 552 83.408 14.803 13.363 1.00 23.52 ATOM 2834 CG2 THR 552 81.125 14.112 13.529 1.00 25.31 ATOM 2835 C THR 552 83.138 15.886 10.824 1.00 24.74 ATOM 2836 0 THR 552 82.939 17.103 10.782 1.00 22.75 ATOM 2837 N GLN 553 84.276 15.334 10.431 1.00 26.82 ATOM 2838 CA GLN 553 85.387 16.153 9.980 1. 00 26.99 ATOM 2839 CE GLN 553 86.686 15.627 10.602 1.00 26.40 ATOM 2840 CG GLN 553 86.632 15.494 12.f41 1.00 22.69 ATOM 2841 CD GIN 553 86.438 16.836 12.823 1.00 25.90 ATOM 2842 OE1 GLN 553 87.259 17.729 12.656 1.00 29.03 ATOM 2843 NE2 GLN 553 85.351 16.994 13.566 1.00 23.53 ATOM 2844 C GLN 553 85.502 16.216 8.466 1.00 26.23 ATOM 2845 0 GLN 553 85.177 15.259 7.779 1.00 30.00 ATOM 2846 N ASP 554 85.863 17.394 7.968 1.00 26.54 ATOM 2847 CA ASP 554 86.084 17.631 6.531 1.00 28.38 ATOM 2848 CB ASP 554 87.410 17.031 6.105 1.00 26.78 ATOM 2849 CG ASP 554 88.538 17.570 6.912 1.00 31.53 ATOM 2850 ODi ASP 554 88.789 18.795 6.823 1.00 35.18 ATOM 2851 0D2 ASP 554 89.141 16.795 7.665 1.00 29.04 ATOM 2852 C ASP 554 85.011 17.221 5.545 1.00 29.14 ATOM 2853 0 ASP 554 85.278 16.468 4.610 1.00 31.22 ATOM 2854 N GLY 555 83.824 17.793 5.709 1.00 31.20 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 434 ATOM 2855 CA GLY 555 82.723 17.490 4.811 1.00 28.83 ATOM 2856 C GLY 555 81.446 17.413 5.602 1.00 24.84 ATOM 2857 0 GLY 555 81.448 17.647 6.814- 1.00 21.78 ATOM 2858 N PRO 556 80.317 17.093 4.953 1.00 24.29 ATOM 2859 CD PRO 556 80.213 16.781 3.510 1.00 19.37 ATOM 2860 CA PRO 556 79.010 16-973 5.615 1.00 25.11 ATOM 2861 CB PRO 556 78.107 16.497 4.477 1.00 22.88 ATOM 2862 CG PRO 556 79.077 15.832 3.485 1.00 23.50 ATOM 2863 C PRO 556 79.006 15.982 6.777 1.00 27.67 ATOM 2864 0 PRO 556 79.676 14.947 6.736 1.00 27.13 ATOM 2865 N LEU 557 78.253 16.297 7.820 1.00 29.27 ATOM 2866 CA LEU* 557 78.164 15.405 8.972 1.00 31.19 ATOM 2867 CB LEU 557 77.583 16.130 10.188 1.00 29.94 ATOM 2868 CG LEU 557 77.01-9 15.260 11.323 1.00 26.87 ATOM 2869 CD1 LEU 557 781131 14.540 12.062 1.00 23.83 ATOM 2870 CD2 LEU 557 76.237 16.146 12.275 1.00 23.80 ATOM 2871 C LETJ 557 77.291 14. 193 8.651 1.00 31.97 ATOM 2872 0 LEU 557 76.158 14.332 8.184 1.00 31.18 ATOM 2873 N TYR 558 77.857 13.010 8.882 1.00 31.12 ATOM 2874 CA TYR 558 77.145 11.767 8.664 1.00 28.86 ATOM 2875 CR TYR 558 77.905 10.869 7.694 1.00 28.58 ATOM 2876 CG TYR 558 78.017 11.395 6.281 1.00 32.33 ATOM 2877 CD1 TYR 558 79.034 10.962 5.443 1.00 35.23 ATOM 2878 CEl TYR .558 79.161 11.447 4.151 1.00 37.54 ATOM 2879 CD2 TYR 558 77.123 12.336 5.787 1.00 35.27 ATOM 2880 CE2 TYR *558 77.248 12.832 4.493 1.00 36.43 ATOM 2881 CZ TYR 558 78.276 12.382 3.680 1.00 37.05 ATOM 2882 OH TYR 558 78.423 12.869 2.394 1.00 39.97 ATOM 2883 C TYR 558 77.000 11.071 10.004 1.00 26.63 ATOM 2884 0 TYR 558 77.985 10.885 10.725 1.00 24.67 ATOM 2885 N VAL 559 75.756 10.774 10.365 1 *oo0 28.15 ATOM 2886 CA VAL 559 75.429 10.070 11.610 1.00 27.70 ATOM 2887 CB VAL 559 74.262 10.770 12.372 1.00 26.63 ATOM 2888 CG1 VAL 559 73.876 9_959 13.603 1.00 24.70 ATOM 2889 CG2 VAL 559 74.673 12. 186 12.792 1.00 26.71 ATOM 2890 C VAL 559 75..061 8.635 11.205 1.00 27.08 ATOM 2891 0 VAL 559 73.965 8.357 10.710 1.00 25.39 ATOM 2892 N ILE 560 76.002 7. 729 11.399 1.00 28.25 ATOM 2893 CA ILE 560 75.820 6.335 11.000 1.00 29.62 ATOM 2894 CB ILE 560 77.225 5.682 10.678 1.00 30.06 ATOM 2895 CG2 ILE 560 77.045 4.279 10.101 1.00 31.58 ATOM 2896 CG1 ILE 560 78.004 6.557 9.686 1.00 27.50 ATOM 2897 CD1 ILE 560 79.492 6.239 9.629 1.00 23.31 ATOM 2898 C ILE 560 75.075 5.488 12.032 1.00 29.88 ATOM 2899 0 ILE 560 75.586 5.234 13.130 1.00 27.32 ATOM 2900 N VAL 561 73.857 5.078 11.687 1.00 29.09 ATOM 2901 CA VAL 561 73.053 4.228 12.568 1.00 28.70 ATOM 2902 CB VAL 561 71.743 4.932 13.037 1.00 25.29 ATOM 2903 CG1 VAL 561 72.072 6.139 13.872 1.00 22.91 ATOM 2904 CG2 VAL.- 561 70.887 5.312 11.870 1.00 22.38 ATOM 2905 C VAL 561 72.731 2.848 11.945 1.00 27.99 ATOM 2906 0 VAL 561 73.052 2.5-90 10.783 1.00 27.88 SSSD/55034. V01 WO 98/07835 WO 9807835PCT/US97/14885 435

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

2907 N GLU 2908 CA GLU 2909 CB GLU 2910 CG GLU 2911 CD GLU 2912 OE1 GLU 2913 0E2 GLU 2914 C GLU 2915 0 GLU 2916 N TYR 2917 CA TYR 2918 CB TYR 2919 CG TYR 2920 CD1 TYR 2921 CEl TYR 2922 CD2 TYR 2923 CE2 TYR 2924 CZ TYR 2925 OH TYR 2926 C TYR 2927 0 TYR 2928 N ALA 2929 CA ALA 2930 CB ALA 2931 C ALA 2932 0 ALA 2933 N SER 2934 CA SER 2935 CB SER 2936 OG SER 2937 C SER 2938 0 SER 2939 N LYS 2940 CA LYS 2941 CB LYS 2942 CG LYS 2943 CD LYS 2944 CE LYS 2945 NZ LYS 2946 C LYS 2947 0 LYS 2948 N GLY 2949 CA GLY 2950 C GLY 2951 0 GLY 2952 N ASN 2953 CA ASN 2954 CB ASN 2955 CG ASN 2956 OD1 ASN 2957 ND2 ASN 2958 C ASN 562 562 562 562 562 562 562 562 562 563 563 563 563 563 563 563 563 563 563 563 563 564 564 564 564 564 565 565 565 565 565 565 566 566 566 566 566 566 566 566 566 567 567 567 567 568 568 568 568 568 568 568 72.143 1.969 12.754 1.00 27.38 71.759 0.616 12.347 1.00 28.01 71.246 -0.161 13.555 1.00 25.37 72.322 -0.487 14.570 1.00 29.22 71.785. -1.190 15.796 1.00 30.94 72.440 -2.135 16.271 1.00 34.82 70.716 -0.795 16.297 1.00 32.77 70.695 0.610 11.266 1.00 29.83 69.822 1.452 11.274 1.00 34.69 70.7.55 -0.364 10.362 1.00 31.35 G9.806 -0.527 9.255 1.00 33.79 70.586 -0.987 8.022 1.00 32.37 69.759 -1.232 6.778 1.00 31.70 68.858 -0.277 6.319 1.00 35.00 68.101 -0.490 5.161 1.00 35.62 69.888 -2.416 6.053 1.00 31.64 69.138 -2.644 4.894 1.00 32.96 68.242 -1.674 4.462 1.00 36.20 67.494 -1.906 3.340 1.00 39.54 68.668 -1.527 9.593 1.00 37.26 68.915. -2.566 10.212 1.00 38.86 67.428 -1.180 9.220 1.00 39.09 66.256 -2.027 9.467 1.00 37.64 65.290 -1.317 10.366 1.00 41.34 65.600 -2.337 64.700 -1.628 66.033 -3.432 65.567 -3.867 66.302 -5.133 66.174 -6.084 64.095 -4.087 63.657 -4.155 63.322 -4.2 48 61.893 -4.462 61.455 -5.681 62.003 -6.977 61.929 -8.148 62.582 -9.362 62.706 -10.465 61.029 -3.234 59.815 -3.337 61.663 -2.061 60.956 -0.808 60.306 -0.640 60.727 -1.265 59.296 0.218 58.63-5 0.447 8.124 1.00 39.33 7.661 1.00 41.28 7.515 1.00 40.21 6.202 1.00 40.22 5.808 1.00 38.50 6.847 1.00 37.66 5.987 1.00 42.30 4.840 1.00 46.83 7.054 1.00 42.84 6.883 1.00 41.84 7.684 1.00 44.88 7.088 1.00 48.86 8.040 1.00 51.41 7.426 1.00 53.89 8.417 1.00 59.37 7.143 1.00 41.89 7.341 1.00 43.68 7.100 1.00 39.50 7.291 1.00 36.69 8.644 1.00 35.86 9.614 1.00 35.90 8.711 1.00 35.45 9.966 1.00 38.10 57.961 1.839 10.029 1.00 40.77 56.701 1.962 9.163 1.00 43.52 55.718 1.241 9.338. 1.00 44.01 56.710 2.932 8.263 1.00 45.39 57.610 -0.657 10.269 1.00 38.91 SSSD/55034. V01l WO 98/07835 PCT/US97/14885 436 ATOM 2959 0 ASN 568 57.218 -1.420 9.384 1.00 39.95 ATOM 2960 N LEU 569 57.204 -0.717 11.534 1.00 38.93 ATOM 2961 CA LEU 569 56.256 -1.692 12.047 1.00 36.49 ATOM 2962 CB LEU 569 56.126 -1.507 13.555 1.00 36.53 ATOM 2963 CG LEU 569 55.150 -2.417 14.290 1.00 35.27 ATOM 2964 CD1 LEU 569 55.550 -3.865 14.047 1.00 31.86 ATOM 2965 CD2 LEU 569 55.148 -2.067 15.768 1.00 35.00 ATOM 2966 C LEU 569 54.875 -1.622 11.391 1.00 37.19 ATOM 2967 0 LEU 569 54.231 -2.654 11.175 1.00 38.40 ATOM 2968 N ARG 570 54.386 -0.420 11.101 1.00 36.63 ATOM 2969 CA ARG 570 53.068 -0.294 10.485 1.00 36.68 ATOM 2970 CB ARG 570 52.739 1.168 10.188 1.00 37.76 ATOM 2971 CG ARG 570 51.339 1.361 9.623 1.00 46.41 ATOM 2972 CD ARG 570 51.210 2.680 8.889 1.00 56.33 ATOM 2973 NE ARG 570 52.162 2.785 7.779 1.00 63.05 ATOM 2974 CZ ARG 570 53.010 3.798 7.603 1.00 66.33 ATOM 2975 NH1 ARG 570 53.032 4.809 8.468 1.00 65.15 ATOM 2976 NH2 ARG 570 53.853 3.786 6.580 1.00 66.56 ATOM 2977 C ARG 570 53.046 -1.094 9.193 1.00 35.55 ATOM 2978 0 ARG 570 52.248 -2.015 9.018 1.00 35.33 ATOM 2979 N GLU 571 53.978 -0.758 8.320 1.00 37.20 ATOM 2980 CA GLU 571 54.128 -1.401 7.030 1.00 38.32 ATOM 2981 CB GLU 571 55.247 -0.695 6.261 1.00 40.15 ATOM 2982 CG GLU 571 55.001 0.803 6.152 1.00 49.09 ATOM 2983 CD GLU 571 56.118 1.557 5.442 1.00 58.16 ATOM 2984 OE1 GLU 571 57.279 1.073 5.421 1.00 61.41 ATOM 2985 OE2 GLU 571 55.824 2.660 4.914 1.00 61.27 ATOM 2986 C GLU 571 54.406 -2.906 7.170 1.00 36.74 ATOM 2987 0 GLU 571 53.863 -3.721 6.410 1.00 35.74 ATOM 2988 N TYR 572 55.241 -3.266 8.141 1.00 35.13 ATOM 2989 CA TYR 572 55.591 -4.665 8.401 1.00 37.12 ATOM 2990 CB TYR 572 56.591 -4.736 9.560 1.00 34.39 ATOM 2991 CG TYR 572 56.984 -6.128 10.029 1.00 33.48 ATOM 2992 CD1 TYR 572 57.980 -6.869 9.367 1.00 29.76 ATOM 2993 CEl TYR 572 58.394 -8.119 9.845 1.00 27.14 ATOM 2994 CD2 TYR 572 56.406 -6.681 11.183 1.00 32.40 ATOM 2995 CE2 TYR 572 56.814 -7.931 11.669 1.00 30.83 ATOM '2996 CZ TYR 572 .57.807 -8.641 10.995 1.00 33.73 ATOM 2997 OH TYR 572 58.201 -9.872 11.480 1.00 37.16 ATOM 2998 C TYR 572 54.330 -5.468 8.729 1.00 38.92 ATOM 2999 0 TYR 572 54.108 -6.553 8.183 1.00 39.22 ATOM 3000 N LEU 573 53.507 -4.922 9.618 1.00 38.41 ATOM 3001 CA LEU 573 52.261 -5.563 10.016 1.00 37_.56 ATOM 3002 .CB LEU 573 51.573 -4.711 11.084 1.00 36.44 ATOM 3003 CG LEU 573 52.270 -4.617 12.437 1.00 33.91 ATOM 3004 CD1 LEU 573 51.555 -3.626 13.372 1.00 31.60 ATOM 3005 CD2 LEU 573 52.313 -6.024 13.003 1.0 30.78 ATOM 3006 C LEU 573 51.315 -5.738 8.826 1.00 37.51 ATOM 3007 0 LEU 573 50.847 -6.836 8.539 1.00 36.70 ATOM 3008 N GLN 574 51.045 -4.643 8.125 1.00 40.10 ATOM 3009 CA GLN 574 50.141 -4.678 6.986 1.00 41.10 ATOM 3010 CB GLN 574 49.938 -3.272 6.439 1.00 40.12 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 437

ATOM

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3011 3012 3013 3014 3015 3016 3017 3018 3019 3020 3021 3022 3023 3024 3025 3026 3027 3028 3029 3030 3031 3032 3033 3034 3035 3036 3037 3038 3039 3040 3041 3042 3043 3044 3045 3046 3047 3048 3049 3050 3051 3052 3053 3054 3055 3056 3057 3058 3059 3060 3061 3062

CG

CD

OE1 NE2

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD

NE

CZ

NHII

NH2

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

0

N

CA

CB

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

OG

C

0

GLN

GLN

GLN

GLN

GLN

GLN

ALA

ALA

ALA

ALA

ALA

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

GLN

GLN

GLN

GLN

GLN

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

SER

SER

SER

SER

SER

SER

574 574 574 574 574 574 575 575 575 575 575 576 576 576 576 576 576 576 576 576 576 576 577 577 577 577 577 577 577 577 577 577 577 594 594 594 594 594 595 595 595 595 595 595 595 595 596 596 596 596 596 596 49.171 49.079 49.679 48.357 50.546 49.699 51.840 52.317 53.745 52.197 52.527 51.757 51.624 52.679 54.095 55.156 56.514 56. 981 56.219 58.215 50.232 50 .043 49.258 47.877 46 .994 47.101 46.329 46.213 45 .584 45.020 45.481 47.298 47.246 53.349 52 .144 51.259 52 .535 53 .192 52.159 52.489 52.599 53.532 53.375 54.967 51.469 50.314 51.927 51.100 51.883 52.806 50.796 51.492 3-81 -0.987 -0.652 143 -5.638 -6.323 -5.735 -6.628 301 096 -8.975 -8.359 726 -9.988 958 -9.943 -9.870 -8.856 -7.803 902 -10. 014 -10. 943 216 401 -8.239 -6.995 831 -4.735 -3.587 -3.368 -2.676 -10.740 -11. 031 -13.948 -14. 067 -15.220 -14.284 -15.264 -13.335 -13.422 -12.008 -11. 147 -9.692 -11.598 -14.237 -14.359 -14. 845 -15.642 -16. 841 -16.435 -14.756 -13.767 7.374 6 .852 5.835 7 .558 5.875 5.309 5.601 4 .555 4 .218 4.947 4.165 6 .168 6.641 7 .716 7.161 8.257 7 .695 6 .969 6 .703 6.497 7 .180 7 .970 6 .753 7.196 6.723 7.581 6.999 7.957 7.725 6.549 8.686 6.743 5.550 7.960 8.772 8.277 10.233 10.580 11.074 12.480 13.056 12.203 12.533 12.382 13.251 12.834 14.341 15.229 15.736 16.737 16.423 16.649 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 40.77 43.90 46.93 46.85 41.31 44.33 41.46 39.80 40.58 40.86 41.50 42.47 42.68 41.04 42.73 45.59 43.89 43.35 44.85 41.84 44.86 46.08 46.72 47.61 46.35 47.71 49.15 53.23 54.38 56.41 58.13 47.36 48.52 68.05 66.75 66.87 64.71 64.86 61.14 58.19 56.33 57.36 59.51 56.98 56.25 56.60 53.07 48.64 46.41 46.50 48.95 49.39 SSSD/55034. VOl WO 98/07835 PCTIIJS97/14885' 438 ATOM 3063 N SER 597 49.833 -15.163 17.242 1.00 50.27 ATOM 3064 CA SER 597 49.469 -14.387 18.424 1.00 51.93 ATOM- 3065 CB SER 597 48.391 -15.123 19.225 1.00 52.03 ATOM 3066 OG SER 597 47.540 -15.854 18.365 1.00 52.95 ATOM 3067 C SER 597 50.685 -14.143 19.314 1.00 52.72 ATOM 3068 0 SER 597 50.792 -13.093 19.943 1.00 55.04 ATOM 3069 N LYS 598 51.613 -15.100 19.344 1.00 53.55 ATOM 3070 CA LYS 598 52.824 -14.961 20.159 1.00 53.84 ATOM 3071 CB LYS 598 53.566 -1G.295 20.248 1.00 54.25 ATOM 3072 CG LYS 598 54.376 -16.457 21.524 1.00 57.30 ATOM 3073 CD LYS 598 55.057 -17.824 21.570 1.00 58.11 ATOM 3074 CE LYS 598 55.780 -18.055 22.893 1.00 59.00 ATOM 3075 NZ LYS 598 54.840 -18.169 24.043 1.00 57.85 ATOM 3076 C LYS 598 53.728 -13.909 19.527 1.00 52.48 ATOM 3077 0 LYS 598 54.273 -13.052 20.227 1.00 52.72 ATOM 3078 N ASP 599 53.842 -13.960 18.198 1.00 50.65 ATOM 3079 CA ASP 599 54.657 -13.021 17.435 1.00 48.52 ATOM 3080 CB ASP 599 54.568 -13.294 15.929 1.00 46.71 ATOM 3081 CG ASP 599 55.233 -14.607 15.515 1.00 48.88 ATOM 3082 ODi ASP 599 55.898 -15.260 16.344 1.00 53.76 ATOM 3083 0D2 ASP 599 55.100 -14.986 14.330 1.00 46.70 ATOM 3084 C ASP 599 54.173 -11.598 17.706 1.00 48.66 ATOM 3085 0 ASP 599 54.976 -10.703 17.960 1.00 52.86 ATOM 3086 N LEU 600 52.852 -11.406 17.684 1.00 44.53 ATOM 3087 CA LEU 600 52.272 -10.099 17.938 1.00 41.06 ATOM 3088 CB LEU 600 50.774 -10.100 17.632 1.00 39.23 ATOM 3089 CG LEU 600 50.354 -10.374 16.178 1.00 36.50 ATOM 3090 CD1 LEU 600 48.850 -10.272 16.063 1.00 34.99 ATOM 3091 CD2 LEU 600 51.000 -9.393 15.232 1.00 33.72 ATOM 3092 C LEU 600 52.543 -9.633 19.369 1.00 40.96 ATOM 3093 0 LEU 600 52.890 -8.467 19.580 1.00 42.04 ATOM 3094 N VAL 601 52.417 -10.533 20.348 1.00 41.02 ATOM 3095 CA VAL 601 52.685 -10.156 21.744 1.00 43.57 ATOM 3096 CB VAL. 601 52.236 -11.229 22.791 1.00 43.60 ATOM 3097 CG1 VAL 601 52.254 -10.607 24.205 1.00 43.44 ATOM 3098 CG2 VAL 601 50.848 -11.761 22.464 1.00 42.33 ATOM 3099 C VAL 601 54.192 -9.904 21.901 1.00 42.85 ATOM 3100 0 VAL 601 54.611 -8.989 22.611 1.00 44.28 ATOM 3101 N SER 602 54.986 -10.685 21.175 1.00 41.33 ATOM 3102 CA SER 602 56.442 -10.581 21.180 1.00 41.43 ATOM 3103 CB SER 602 57.014 -11.648 *20.245 1.00 40.94 ATOM 3104 OG SER 602 58.434 -11.612 20.184 1.00 46.26 ATOM 3105 C SER 602 56.859 -9.176 20.722 1.00 40.58 ATOM 3106 0 SER 602 57.629 -8.497 21.403 1.00 42.32 ATOM 3107 N CYS 603 56.318 -8.737 19.589 1.00 38.34 ATOM 3108 CA CYS 603 56.580 -7.409 19.051 1.00V37.28 ATOM 3109 CE CYS 603 55.715 -7.170 17.815 1.00 38.09 ATOM 3110 SG CYS -603 55.735 -5.497 17.170 0.50 42.18 ATOM 3111 C CYS 603 56.282 -6.337 20.105 1.00 35.81 ATOM 3112 0 CYS 603 57.038 -5.380 20.241 1.00 37.87 ATOM 3113 N' ALA 604 55.198 -6.508 20.858 1.00 33.96 ATOM 3114 CA ALA 604 54.804 -5.572 21.911 1.00 34.97 SSSD/55034. V01 WO 98/07835 PCTIU997/14885 439

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3115 3116 3117 3118 3119 3120 3121 3122 3123 3124 3125 3126 3127 3128 3129 3130 3131 3132 3133 3134 3135 3136 3137 3138 3139 3140 3141 3142 3143 3144 3145 3146 3147 3148 3149 3150 3151 3152 3153 3154 3155 3156 3157 3158 3159 3160 3161 3162 3163 3164 3165 3166 CB ALA C ALA 0 ALA N TYR CA TYR CB TYR CG TYR CD1 TYR CEl TYR CD2 TYR CE2 TYR CZ TYR OH TYR C TYR O TYR N GLN CA GLN CE GLN CG GLN CD GLN QEl GLN NE2 GLN C GLN 0 GLN N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL O VAL N ALA CA ALA CB ALA C ALA O ALA N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NH1 ARG NH2 ARG C ARG 0 ARG N GLY CA GLY C GLY 0 GLY N MET 604 604 604 605 605 605 605 605 605 605 605 605 605 605 605 666 606 606 606 606 606 606 606 606 607 607 607 607 607 607 607 608 608 608 608 608 609 609 609 609 609 609 609 609 609 609 609 610 610 610 610 611 53.393 55.791 56.085 56.281 57.254 57.533 58.635 58.498 59.52 0 59.812 60. 848 60.692 61.707 58.549 59.053 59.053 60.276 60.594 61.105 61. 33 9 62.274 60.471 60 .210 61.206 59.040 58.839 57.489 57.219 57.535 58.868 59.46 9 58.224 58.187 57.242 59. 585 59.950 60.377 61.733 62.394 61. 672 62.636 63.319 64.441 65.012 64.954 62.581 63.144 62.624 63.395 63.010 63.857 61. 712 -5 .917 -5.610 -4.585 -6.807 -7.005 -8.498 -8.806 -8.509 -8.809 -9.407 711 -9.409 704 -6 .267 -5.485 -6.501 872 -6.415 -7.851 -8.388 -7.988 -9.285 -4 .335 -3.660 -3 .798 -2 .35-0 -1.982 -0.488 -2.416 -1.766 -0.705 -2 .451 -2 .001 -2 .874 -2 .019 -1 .144 -3 .013 -3 .120 -4 .405 -5.647 -6 .791 -6 .838 -7.510 -8 .179 -7.569 -1 .918 -1 .221 -1 .650 -0 .534 0 .730 1 .507 0 .907 22.409 23 .081 23.704 23.385 24 .461 24.643 25.622 26.974 27.893 25.198 26.105 27.454 28.348 24.123 24.937 22.908 22.398 21. 002 21.005 19.608 18.907 19.182 22.355 22.632 22.006 21.944 21. 221 21.298 19.742 23.3,64 23.591 24.311 25.694 26.494 26.309 27.094 25.932 26.440 25. 953 26.373 26.448 27.733 27.955 26.964 29. 186 26.024 26.885 24.717 24.199 24.930 25.345 25.131 1.00 34.13 1.00 36.68 1.00 36.-78 1.00 37.68 1.00 38.38 1.00 37.62 1.00 36.56 1.00 39.05 1.00 41.37 1.00 38.09 1.00 38.55 1.00 40.73 1.00 41.44 1.00 38.44 1.00 40.78 1.00 36.07 1.00 35.28 1.00 34.24 1.00 32.26 1.00 30.17 1.00 31.89 1.00 30.68 1.00 36.39 1.00 39.59 1.00 32.78 1.00 30.29 1.00 28.48 1.00 28.68 1.00 22.96 1.00 30.21 1.00 31.24 1.00 27.88 1.00 27.66 1.00 26.42 1.00 29.04 1.00 27.53 1.00 28.91 1.00 31.64 1.00 33.78 1.00 38.53 1.00 41.78 1.00 47.58 1.00 51.52 1.00 50.61 1.00 54.36 1.00 33.26 1.00 34.50 1.00 30.25 1.00 25.40 1.00 24.12 1.00 24.74 1.00 25.81 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 440 ATOM 3167 CA MET 611 61.192 2.062 *25.843 1.00 26.95 ATOM 3168 CB MET 611 59.672 2.121 25.702 1.00 24.60 ATOM 3169 CG MET 611 59.215 2.462 24.303 1.00 24.10 ATOM 3170 SD MET 611 59.972 4.035 23.821 1.00 26.77 ATOM 3171 CE MET 611 59.546 5.090 25.184 1.00 19.21 ATOM 3172 C MET 611 61.600 2.071 27.314 1.00 27.68 ATOM 3173 0 MET 611 61.891 3.128 27.865 1.00 28.22 ATOM 3174 N GLU 612 61.562 0.908 27.967 1.00 31.07 ATOM 3175 CA GLU 612 61.955 0.791 29.382 1.00 35.25 ATOM 3176 CB GLU 612 61.809 -0.659 29.872 1.00 34.95 ATOM 3177 CG GLU 612 62.383 -0.937 31.257 1.00 31.64 ATOM 3178 CD GLU 612 62.392 -2.422 31.631 1.00 32.34 ATOM 3179 OE1 GLU 612 62.599 -3.275 30.738 1.00 30.09 ATOM 3180 0E2 GLU 612 62.226 -2.737 32.831 1.00 33.90 ATOM 3181 C GLU 612 63.409 .1.252 29.468 1.00 37.14 ATOM 3182 0 GLU 612 63.791 1.995 30.390 1.00 35.60 ATOM 3183 N TYR 613 64.196 0.868 28.457 1.00 37.89 ATOM 3184 CA TYR 613 65.601 1.247 28.392 1.00 36.68 ATOM 3185 CB TYR 613 66.328 0.531 27.246 1.00 34.23 ATOM 3186 CG TYR 613 67.801 0.888 27.175 1.00 36.59 ATOM 3187 CD1 TYR 613 68.734 0.263 28.005 1.00 36.83 ATOM 3188 CEl TYR 613 70.090 0.649 28.013 1.00 34.51 ATOM 3189 CD2 TYR 613 68.252 1.909 26.339 1.00 35.28 ATOM 3190 CE2 TYR 613 69.596 2.306 26.340 1.00 34.09 ATOM 3191 CZ TYR 613 70.512 1.674 27.181 1.00 35.91 ATOM 3192 OH TYR 613 71.826 2.089 27.212 1.00 29.78 ATOM 3193 C TYR 613 65.724 2.760 28.233 1.00 37.58 ATOM 3194 0 TYR 613 66.362 3.414 29.056 1.00 39.84 ATOM 3195 N LEU 614 65.081 3.326 27.214 1.00 35.53 ATOM 3196 CA LEU 614 65.156 4.766 26.988 1.00 34.58, ATOM 3197 CB LEU 614 64.314 5.157 25.781 1.00 31.88 ATOM 3198 CG LEU 614 64.760 4.601 24.429 1.00 29.62 ATOM 3199 CD1 LEU 614 63.783 5.016 23.346 1.00 29.19 ATOM 3200 CD2 LEU 614 66.134. 5.133 24.111 1.00 32.49 ATOM 3201 C LEU 614 64.698 5.538 28.218 1.00 36.38 ATOM 3202 0 LEU 614 65.325 6.525 28.618 1.00 33.81 ATOM 3203 N ALA 615 63.608 5.076 28.821 1.00 38.08 ATOM 3204 CA ALA 615 63.066 5.711 30.018 1.00 41.01 ATOM 3205 CB ALA 615 61.767 5.018 30.444 1.00 42.33 ATOM 3206 C ALA 615 64.099 5.683 31.147 1.00 40.47 ATOM 3207 0 AL~A 615 64.291 6.690 31.831 1.00 41.28 ATOM 3208 N SER 616 64.788 4.553 31.307 1.00 38.78 ATOM 3209 CA SER 616 65.806 4.441 32.347 1.00 40.97 ATOM 3210 CB3 SER 616 66.354 3.009 32.454 1.00 37.82 ATOM 3211 OG SER 616 67.172 2.651 31.359 1.00 34.73 ATOM 3212 C SER 616 66.941 5.416 32.061 1.00 42.68 ATOM 3213 0 SER 616 67.714 5.769 32.957 1.00 45.78 ATOM 3214 N LYS 617 67.015 -5.869 30.81 5 1.00 40.92 ATOM 3215 CA LYS 617 68.025 6.816 30.380 1.00 38.04 ATOM 3216 CB LYS 617 68.541 6.411 29.003 1.00 38.25 ATOM 3217 CG LYS 617 69.293 5.111 29.021 1.00 36.40 ATOM 3218 CD LYS 617 70.421 5.221 29.992 1.00 38.14 SSSD/55034. V01 WO 98/07835 WO 9807835PCT[US97/14885 441

ATOM

ATOM

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ATOM

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ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

3219 3220 3221 3222 3223 3224 3225 3226 3227 3228 3229 3230 3231 3232 3233 3234 3235 3236 3237 3238 3239 3240 3241 3242 3243 3244 3245 3246 3247 3248 3249 3250 3251 3252 3253 3254 3255 3256 3257 3258 3259 3260 3261 3262 3263 3264 3265 3266 3267 3268 3269 3270

CE

NZ

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CA

CB

SG

C

0

N

CA

CE

CG2 CG1 CD1

C

0

N

CA

CB

CG

CD2 ND1 CEl NE2

C

0

N

CA

CB

CG

GD

NE

CZ

NH1 NH2

C

0

N

GA

CB

.G

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

CYS

CYS

CYS

CYS

CYS

CYS

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ASP

ASP

ASP

ASP

617 617 617 617 618 618 618 618 618 618 618 618 618 619 619 619 619 619 619 620 620 620 620 620 620 620 620 621 621 621 621 621 621 621 621 621 621 622 622 622 622 622 622 622 622 622 622 622 623 623 623 623 71..215 72 530 67.475 68 072 66 .323 65 .674 66 .653 67 .340 66 .377 67 .070 66 105 65 .167 64 856 65 .058 64 .603 65 .351 65 .006 63 .108 62 .510 62 .515 61 .091 60.435 58 955 60 .578 60 .065 61 034 61.481 60 .472 60.354 59 .933 60 .076 60 .663 59 .528 59 .774 60 .456 59 .365 59 .555 58 .256 57 .225 57 .783 58 .211 58 .799 59 .249 60 .409 61.249 60 .711 56 .447 55 .438 S6 .923 56 197 S6 .628 55 .727 3. 941 4.210 8.242 9.133 8.444 9. 743 10.780 10.392 10.361 9. 945 10.039 10.222 11.396 9.308 9.666 8.843 9.223 9.546 8.472 10.679 10.763 11-966 12.031 11.848 13.046 10.972 11.993 9. 990 9.970 8.552 8.288 7.262 9.106 8.596 7.473 10. 992 11.481 11. 216 12.169 13.582 14.156 15.551 16.043 15.707 14.883 16.158 11.806 12.430 10. 818 10.400 11.171 10.869 30.086 30.751 30.350 29.744 30.985 31.067 31.632 32 .938 34 .092 35.373 36.510 29.706 29.535 28 .751 27.412 26.365 24 .650 27.194 27.373 26.827 26 .528 27.212 26.860 28.727 29. 463 25.018 24.512 24 .318 22.864 22.420 20.951 20.286 19.979 18 .783 18 .942 22.320 21.220 23.028 22.580 22.462 23 .778 23.635 24.930 25.499 24.877 26.714 21.297 20.999 20.537 19.. 335 18.081 16 .863 1.00 38.43 1.00 43.07 1.00 38 .42 1.00 41.37 1.00 37.25 1.00 36.75 1.00 43.27 1.00 51.59 1.00 61.24 1.00 67.83 1.00 75.22 1.00 36.61 1.00 35.94 1.00 36.26 1.00 33.41 1.00 32.17 1.00 26.92 1.00 32.29 1.00 29.13 1.00.31.60 1.00 31.21 1.00 29.57 1.00 31.49 1.00 27.85 1.00 26.50 1.00 32.18 1.00 33.18 1.00 31.93 1.00 32.59 1.00 29.51 1.00 27.45 1.00 25.84 1.00 25.20 1.00 25.07 1.00 23.24 1.00 35.31 1.00 39.24 1.00 36.50 1.00 35.78 1.00 32.55 1.00 30.54 .0.50 27.28 0.50 24.53 0.50 27.85 0.50 27.61 0.50 25.34 1.00 35.76 1.00 36.61 1.00 34.69 00 34.09 1.00 34.77 1.00 43.51 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 442

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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ATOM

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ATOM

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ATOM

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ATOM

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ATOM

ATOM

ATOM

ATOM

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ATOM

3271 3272 3273 3274 3275 3276 3277 3278 3279 3280 3281 3282 3283 3284 3285 3286 3287 3288 3289 3290 3291 3292 3293 3294 3295 3296 3297 3298 3299 3300 3301 3302 3303 3304 3305 3306 3307 3308 3309 3310 3311 3312 3313 3314 3315 3316 3317 3318 3319 3320 3321 3322 ODi ASP 0D2 ASP C ASP O ASP N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LET) O LEU N ALA CA ALA CB ALA C ALA O ALA N ALA CA ALA CB ALA C ALA O ALA N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NI1 ARG NH2 ARG C ARG O ARG N ASN CA ASN CB ASN CG ASN 001 ASN ND2 ASN C ASN O ASN N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL 0- VAL N LET) CA .LET) CBR LEU CG LET) 623 623 623 623 624 624 624 624 624 624 624 624 625 625 625 625 625 626 626 626 626 626 627 627 627 627 627 627 627 627 627 627 627 628 628 628 628 628 628 628 628 629 629 629 629 629 629 629 630 630 630 630 56.213 54.538 56.321 56.635 56.081 56.152 56. 133 55.983 57.108 56.001 54. 954 53.805 55.224 54.170 53.707 54.800 56.022 53 .982 54.499 *53.350 55.366 56.329 55.022 55.777 55.134 55.046 54.552 54.108 52.867 51. 942 52 .55 57.209 58.137 57.385 58.689 58. 578 58.383 58.992 57. 522 59.437 60.378 58.998 59.621 58.589 59.169 58.158 60. 077 59.284 61.352 61.862 63.105 62.856 10. 992 10.509 8.903 8.435 8.135 6 .689 6.029 4 .510 3.809 4.088 6.238 6. 564 5.561 5 .066 6.170 3.-948 3. 841 3.107 1. 993 1. 155 2.504 1.859 3.680 4.301 5.637 6.672 8.037 8.878 8.889 8.114 9.634 4.549 4.468 4.804 5.092 6.226 7.571 7.865 8.391 3. 903 4. 062 2. 712 1.450 0.522 -0.883 1.121 0.805 .0.679 0.469 158 0.577 15. 714 17.032 19.115 18 .025 20 .164 20.030 21 .403 21.460 20.700 22.912 19.187 19. 505 18 .076 17.192 16 .289 16. 389 16 .355 15 .758 14. 956 14 .401 13 .831 13.454 13.314 12.246 11. 837 12 .961 12.477 13 .590 14. 059 13.515 15. 108 12. 711 11. 911 14 .010 14 .596 15 .611 14. 941 13. 924 15.503 15.185 15. 972 14.802 15.224 15. 906 16.089 17.244 13 .918 12.978 13 .809 12-.601 12 .122 1.00 47.45 1.00 47.51 1.00 32.51 1.00 31.80 1.00 31.80 1.00 31.07 1.00 28.11 1.00 27.88 1.00 23.96 1.00 29.50 1.00 32.04 1.00 36.02 1.00 28.91 1.00 25.66 1.00 23.37 1.00 27.71 1.00 29.77 1.00 29.46 1.00 28.16 1.00 28.02 1.00 26.78 1.00 26.69 1.00 26.09 1.00 26.78 1.00 27.01 1-.00 29.34 1.00 34.26 1.00 36.96 1.00 40.84 1.00 42.56 1.00 45.20 1.00 29.11 1.00 30.39 1.00 30.37 1.00 27.02 00 24.35 1.00 25.95 1.00 32.01 1.00 24.34 1.00 26.74 1.00 28.49 1.00 27.34 1.00 24.94 1.00 22.20 1.00 18.03 1.00 18.34 1.00 26.84 1.00 26.50 1.00 27.66 1.00 30.14 1.00 28.00 2.086 12.027 1.00 26.06 SSSD/55034. V01 WO 98/07835 PCT1US97/14885 443

ATOM

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ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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3323 3324 3325 3326 3327 3328 3329 3330 3331 333'2 3333 3334 3335 3336 3337 3338 3339 3340 3341 3342 3343 3344 3345 3346 3347 3348 3349 3350 3351 3352 3353 3354 3355 3356 3357 3358 33.59 3360 3361 3362 3363 3364 3365 3366 3367 3368 3369 3370 3371 3372 3373 3374 CD1 LEU CD2 LEU C -LEU O LEU N VAL CA VAL CB VAL CG1 VAL CG2 VAL C VAL 0 VAL N THR CA THR CB THR OGi THR CG2 THR C THR 0 TR N GLU CA GLU CB GLU CG GLU CD GLU OE1 GLU 0E2 GLU C GLU O GLU N ASP CA ASP CB ASP CG ASP ODi ASP 0D2 ASP C ASP 0 ASP N ASN CA ASN CB ASN CG ASN ODi ASN ND2 ASN C ASN 0 ASN N VAL CA VAL CB VAL CG1 VAL CG2. VAL C VA.L 0 VAL N MET CA MET 630 630 630 630 631 631 631 631 631 631 631 632 632 632 632 632 632 632 633 633 633 633 633 633 633 633 633 634 634 634 634 634 634 634 634 635 635 635 635 635 635 635 635 636 636 636 636 636 636 Z636 637 637 64.150 61.880 62.145 62.437 61.991 62.195 60.915 61.071 59.724 63.371 63.428 64.319 65.511 66.675 66.368 66.928 65.283 64.238 66.282 66.219 67.501 67.4 96 66.599 65.933 66.566 66.0.11 65.637 66.278 66.085 67.316 68.570 68.593 69.546 64.850 64.729 63.940 62.690 61.750 61.409 60.750 61.876 62.833 62.028 63.849 64.071 65.584 65.839 66.184 63.434 63.657 62.600 61.940 2 .831 2 .381 -1.627 -1 .982 -2.478 -3 .928 -4.700 -6.208 -4.161 -4.415 -4.171 -5 .098 -5.599 -5 .820 -6.903 -4 .561 -6.893 515 -7.307 -8.540 -8.689 -9 .791 -9 .506 -8.452 -10.369 774 -10.834 -9 .648 -10.774 -10.995 -11.399 -12 .499 -10 .608 -10.549 -11 .138 -9 .697 -9.367 -10.583 -11.116 -10.453 -12 .314 -8.763 -9.045 -7 .927 -7 .291 -7 .162 6.347 -8.535 -5.908 5 .131 -5.625 -4.331 11.832 10.901 12.889 14 .029 11.873 12.006 11.584 11.842 12 .332 11.161 9. 954 11.797 11.096 12. 066 12.955 12.867 10.331 10.466 9.556 8 .768 7. 942 6.864 5.647 5. 567 4 .747 9.648 9.156 10.944 11.843 12.724 11.929 11.328 11.918 12.708 13.776 12.235 12.915 12.972 11.597 10.800 11.305 14 .308 15.189 14.503 15.797 16.083 17.354 16.226 15.782 14.854 16.773 16.887 1.00 23.44 1.00 27.72 1.00 32.90 1.00 33.06 1.00 34.83 1.00 33.02 1.00 30.92 1.00 27.66 1.00 24.46 1.00 35.77 1.00 37.57 1.00 37.96 1.00 39.06 1.00 35.55 1.00 35.76 1.00 35.06 1.00 40.66 1.00 41.79 1.00 43.40 1.00 45.33 1.00 48.67 1.00 54.70 1.00 58.16 1.00 60.68 1.00 60.14 1.00 46.02 1.00 46.75 1.00 46.4.5 1.00 46.14 1.00 52.89 1.00 59.65 1.00 59.91 1.00 62.29 1.00 45.75 1.00 46.38 1.00 45.92 1.00 44.36 1.00 46. 62 1.00 47.56 1.00 50.54 1.00 47.75 1.00 42.78 1.00 44.56 1.00 41.03 1.00 36.87 1.00 35.99 1.00 34.01 1.00 33.65 1.00 34.79 1.00 36.58 1.00 32.04 1.00 31.14 SSSD/55034. V0l WO 98/07835 PCT/US97/14885 444

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3375 CB MET 3376 CG MET 3377 SD MET 3378 CE MET 3379 C MET 3380 0 MET 3381 N LYS 3382 CA LYS 3383 CB LYS 3384 CG LYS 3385 CD LYS 3386 CE LYS 3387 NZ LYS 3388 C LYS 3389 0 LYS 3390 N -ILE 3391 CA ILE 3392 CB ILE 3393 CG2 ILE 3394 CGl ILE 3395 CD1 ILE 3396 C ILE 3397 0 ILE 3398 N ALA 3399 CA ALA 3400 CB ALA 3401 C ALA 3402 0 ALA 3403 N ASP 3404 CA ASP 3405 CB ASP 3406 CG ASP 3407 ODi ASP 3408 0D2 ASP 3409 C ASP 3410 0 ASP 3411 N PE 3412 CA PE 3413 CE PE 3414 CG PE 3415 CD1 PE 3416 CD2 PE 3417 CEl PE 3418 CE2 PE 3419 CZ PE 3420 C PE 3421 .0 PE 3422 N GLY 3423 CA GLY 3424 C GLY 3425 0 GLY 3426 N LEU 637 637 637 637 637 637 638 638 638 638 638 638 638 638 638 639 639 639 639 639 639 639 639 640 640 640 640 640 641- 641 641 641 641 641 641 641 642 642 642 642 642 642 642 642 642 642 642 643 643 *64 3 643 644 60.734 59. 702 58 .835 59.122 62.935 63 .525 63 .044 63. 977 65.214 66.145 67.307 68.369 68 .931 63 .367 62.987 63.277 62.734 62.699 61. 916 62. 127 60.680 63. 656 64.884 63.073 63.857 6.683 63.380 62.307 64.174 63.863 62.662 63. 024 64.149 62.192 63. 661 63. 012 64.265 64.155 64.447 65.806 66.930 65. 962 68.179 67.205 68.323 65.069 64.920 66..000 :'66.'934 -66. 728 :-67.581 65.609 -4.427 -5.501 -5.257 864 -3.342 -3.612 -2.167 133 150 -2.305 -2.274 -3 .242 -2.895 0.260 0. 740 0.905 2 .256 2 .789 4 .094 1.740 1.392 3 .198 3 .161 4 .072 5 .037 4 .777 6.449 6.608 7.456 8.874 9 .310 9.555 9.170 10.144 9.311 10.323 8 .567 8 .860 7.597 7.008 7.476 5 .978 6.928 5.420 5.898 10.007 10.549 -10.377 11 .450 12.7.20 13.593 12 .837 17.817 17. 437 15-. 857 15.035 17.479 18.526 16.861 17.293 16.390 16.655 15.707 16.146 17.473 17.270 16.203 18.437 18.536 19.993 20.046 20.963 20.758 17. 774 17.947 16. 963 16.202 14.736 16 .548 17. 136 16 .180 16. .415 15. 574 14.121 13.716 13.394 17.862 18.140 18.776 20.195 21.013 20.749 21.419 19.838 21.190 19.603 20.282 20.623 21.729 19. 737 20.032 19. 232 19.269 18.517 1.00 35.49 1.00 37.77 1.00 39.62 1.00 34.87 1.00 29.95 1.00 26.48 1.00 29.03 1.00 24.64 1.00 22.85 1.00 17.56 1.00 19.48 1.00 17.71 1.00 24.81 1.00 24.75 1.00 24.35 1.00 24.63 1.00 24.75 1.00 23.98 1.00 21.11 1.00 26.06 1.00 28.45 1.00 26.36 1.00 25.06 1.00 26.70 1.00 27.85 1.00 27.66 1.00 29.56 1.00 29.82 1.00 28.74 1.00 32.13 1.00 35.25 1.00 38.54 1.00 39.85 1.00 41.38 1.00 30.61 1.00 29.45 1.00 30.96 1.00 31.21 1.00 27.06 1.00 24.27 1.00 22.36 1.00 24.87 1.00 23.19 1.00 23.65 1.00 22.95 1.00 34.88 1.00 34.84 1.00 36.20 1.00 35.47 1.00 37.62 1.00 39.16 1.00 39.68 SSSD/55034. V01 WO 98/07835 WO 9807835PCTJ2S97/14885 445 ATOM 3427 CA LEU 644 65.328 14.029 17.712 1.00 43.09 ATOM 3428 CB LEU .644 64.074 13.843 16.860 1.00 40.78 ATOM 3429 CG LEU 644 64.076 12.876 15.681 1.00 36.94 ATOM 3430 CD1 LEU 644 62.790 13.076 14.901 1.00 37..34 ATOM 3431 CD2 LEU 644 65.240 13.157 14.783 1.00 37.72 ATOM 3432 C LEU 644 65.154 15.261 18.591 1.00 47.32 ATOM 3433 0 LEU 644 64.639 15.170 19.702 1.00 50.33 ATOM 3434 N ALA 645 65.598 16.406 18.088 1.00 51.23 ATOM 3435 CA ALA 645 65.507 17.662 18.820 1.00 52.97 ATOM 3436 CB ALA 645 66.367 18.703 18.151 1.00 54.12 ATOM 3437 C ALA 645 64.060 18.137 18.910 1.00 53.00 ATOM 3438 0 ALA 645 63.591 18.528 19.977 1.00 53.59 ATOM 3439 N ASP 652 52.356 21.675 14.855 1.00 79.51 ATOM 3440 CA ASP 652 51.194 21.821 13.993 1.00 78.74 ATOM 3441 CB ASP 652 51.625 22.021 12.531 1.00 78.30 ATOM 3442 CG ASP 652 50.459 22.358 11.608 1.00 77.64 ATOM 3443 ODi ASP 652 49.473 22.968 12.079 1.00 77.67 ATOM 3444 0D2 ASP 652 50.526 22.029 10.410 1.00 78.25 ATOM 3445 C ASP 652 50.339 20.569 14.125 1.00 78.92 ATOM 3446 0 ASP 652 50.645 19.529 13.539 1.00 79.36 ATOM 3447 N TYR 653 49.262 20.682 14.892 1.00 79.17 ATOM 3448 CA TYR 653 48.357 19.560 15.1.11 1.00 80.23 ATOM 3449 CB TYR .653 47.283 19.932 16.136 1.00 81.36 ATOM 3450 CG TYR 653 47.790 20.060 17.557 1.00 84.51 ATOM 3451 CD1 TYR 653 46.998 20.649 18.544 1.00 86.09 ATOM 3452 CEl TYR 653 47.443 20.751 19.865 1.00 88.05 ATOM 3453 CD2 TYR 653 49.049 19.576 17.925 1.00 86.22 ATOM 3454 CE2 TYR 653 49.504. 19.673 19.242 1.00 87.14 ATOM 3455 CZ TYR 653 48.698 20.260 20.207 1.00 88.37* ATOM 3456 OH TYR 653 49.146 20.351 21.510 1.00 88.82 ATOM 3457 C TYR 653 47.687 19.098 13.827 1.00 80.07 ATOM 3458 0 TYR 653 47.170 17.983 13.752 1.00 81.23 ATOM 3459 N TYR 654 47.716 19.953 12.813 1.00 79.01 ATOM 3460 CA TYR 654 47.082 19.640 11.544 1.00 78.81 ATOM 3461 CB TYR 654 46.378 20.884 11.008 1.00 78.48 ATOM 3462 CG TYR 654 45.358 21.422 11.982 1.00 78.53 ATOM 3463 CD1 TYR 654 45.752 21.948 13.213 1.00 77.46 ATOM 3464 CEl TYR 654 44.822 22.382 14.146 1.00 78.94 ATOM 3465 CD2 TYR 654 43.997 21.350 11.704 1.00 80.18 ATOM 3466 CE2 TYR 654 43.054 21.785 12.632 1.00 82.55 ATOM 3467 CZ TYR 654 43.473 22.295 13.851 1.00 80.98 ATOM 3468 OH TYR 654 42.548 22.703 14.785 1.00 82.29 ATOM 3469 C TYR 654 48.010 19.042 10.499 1.00 79.04 ATOM 3470 0 TYR 654 47.575 18.720 9.393 1.00 80.09 ATOM 3471 N LYS 655 49.277 18.859 10.848 1.00 78.74 ATOM 3472 CA LYS 655 50.217 18.282 9.906 1.00 80.69 ATOM 3473 CB LYS 655 51.651 18.687 10.247 1.00 83.97 ATOM 3474 CG LYS 655 52.674 18.124 9.281 1.00 89.76 ATOM 3475 CD LYS 655 54.084 18.565 9.611 1.00 93.90 ATOM 3476 CE LYS 655 55.075 17.844 8.70B 1.00 97.62 ATOM 3477 NZ LYS 655 56.489 18.177 9.038 1.00101.35 ATOM 3478 C LYS 655 50.070 16.763 9.922 1.00 80.98 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 446

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3479 3480 3481 3482 3483 3484 3485 3486 3487 3488 3489 3490 3491 3492 3493 3494 3495 3496 3497 3498 3499 3500 3501 3502 3503 3504 3505 3506 3507 3508 3509 3510 3511 3512 3513 3514 3515 3516 3517 3518 3519 3520 3521 3522 3523 3524 3525 3526 3527 3528 3529 3530 0 LYS N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS 0 LYS N GLY CA GLY C GLY O GLY N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NHl ARG NH2 ARO C ARG O ARG N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU 0 LEU N PRO CD PRO CA PRO CB PRO CG PRO C PRO O PRO N VAL CA VAL CIB VAL CG1 VAL CG2 VAL C VAL 0 VAL N LYS CA LYS CB LYS CG LYS CD LYS 655 656 -6 56 656 656 656 656 656 656' 656 660 660 660 660 661 661 661 661 661 661 661 661 661 661 661 662 662 662 662 662 662 662 662 663 663 663 663 663 663 663 664 664 664 664 664 664 664 665 665 665 665 665 50.187 49.766 49.599 48.723 47.258 46.518 45.019 44.291 50.940 51.923 49.197 48.231 47.492 46.403 48.080 47.477 47.900 47.612 47.801 47.691 47.955 48.343 47.836 47.894 48.833 47.194 47.4'96 46.220 45.485 44.084 46.261 48.154 47.515 49.448 50.320 50.224 51.537 51.702 49. 569 49.779 48.759 48.080 47.195 48.060 46.143 47.268 47.080 46.873 46.105 45.517 44.415 43.979 16. 130 16. 194 14. 749 14. 426 14. 779 14. 565 14. 620 14. 565 14. 026 14. 596 9. 779 10. 860 10. 866 11.432 10. 222 10. 155 8.861 7.566 6.331 5. 061 3. 866 3. 760 2. 772 11.379 12. 096 11.618 12. 735 13.496 14. 281 14.621 15. 535 12.237 11.570 12.549 13.216 12.148 12.887 12.836 12.499 11.814 13.5-58 13. 964 15. 242 16.409 15.038 12.787 12.654 11.883 10. 704 10.037 10.873 10.366 10 .975 8 .759 8.630 7.423 7 .596 6 .295 6.493 5.183 8.513 8 .032 5.831 5. 961 7 .285 7.388 8.288 9.617 10.338 9.563 10.456 9.734 10.264 11.529 9 .523 10.439 10.063 11. 537 12 .428 12.789 11 .696 12 .158 11.358 13 .712 14 .536 13.895 12 .914 15.070 14 .872 13.403 16.398 17.399 16 .414 17 .632 17.427 17.038 16.345 18. 172 19.388 17.282 17.668 16.423 15.786 14.418 1.00 80.95 1.00 81.29 1.00 81.06 1.00 81.40 1.00 81.60 1.00 84.93 1.00 87.78 1.00 91.78 1.00 80.44 1.00 80.35 1.00 57.41 1.00 55.59 1.00 53.27 1.00 53.03 1.00 51.92 1.00 48.40 1.00 50.20 1.00 49.76 1.00 52.48 1.00 52.60 1.00 50.93 1.00 48.54 1.00 52.75 1.00 43.91 1.00 43.23 1.00 40.56 1.00 37.52 1.00 33.26 1.00 31.29 1.00 24.03 1.00 28.65 1.00 36.78 1.00 37.27 1.00 36.46 1.00 38.35 1.00 35.98 1.00 34.95 1.00 39.18 1.00 35.53 1.00 38.34 1.00 32.71 1.00 30.18 1.00 31.31 1.00 28.93 1.00 34.42 1.00 29.48 1.00 30.41 1.00 29.29 1.00 28.55 1.00 26.97 1.00 27.88 1.00 29.41 SSSD/55034. V01 WO 98/07835 WO 9807835PCTIUS97/14885 447

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3531 3532 3533 3534 3535 3536 3537 3538 3539 3540 3541 3542 3543 3544 3545 3546 3547 3548 3549 3550 3551 3552 3553 3554 3555 3556 3557 3558.

3559 3560 3561 3562 3563 3564 3565 3566 3567 3568 3569 3570 3571 3572 3573 3574 3575 3576 3577 3578 3579 3580 3581 3582 CE LYS NZ 'LYS C LYS O LYS N TRP_ CA TRP CB TRP CG TRP CD2 TRP CE2 TRP CE3 TRP CD1 TRP NEl TRP CZ2 TRP CZ3 TRP CH2 TRP C TRP O TRP N MET CA MET CB MET CG MET SD MET CE MET C MET O MET N ALA CA ALA CB ALA C ALA O ALA N PRO CD PRO CA PRO CB PRO CG PRO C PRO 0 PRO N GLU CA GLU CB GLU CG GLU CD GLU OE1 GLU 0E2 GLU C GLU 0 GLU N ALA CA ALA CB ALA C ALA- 0 ALA 665 665 665 665 666 666 666 666 666 666 666 666 666 666 666 666 666 666 667 667 667 667 667 667 667 667 668 668 668 668 668 669 669 669 669 669 669 669 670 670 670 670 670 670 670 670 670 671 671 671 671 671 42 .7-85 42.363 46.890 46 .315 48.181 49.005 50.323 50.205 49 .67'6 49.740 49. 151 50.565 50.287 49.295 48.707 48.778 49.316 49.790 49.021 49.306 49.308 50.606 50.479 50.932 48.432 47.211 49.072 48.383 49.388 47.666 48.156 46.521 45.868 45.723 44.638 44.444 46.517 46.442 47.303 48.096 48.776 49.928 49.506 50.395 48.297 49.145 49.435 49.697 50.708 51. 460 50.063 50.602 11 .162 10 .809 9. 730 8 802 9. 976 9 .128 8 .755 7 .582 7 .603 6 .276 8 .607 6 .289 5 .506 5 .930 8.256 6 .929 9 .836 9 .219 11 .128 11 .948 13.419 13 .939 15 .723 15 .858 11 .775 11 .672 11 .820 11 .704 11 .473 13 .033 14 .072 13 .027 11 .840 14 .229 13 .708 12.301 15.391 16 .523 15 .113 16 .169 15 .657 14 .705 13 .252 12 .384 12 .974 16 .795 17 .979 15 .999 16.495 15.333 17 .364 18 .398 13.899 12.508 18.556 19.113 18.736 19.599 18.913 17.977 16.642 16.162 15.818 18.238 17.147 14.872 14.536 14.081 20.907 21.867 20.947 22.110 21.723 21.150 20.906 19.204 23.346 23.255 24. 505 25.773 26.894 25.966 25.521 26.665 27.243 26.923 27.864 27.379 27.535 27.056 28.569 29.200 30.464 30. 205 30. 150 30.257 30.013 28.276 28.380 27.367 26.440 25.814 25.361 24.977 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 26.35 26.16 28.81 29.38 28 .98 31.67 29.46 28 .92 27.62 27.15 25.27 24.30 27. 82 26.95 25. 28.35 33.46 34.77 35.61 37.94 40.22 40.77 44.04 39.07 39.61 42.46 38.46 37.78 38.21 37.46 35.74 37.55 38.19 39.30 39.82 39.13 -40.55 39.87 41.15 42.80 42.97 42.82 44.16 40.43 46.36 43.00 40.37 44 .03 44.90 42.47 47.79 47.27 SSSD/55034. V0l WO 98/07835 PCTIUS97/14885 448 ATOM 3583 N LEU 672 48.877 16.952 24.922 1.00 51.20 ATOM 3584 CA LEU 672 48.131 17.650 23.881 1.00 52.90 ATOM 3585 CB LEU 672 47.092 16.685 23.288 1.00 54.84 ATOM 3586 CG LEU 672 46.307 17.010 22.015 1.00 57.19 ATOM 3587 CD1 LEU 672 47.230 17.328 20.869 1.00 57.53 ATOM 3588 CD2 LEU 672 45.443 15.813 21.659 1.00 56.95 ATOM 3589 C LEU 672 47.456 18.913 24.445 1.00 53.4S ATOM 3590 0 LETJ 672 47.502 19.988 23.841 1.00 52.71 ATOM 3591 N 'PEE 673 46.866 18.777 25.627 1.00 53.82 ATOM 3592 CA PHE 673 46.179 19.878 26.281 1.00 55.95 ATOM 3593 CB PHE 673 44.974 19.340 27.060 1.00 53.37 ATOM 3594 CG PEE 673 43.967 18.612 26.200 1.00 52.79 ATOM 3595 CD1 PEE 673 43.477 17.368 26.580 1.00 54.64 ATOM 3596 CD2 PHE 673 43.491 19.173 25.022 1.00 53.89 ATOM 3597 CEl PEE 673 42.530 16.702 25.808 1.00 55.44 ATOM 3598 CE2 PEE 673 42.540 18.507 24.239 1.00 54.80 ATOM 3599 CZ PRE 673 42.062 17.269 24.637 1.00 54.86 ATOM 3600 C PEE 673 47.071 20.733 27.200 1.00 58.97 ATOM 3601 0 PEE 673 47.084 21.959 27.095 1.00 60.79 ATOM 3602 N ASP 674 47.832 20.086 28.077 1.00 60.63 ATOM 3603 CA ASP 674 48.698 20.798 29.026 1.00 61.52 ATOM 3604 CB ASP 674 48.638 20.137 30.410 1.00 61.39 ATOM 3605 CG ASP 674 47.247 20.143 31.010 1.00 62.87 ATOM 3606 ODi ASP 674 46.706 19.039 31.246 1.00 62.99 ATOM 3607 0D2 ASP 674 46.698 21.239 31.253 1.00 63.55 ATOM 3608 C ASP 6.74 50.176 20.898 28.618 1.00 61.58 ATOM 3609 0 ASP 674 51.014 21.284 29.446 1.00 60.41 ATOM 3610 N ARG 675 50.499 20.5.19 27.380 1.00 61.38 ATOM 3611 CA ARG 675 51.885 20.526 26.883 1.00 59.23' ATOM 3612 CB ARG 675 52.336 21.944 26.515 1.00 59.05 ATOM 3613 CG ARG 675 51.548 22.564 25.367 1.00 64.48 ATOM 3614 CD ARG 675 52.036 23.967 25.014 1.00 68.61 ATOM 3615 NE ARG 675 53.348 23.969 24.359 1.00 69.16 ATOM 3616 CZ ARG 675 54.076 25.061 24.145 1.00 68.19 ATOM 3617 NH1 ARG 675 53.622 26.250 24.531 1.00 66.97 ATOM 3618 NH2 ARG 675 55.265 24-965 23.564 1.00 67.00 ATOM 3619 C ARG 675 52.849 19.885 27.892 1.00 57.27 ATOM '3620 0 ARG 675 54.002 20.300 28.033 1.00 57.05 ATOM 3621 N ILE 676 52.356 18.867 28.591 1.00 55.44 ATOM 3622 CA ILE 676 53.136 18.140 29.589 1.00 53.31 ATOM 3623 CB ILE 676 52.314 17.899 30.874 1.00 50.96 ATOM 3624 CG2 ILE 676 52.934 16.787 31.718 1.00 47.57 ATOM 3625 CG1 ILE 676 52.213 19.196 31.669 1.00 50.88 ATOM 3626 CD1 ILE 676 51.443 19.073 32.964 1.00 53.09 ATOM 3627 C ILE 676 53.608 16.801 29.029 1.00 54.75 ATOM 3628 0 ILE 676 52.810 15.891 28.824 1.00 57.06 ATOM 3629 N TYR 677 54.902 16.681 28.777 1.00 53.61 ATOM 3630 CA TYR 677 55.459 15.447 28.243 1.00 52.80 ATOM 3631 CB TYR 677 56.332 15.747 27.023 1.00 53.40 ATOM 3632 CG TYR 677 55.554 16.184 25.794 1-00 57.32 ATOM 3633 CD1 TYR 677 55.256 17.535 25.575 1.00 55.94 ATOM 3634 CEl TYR 677 54.574 17.946 24.436 1.00 54.18 SSSD/55034. V01 WO 98/07835 WO 9807835PCTfUS97/14885 449

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ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3635 3636 3637 3638 3639 3640 3641 3642 3643 3644 3645 3646 3647 3648 3649 3650 3651 3652 3653 3654 3655 3656 3657 3658 3659 3660 3661 3662 3663 3664 3665 3666 3667 3668 3669 3670 3671 3672 3673 3674 3675 3676 3677 3678 3679 3680 3681 3682 3683 3684 3685 3686 CD2 CE2 Cz

OH

C

0

N

CA

CB

OGi CG2

C

0

N

CA

CB

CG

CD2 ND1 CEl NE2

C

0

N

CA

CB

CG

CD

OE1 NE2

C

0

N

CA

CB

OG

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG1 CG2

C

TYR

TYR

TYR

TYR

TYR

TYR

THR

THR

THR

THR

THR

THR

THR

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

SER

SER

SER

SER

SER

SER

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

VAL

VAL

VAL

VAL

VAL

VAL

677 677 677 677 677 677 678 678 678 678 678 678 678 679 679 679 679 679 679 679 679 679 679 .680 680 680 680 680 680 680 680 680 681 681 '681 681 681 681 682 682 682 682 682 682 682 682 683 683 683 683 683 55. 140 54.459 54 .183 53 .555 56 .268 57 .186 55. 881 56 .571 55.776 54 .615 55.346 56 .742 56.371 57. 334 57.L507 58.410 59. 833 60. 501 60.759 61.938 61. 807 56.145 55 .930 55.227 53 .881 53-.187 53 .762 53 .813 52 .818 54 .990 53 .070 52 .194 53 .368 52 .656 52 .979 54.366 53 .090 52 .285 54 .356 54 .920 56 .411 57.332 58 .545 56 .886 54 .178 54 .012 53 .758 53 .011 52 .895 51.752 54 .202 51 .638 15.251 15.654 17. 004 17.426 14 .713 15-283 13.471 12.648 12 .597 11. 764 13 .996 11.218 10 .917 10.351 8.969 8.216 8.677 9.505 8.236 8 .762 9.539 8.301 7.358 8.8303 8.261 8.664 7.980 6.450 5.762 5.919 8.676 7.933 9.843 10.264 11.712 11. 936 9.309 8. 953 8.881 7.921 7.673 8.520 8 .283 9.391 6.599 5.868 6.296 5. 072 4.852 3 .900 4.282 5.091 24.829 23.680 23.490 22.340 29.304 29.904 29. 579 30.568 31.910 31.764 32.345 30.041 28.912 30.854 30.456 31. 428 31. 418 32.253 30.498 30.774 31.832 30.429 29.678 3i .254 31.324 32.625 33.874 33.770 33.993 33.464 30.103 29. 656 29. 531 28.325 27.968 27.943 27.208 26.335 27.269 26.315 26.586 25.717 25.828 24.936 26.463 25.488 27.691 27.987 29. 544 29. 890 30.080 27.279 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 56 .63 54 .84 56.38 57.46 51.49 52 48-.54 46.14 47 .34 50.96 47.47 43 .21 41 .64 42 .21 39.96 39.23 43 .24 43 .12 42 .63 42 .66 43.80 40.78 42 .66 40 .26 39.10 39.23 41.07 39.96 39.53 32.85 39.20 39.29 38.01 39.27 40 .93 39.70 39.93 40.46 37.28 35.38 33.58 33.16 31.76 30.06 34.70 35.67 34.44 35.14 35.48 34 28.77 32 .81 SSSD/55034. V0l WO 98/07835 PCT/US97/14885 450 ATOM 3687 0 VAL 683 51.173 4.050 26.801 1.00 31.24 ATOM 3688 N TRP 684 51.018 6.271 27.187 1.00 30.88 ATOM 3689 CA TRP 684 49.731 6.426 26.502 1.00 31.79 ATOM 3690 CB TRP 684 49.189 7.849 26.679 1.00 34.88 ATOM 3691 CG TRP 684 47.972 8.173 25.833 1.00 37.61 ATOM 3692 CD2 TRP 684 46.635 8.396 26.305 1.00 39.13 ATOM 3693 CE2 TRP 684 45.851 8.741 25.184 1.00 38.42 ATOM 3694 CE3 TRP 684 46.024 8.349 27.567 1.00 39.05 ATOM 3695 CDI TRP 684 47.938 8.374 24.476 1.00 36.48 ATOM 3696 NEI TRP 684 46.669 8.720 24.085 1.00 38.70 ATOM 3697 CZ2 TRP 684 44.483 9.036 25.290 1.00 37.82 ATOM 3698 CZ3 TRP 684 44.668 8.644 27.664 1.00 38.19 ATOM 3699 CH2 TRP 684 43.918 8.980 26.536 1.00 37.68 ATOM 3700 C TRP 684 49.947 6.131 25.020 1.00 31.09 ATOM 3701 0 TRP 684 49.214 5.332 24.430 1.00 32.25 ATOM 3702 N SER 685 50.977 6.750 24.444 1.00 28.90 ATOM 3703 CA SER 685 51.345 6.536 23.052 1.00 27.10 ATOM 3704 CB SER 685 52.620 7.312 22.748 1.00 23.88 ATOM 3705 OG SER 685 52.459 8.710 22.974 1.00 25.82 ATOM 3706 C SER 685 51.567 5.028 22.786 1.00 27.85 ATOM 3707 0 SER 685 51.172 4.493 21.746 1.00 28.89 ATOM 3708 N PHE 686 52.178. 4.334 23.741 1.00 28.84 ATOM 3709 CA PHE 686 52.410 2.893 23.622 1.00 27.86 ATOM 3710 CB PHE 686 53.2.55 2.403 24.800 1.00 28.14 ATOM 3711 CG PHE 686 53.498 0.914 24.803 1.00 28.41 ATOM 3712 CDI PHE 686 54.256 0.313 23.802 1.00 27.54 ATOM 3713 CD2 PHE 686 52.949 0.109 25.796 1.00 29.15 ATOM 3714 CEl PHE 686 54.465 -1.057 23.792 1.00 24.25 ATOM 3715 CE2 PHE 686 53.151 -1.268 25.790 1.00 27.86 ATOM 3716 CZ PHE 686 53.912 -1.850 24.782 2.00 26.09 ATOM 3717 C PHE 686 51.072 2.122 23.566 1.00 30.99 ATOM 3718 0 PHE 686 50.960 1.109 22.873 1.00 29.21 ATOM 3719 N GLY 687 50.051 2.603 24.286 1.00 30.57 ATOM 3720 CA GLY 687 48.758 1.939 24.273 1.00 31.78 ATOM 3721 C GLY 687 48.202 1.923 22.862 1.00 32.51 ATOM 3722 0 GLY 687 47.687 0.908 22.373 1.00 31.25 ATOM 3723 N VAL 688 48.292 3.073 22.204 1.00 32.58 ATOM 3724 CA VAL 688 47.825 3.202 20.827 1.00 30.66 ATOM 3725 CB VAL 688 47.804 4.684 20.362 1.00 28.55 ATOM 3726 CG1 VAL 688 47.231 4.795 18.950 1.00 27.25 ATOM 3727 CG2 VAL 688 46.944 5.522 21.320 1.00 27.12 ATOM 3728 C VAL 688 48.684 2.326 19.910 1.00 29.96 ATOM 3729 0 VAL 688 48.160 1.731 18.974 1.00 30.83 ATOM 3730 N LEU 689 49.973 2.202 20.219 1.00 30.02 ATOM 3731 CA LEU 689 50.893 1.371 19.430 1.00 30.48 ATOM 3732 CB LEU 689 52.359 1.571 19.877 1.00 28.13 ATOM 3733 CG LEU 689 53.466 0.966 18.995 1.00 26.34 ATOM 3734 CD1 LEU 689 54.790 1.697 19.174 1.00 25.54 ATOM 3735 CD2 LEU 689 53.628 -0.505 19.264 1.00 24.99 ATOM 3736 C LEU 689 50.479 -0.096 19.567 1.00 30.54 ATOM 3737 0 LEU 689 50.540 -0.849 18.602 1.00 27.86 ATOM 3738 N LEU 690 50.013 -0.468 20.759 1.00 33.73 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 451

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3739 CA LEU 3740 CB LEU 3741 CG LEU 3742 CD1 LEU 3743 CD2 LEU 3744 C LEU 3745 0 LEU 3746 N TRP 3747 CA- TRP 3748 CB TRP 3749 CG TRP 3750 CD2 TRP 3751 CE2 TRP 3752 CE3 TRP 3753 CD1 TRP 3754 NEl TRP 3755 CZ2 TRP 3756 CZ3 TRP 3757 CH2 TRP 3758 C TRP 3759 0 TRP 3760 N GLU 3761 CA GLU 3762 CB GLU 3763 CG GLU 3764 CD GLU 3765 OE1 GLU 3766 OE2 GLU 3767 C GLU 3768 0 GLU 3769 N ILE 3770 CA ILE 3771 CB ILE 3772 CG2 ILE 3773 CG1 ILE 3774 CDI ILE 3775 C ILE 3776 0 ILE 3777 N PHE 3778 CA PHE 3779 CB PHE 3780 CG PHE 3781 CD1 PHE 3782 CD2 PHE 3783 CEI PHE 3784 CE2 PHE 3785 CZ PHE 3786 C PHE 3787 0 PHE 3788 'N THR 3789 CA THR 3790 CB THR 690 690 690 690 690 690 690 691 691 691 691 691 691 691 691 691 691 691 691 691 691 692 692 692 692 692 692 692 692 692 693 693 693 693 693 693 693 693 694 694 694 694 694 694 694 694 694 694 694 695 695 695 49.553 49.141 50.136 49.396 50.771 48.335 48.223 47.423 46.230 45.424 44.086 43.812 42.434 44.599 42.889 41.894 41.831 44.003 42.630 46.661 46.062 47.669 48.207 49.383 49 .009 50 .195 51.001 50.333 48 .682 48.545 49.262 49.774 50.666 51.140 51.879 52.744 48.643 48.633 47.654 46.550 45.980 46.988 47.500 47.560 48.576 48.633 49.149 45.516 44.684 45.604 44.747 44.107 -1.830 21.029 1.00 32.47 -1.982 22.496 1.00 31.82 -2.220 23.634 1.00 29.71 -2.129 24.956 1.00 31.53 -3.605 23.483 1.00 31.69 -2.101 20.136 1.00 33.01 -3.168 19.521 1.00 32.68 -1.131 20.089 1.00 32.37 -1.215 19.256 1.00 32.11 0.083 19.373 1.00 33.19 0.055 18.678 1.00 33.95 0.469 17.337 1.00 30.48 0.294 17.118 1.00 32.75 0.989 16.301 1.00 29.47 -0.352 19.199 1.00 34.34 -0.211 18.272- 1.00 36.53 0.601 15.900 1.00 30.85 1.289 15.100 1.00 30.51 1.104 14.907 1.00 30.29 -1.421 17.805 1.00 31.49 -2.221 17.092 1.00 31.20 -0.656 17.374 1.00 32.90 -0.734 16.019 1.00 29.78 0.233 15.809 1.00 25.56 1.696 15.713 1.00 25.85 2.570 15.363 1.00 27.76 2.850 16.265 1.00 29.52 2.981 14.191 1.00 26.84 -2.136 15.696 1.00 31.08 -2.593 14.553 1.00 32.57 -2.804 16.689 1.00 31.81 -4.163 16.506 1.00 31.87 -4.614 17.699 1.00 33.50 -6.075 17.513 1.00 33.06 -3.703 17.827 1.00 34.04 -4.008 19.025 1.00 31.52 -5.177 16.335 1.00 31.43 -5.982 15.403 1.00 29.55 -5.087 17.207 1.00 33.58 -6.027 17.178 1.00 36.72 -6.179 18.589 1.00 36.27 -6.724 19.547 1.00 34.29 -5.949 20.581 1.00 34.95 -7.972 19.297 1.00 31.60 -6.413 21.344 1.00 35.73 -8.443 20.049 1.00 31.12 -7.661 21.066 1.00 33.97 -5.870 16.065* 1.00 37.70 -6.756 15.839 1.00 37.99 -4.745 15.355 1.00 36.11 -4.485 14.205 1.00 31.23 -3.081 14.236 1.00 30.49 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 452

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM.

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3791 3792 3793 3794 3795 3796 3797 3798 3799 3800 3801 3802 3803 3804 3805 3806 3807 3808 3809 3810 3811 3812 3813 3814 3815 3816 3817 3818 3819 3820 3821 3822 3823 3824 3825 3826 3827 3828 3829 3830 3831 3832 3833 3834 3835 3836 3837 3838 3839 .384 0 3841 3842 OGI THR CG2 THR C THR 0 THR N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU 0 LEU N GLY CA GLY C GLY O GLY N GLY CA GLY C GLY O GLY N SER CA SER CB SER OG SER C SER O SER N PRO CD PRO CA PRO CB PRO CG PRO C PRO 0 PRO N TYR CA TYR CB TYR CG TYR CD1 TYR CEl TYR CD2 TYR CE2 TYR CZ TYR OH TYR C TYR 0 TYR N PRO CD PRO CA PRO CB PRO CG PRO C PRO O PRO 695 695 695 695 696 696 696 696 696 696 696 696 697 697 69 7 697 698 698 698 698 699 699 699 699 699 699 700 700 700 700 700 700 700 701 701 701 701 701 701 701 701 701 701 701 701 702 702 702 702 702 702 702 45.133 43.329 45.612 45.163 46.859 47.826 47.456 47.281 47.142 48.468 48.101 48.210 48.314 48.609 47 .4-32 47.398 46.455 45.277 45.504 46.454 44.569 44.608 44.095 44 .047 43.695 42.490 44.259 45.693 43.408 44.428 45.662 42.574 43.032 41.306 40.359 40.655 40.45 2 41. 452 41. 258 39.256 39.060 40.056 39.847 40.273 40.393 40.015 39.761 39. 920 39.709 .39.054 38.79o -2.079 14.134 1.00 30.14 -2.888 -4.619 -4 .325 -5.051 -5 .259 -6.495 -7.848 -8.941 -8.138 -4.076 -4.235 -2 .900 -1.705 -0.763 0. 099 -0.922 -0.081 1 .411 1 .858 2 .174 3 .618 4 .219 5 .639 4 .024 3 .755 4 .591 4 .761 5 .007 5 .358 5 .745 6 .208 7 .062 6 .190 7 .272 8 .474 8 .215 8 .518 8 .305 7 .688 7 .469 7 .782 7 .592 7 .722 8 .904 6 .777 5 .346 7 .145 5.800 4 .971 8 .117 15. 512 12. 965 11.862 13.164 12.081 11.245 11. 946 10. 909 12.800 11.160 9.946 11.745 10.960 10.817 9.941 11.700 11.643 11.820 12.449 11.282 11.352 10.046 10.095 12.492 12.450 13.573 13 .881 14.695 15.777 14.989 14.279 13 .527 14 .660 14.367 15.269 16.749 17.675 19-041 17.229 18.584 19.485 20.837 12.909 12 .611 11.986 12.186 10.569 9.882 10.917 10.264 1.00 31.07 1.00 29.79 1.00 31.31 1.00 29.75 1.00 28.46 1.00 29.96 1.00 30.38 1.00 30.43 1.00 32.35 1.00 28.76 1.00 26.97 1.00 32.70 1.00 31.69 1.00 32.24 1.00 31.81 1.00 32.63 1.-00 31.93 1.00 28.95 1.00 26.05 1.00 30.03 1.00 30.52 1.00 31.24 1.00 33.61 1.00 30.45 1.00 29.11 1.00 32.27 1.00 29.61 1.00 31.34 1.00 31.30 1.00 29.66 1.00 29.65 1.00 30.44 1.00 30.37 1.00 30.01 1.00 35.19 1.00 39.32 1.00 43.08 1.00 46.20 1.00 40.66 1.00 43.51 1.00 45.75 1.00 50.92 1.00 29.04 1.00 28.53 1.00 28.69 1.00 26.94 1.00 27.55 1.00 27.91 1.00 29.04 1.00 29.20 37.631 7.880 10.617 1.00 32.39 SSSD/55034. V01 WO 98/07835 WO 9807835PCTIUS97/14885 453

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3843 3844 3845 3846 3847 3848 3849 3850 3851 3852 3853 3854 3855 3856 3857 3858 3859 3860 3861 3862 3863 3864 3865 3866 3867 3868 3869 3870 3871 3872 3873 3874 3875 3876 3877 3878 3879 3880 3881 3882 3883 3884 3885 3886 3887 3888 3889 3890 3891 3892 3893 3894

N

CA

C

0

N

CA

CB

CG1 CG2

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG1 CG2 c 0

N

CA

CB

C

0

N

CA

CB

CG

CD

OE1 0E2

C

0

N

CA

CB

CG

CD1 CD2

C

0

N

CA

CB

CG

CD1

GLY

GLY

GLY

GLY

VAL

VAL

VAL

VAL

VAL

VAL

VAL

PRO

PRO

PRO

PRO

PRO

PRO

PRO

VAL

VAL

VAL

VAL

VAL

VAL

VAL

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PHE

PHE

PHE

PHE

PHE

703 703 703 703 704 704 704 704 704 704 704 705 705 705 705 705 705 705 706 706 706 706 706 706 706 707 707 707 707 707 708 708 708 708 708 708 708 708.

708 709 709 709 709 709 709 709 709 710 710 710 710 710 39.148 38 .191 37 .960 37.175 38.621 38.480 38 .606 38.577 37.482 39.490 40.683 39.030 37.669 39.910 39.065 37 .674 40.331 39.709 41.372 41.945 42.991 43 .657 44.035 40 .938 40.994 39.991 39.009 38.208 38.084 37.739 37.724 36.840 36.334 35.505 34.288 33.659 33.954 37.551 36.944 38.838 39.638 41.079 42.061 41.861 43.459 39.644 39.460 39.'833 39.845 40.024 41.376 42.459 9.213 10.236 11.289 12.213 11.139 12.061 11.324 12 .324 10.311 13.210 13.001 14.430 14.770 15.599 16.641 16.273 16.053 15 .686 16.879 17.389 18.505 18 .907 18.057 17. 923 17.581 18 .724 19.308 20.361 18 .264 18.344 17.260 16.212 15.377 16 .163 16.851 16.305 17.955 15.337 14.900 15. 086 14.277 14.120 13.338 11.834 13 .712 14. 961 14.313 16.276 17.021 18.524 18.888 18.024 9.591 9.226 10.297 10.079 11. 448 12.576 13.944 15.111 14.103 12.557 12.757 12.281 11.819 12.243 11.518 11.906 13.635 14.634 13.676 14 .925 14.664 15.974 13.618 15.953 17.140 15.483 16.370 15.619 16.994 18.177 16.206 16.684 15.515 14.496 15.099 16 .040 14.604 17.704 18.684 17.471 18.393 17.892 18.787 18.689 18.395 19.751 20.787 19.749 21. 001 20.747 20.225- 20.403 1 .00 1.00 1.00 1.00 1.00 1 .00 1.00 1. 00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.010 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00.

1.00 1.00 28.34 25. 97 28. 00 26.40 29.54 30.61 32. 54 31. 34.62 31.37.

31. 73 32. 33. 31.90 32.66 35.32 31.85 31.50 32.32 36. 88 39.77 39.17 38. 37.80 37.45 38.19 37.31 37.46 39.56 41.39 39.99 40.08 43 .96 46.61 52.77 52. 52 57. 04 39.89 39.47 38.99 37.51 34 30.94 28.48 29.02 38.18 38.08 39.68 43.27 43.66 46.36.

48.33 SSSD/55034. VOl WO 98/07835 PCT/US97/14885 454

ATOM

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ATOM

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ATOM

ATOM

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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ATOM

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ATOM

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ATOM

ATOM

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ATOM

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ATOM

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ATOM

ATOM

ATOM

ATOM

3895 3896 3897 3898 3899 3900 3901 3902 3903 3904 3905 3906 3907 3908 3909 3910 3911 3912 3913 3914 3915 3916 3917 3918 3919 3920 3921 3922 3923 3924 3925 3926 3927 3928 3929 3930 3931 3932 3933 3934 3935 3936 3937 3938 3939 3940 3941 3942 3943 3944 3945 3946 CD2 PHE CEl PilE CE2 PHE CZ PHE C PilE 0 PHE N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS 0 LYS, N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU O LEU N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU C LEU 0 LEU N LYS CA LYS CB LYS CG LYS CD LYS CE LYS NZ LYS C LYS 0 LYS N GLU CA GLU CB GLU CG GLU CD GLU OE1 GLU 0E2 GLU .C GLU 0 GLU N GLY CA GLY C GLY 710 710 710 710 710 710 711 711 711 711 711 711 711 711 711 712 712 712 712 712 712 712 712 713 713 713 713 713 713 713 713 714 714 714 714 714 714 714 714 714 715 715 715 715 715 715 715 715 715 716 716 716 41.579 43.723 42.839 43. 916 38.558 38.587 37.445 36.146 35.031 33.645 32.556 31.197 30.101 36.052 35.635 36.467 36.432 37.012 36.159 36.899 34.842 37.232 36.796 38.407 39.271 40.619 41.569 42.856 41.873 38.589 3 8. 548B 38.002 37.304 36.818 37.955 37.497 38.701 39.792 36.142 35.861 35.498 34.392 33.518 32.930 32.032 32.215 31.139 34.878 34 .076 36.184 36.727 36.602 20. 084 18 .343 20 .417 19 .544 16 .746 16 .422 16 .777 16.529 16.870 16 .758 17 .224 16.809 17.220 15. 078 14 .827 14 .125 12. 719 11 .814 11.449 10.440 10. 868 12 .513 11. 785 13. 141 13. 034 13. 726 13 .004 13.796 11.591 13.594 12. 919 14. 785 15.394 16. 799 17. 761 19. 174 20. 044 20. 059 14. 534 14.499 13.809 12.935 12. 652 13.897 13.571 12.503 14.392 11.607 10. 730 11.452 10.225 9. 034 19.544 19.915 19.046 19.233 21.758 22.952 21.032 21.627 20.634 21. 235 20.293 20.826 19.912 22 .120 23.250 21.294 21.691 20.597 19.381 18.504 19.857 22.974 23.875 23.038 24.207 23.958 22.989 22.817 23.519 25.450 26.472 25.344 26.471 26.114 25.926 25.628 25.235 26.279 26.972 28.167 26.068 26.430 25.195 24.532 23.338 22.704 23.033 27.036 27.348 27.182 27.737 26.799 1.00 47.76 1.00 51.79 1.00 50.36 1.00 53.02 1.00 44.74 1.00 44.99 1.00 45.27 1.00 44.00 1.00 46.68 1.00 52.36 1.00 54.43 1.00 55.93 1.00 63.51 1.00 42.15 1.00 40.85 1.00 40.98 1.00 42.26 1.00 39.67 1.00 39.06 1.00 36.97 1.00 36.48 1.00 43.61 1.00 44.10 1.00 43.57 1.00 43.67 1.00 42.24 1.00 38.81 1.00 30.86 1.00 34.27 1.00 44.78 1.00 46.04 1.00 44.72 1.00 44.34 1.00 43.76 1.00 46.37 1.00 52.22 1.00 57.37 1.00 58.02 1.00 44.17 1.00 45.14 1.00 43.86 1.00 42.94 1.00 46.57 1.00 51.37 1.00 54.24 1.00 54.19 1.00 55.01 1.00 41.36 1.00 38.24 1.00 41.41 1.00 41.78 1.00 42.65 SSSD/55034. V01 WO 98/07835 WO 9807535PCTIUS97/14889 455 ATOM 3947 0 GLY 716

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3948 3949 3950 3951 3952 3953 3954 3955 3956 3957 3958 3959 3960 3961 3962 3963 3964 3965 3966 3967 3968 3969 3970 3971 3972 3973 3974 3975 3976 3977 3978 3979 3980 3981 3982 3983 3984 3985 3986 3987 3988 3989 3990 3991 3992 3993 3994 3995 3996 3997 3998

N

CA

CB

CG

CD2 ND1 CE 1 NE2

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

ODi 0D2

C

0

N

CA

CB

CG

CD

CE

NZ

C

0

N

CD

CA

CB

CG

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ARC

ARC

ARG

ARG

ARG

ARC

ARC

ARG

ARG

ARC

ARG

MET

MET

MET

MET

MET

MET

MET

MET

AS P

ASP

AS P

ASP

ASP

ASP

AS P

ASP

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

PRO

PRO

PRO

PRO

PRO

717 717 717 717 717 717 717 717 717 717 718 718 718 718 718 718 718 718 718 718 718 719 719 719 719 719 719 719 719 720 720 720 720 720 720 720 720 721 721 721 721 721 721 721 721 721 722 722 722 722 722 36.661 7.874 36.439 9.321 36.286 8.291 35.935 8.926 35.860 7.946 34.842 7.171 36.946 7.634 36.604 6.708 35.335 6.408 37.535 7.434 38.649 7.949 37.328 6.118 38.403 5.148 38.571 4.307 38.945 5.125 40.273 5.852 40.722 6.579 40.601 7.896 40.033 8.644 41.122 8.480 38.109 4.250 36.946 3.991 39.149 3.873 38.984 3.021 40.282 2.939 40.652 4.245 42.095 4.104 43.377 3.970 38.519 1.629 38.889 1.102 37.690 1.050 37.135 -0.288 36.089 -0.638 34.916 0.333 34.908 1.331 33.996 0.095 38.208 -1.372 39.263 -1.229 37.926 -2.453 38.833 -3.576 38.335 -4.560 39.024 -5.901 38.493 -6.810 38.484 -8.255 38.158 -9.176 38.861 -4.261 37.822 -4.688 40.053 -4.366 41.356 -3.839 40.167 -5.011 41.663 -4.904 27.225 25.513 24.502 23 .153 22.024 21.581 21.235 20.360 20.550 24.354 24.287 24.283 24.116 25.385 26 .618 26.420 27.608 27 .779 26.845 28.854 22 .912 22.589 22.181 21.013 20 .198 19.509 18 .440 19.604 21.392 22.450 20 .523 20.722 19.647 19.605 20.356 18.792 20.713 20.081 21. 432 21. 509 22.562 22.521 23.597 23.141 24.268 20.155 19.653 19.541 19.972 18.233 17.918 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 2 .00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1:00 1.00 1.00 41.41 44 .56 45.91 46.65 50.03 49.92 51.38 50.10 49.34 47.68 49.77 48.18 46. 45. 47.15 46.61 45.57 45.48 44 .14 43.32 47. 56 48.37 47.33 47. 47.21 45. 79 42.81 43.02 49.99 47. 98 53.40 53 .19 56.95 61.65 68.60 61.19 51.12 50.71 48.85 47.92 47.79 51.08 53.21 54.60 61.37 49.01 52 .79 48 .92 51.11 46 .01 45.64 42.090 -3.690 18.646 1.00 47.86 SSSD/55034. V0l WO 98/07835 PCTIUS97/14885 456 ATOM 3999 C PRO 722

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4000 4001 4002 4003 4004 4005 4006 4007 4008 4009 4010 4011 4012 4013 4014 4015 4016 4017 4018 4019 4020 4021 4022 4023 4024 4025 .4026 4027 4028 4029 4030 4031 4032 4033 4034 4035 4036 4037 4038 4039 4040 4041 4042 4043 4044 4045 4046 4047 4048 4049 4050 0 PRO N SER CA SER CB SER OG SER C SER 0 SER N ASN CA ASN CB ASN CG ASN ODI ASN ND2 ASN C ASN 0 ASN N CYS CA CYS CB CYS SG CYS C CYS O CYS N THR CA THR CB THR OGI THR CG2 THR C THR 0 THR N ASN CA ASN CB ASN CG ASN ODI ASN ND2 ASN C ASN 0 ASN N GLU CA GLU CB GLU CG GLU CD GLU OE1 GLU OE2 GLU C GLU 0 GLU N LEU CA LEU CB LEU CG LEU CD1 LEU CD2 LEU 722 723 723 723 723 723 723 724 724 724 724 724 724 724 724 725 725 725 725 725 725 726 726 726 726 726 726 726 727 727 727 727 727 727 727 727 728 728 728 728 728 728 728 728 72.8 729 729 729 729 729 729 39.745 -6.466 39.719 -7.069 39.360 -7.001 38.991 -8.398 38.260 -8.660 39.112 -8.421 40.339 -9.110 41.299 -8.605 40.405 -10.275 41.651 -11. 034 42.342 -11.215 41.768 -12.357 41.821 -13.506 41.186 -12. 054 42.558 -10.323 43.698 -9.982 41.995 -10.054 42.698 -9.398 42.623 -7.878 43.485 -6.992 42.001 -9.861 40.772 -9.852 42.788 -10.350 42.261 -10.843 43.341 -11. 663 44.292 -10.780 44.074 -12.554 41.843 -9.665 42.403 -8.574 40.868 -9.860 40.401 -8.781 39.246 -9.265 39.584 -10.545 40.704 -10. 718 38.629 -11.454 41.537 -8.254 41.513 -7.107 42.527 -9.111 43.693 -8.764 44.544 -10. 011 45.801 -9.758 46.509 -11.045 46.737 -11.930 46.869' -11.161 44.509 -7.713 44.760 -6.614 44.869 -8.039 45.641 -7.137 45.950 -7.796 47.004 -8.900 46.960 -9.780 48.404 -8.320 18.303 19.381 17.150 17.044 15.734 14.639 17.049 16.493 17.683 17.800 16.453 15.668 16.103 14.513 18.787 18.494 19.954 21.028 20.868 22.169 22.299 22.383 23.244 24.497 25.234 25.829 24.241 25.354 25.219 26.237 27.114 27.992 28.751 29.243 28.825 27.976 28.414 28.215 29. 020 29.289 30.120 30.542 29.685 31.733 28.272 28.785 27.033 26.192 24.846 24.952 23.749 25.139 1.00 43.57 1.00 41.72 1.00 43.14 1.00 41.85 1.00 37.27 1.00 39.44 1.00 41.68 1.00 40.84 1.00 45.99 1.00 49.22 1.00 52.35 1.00 58.07 1.00 62.42 1.00 62.13 1.00 49.77 1.00 51.48 1.00 50.34 1.00 49.83 1.00 47.11 1.00 38.55 1.00 50.11 1.00 50.63 1.00 50.37 1.00 51.05 1.00 53.50 1.00 57.56 1.00 52.55 1.00 52.18 1.00 55.14 1.00 52.55 1.00 53.17 1.00 60.65 1.00 68.99 1.00 73.66 1.00 74.66 1.00 50.79 1.00 48.17 1.00 50. 18 1.00 49.68 1.00 50.61 1.00 55.44 1.00 56.45 1.00 53.73 1.00 57.38 1.00 46.92 1.00 46.08 1.00 42.69 1.00 40.42 1.00 34.84 1.00 34.35 1.00 3-1.03 1.00 33.63 SSSD/55034. V01 WO 98/07835 WO 9807835PCTIUS97/14885 457

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4051 4052 4053 4054 4055 4056 4057 4058 4059 4060 4061 4062 4063 4064 4065 4066 4067 4068 4069 4070 4071 4072 4073 4074 4075 4076 4077 4078 4079 4080 4081 4082 4083 4084 4085 4086 4087 4088 4089 4090 4091 4092 4093 4094 4095 4096 4097 4098 4099 4100 4101 4102

C

0

N

CA

CB

CG

CD1 CEl CD2 CE2 Cz

OH

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

SD

CE

C

0

N

CA

CB

CG

CD

NE

CZ

NH1 NH2

C

0

N

CA

CB

LEU

LEU

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

MET

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ASP

ASP

ASP

729 729 730 730 730 730 730 730 730 730 730 730 730 730 731 731 731 731 731 731 731 731 732 732 732 732 732 732 732 732 733 733 733 733 733 733 733 733 734 734 734 734 734 734 734 734 734 734 734 735 735 735 44.909 45.524 43.591 42.807 41.384 40.507 40.828 40.019 39.352 38.537 38.876 38.041 42.814 42.880 42.753 42 .782 42.488 41.072 39.766 39.849 44.148 44.273 45.168 46.519 47.515 48.966 50.252 50.523 46.460 46 .924 45.798 45.639 44.888 45.614 44.509 45.198 44.838 45.228 43.737 42.893 41. 632 40.723 40.323 39.510 38.182 37.503 37.526 43.694 43.538 44.583 45.465 46.392 -5.817 -4.760 -5.886 -4.694 -5 .052 -3 .846 -2.879 -1.758 -3.661 -2.541 -1.601 -0.541 -3.849 -2.621 -4.4-92 -3.744 -4.668 -5.229 -3.998 -3.788 -3.087 -2.024 -3.728 -3.189 4 .154 -3.646 -4 .870 -5.667 -1.860 -0.835 -1.860 -0.652 -0.932 -1.805 170 -3.684 0.303 1.532 -0.084 0.813 0.095 -0.384 0.741 1.733 1.681 0.681 2 .633 1.387 2.564 0.572 1.000 -0.137 25.985 25.929 25.917 25.720 25.302 25.099 24.142 23.958 25.874 25.696 24.730 24.489 26 .993 26.931 28 .151 29.406 30.590 30.577 30.763 32.581 29.551 30.160 28.986 29.024 28.365 28.369 27. 887 29.390 28.275 28 .782 27.120 26.319 25.013 23.991 22.578 21.929 27.123 27.213 27.731 28.516 29.007 27.894 26.995 27.682 27.774 27.222 28.416 29. 675 30.010 30.244 31.339 31.773 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1. 00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1. 00 1. 00 1. 00 40.58 40.10 39.32 41.49 39.70 39.53 35.10 36.33 38.44 37.68 36. 40.58 43 44 46. 53 48.67 54. 63. 69.82 68.20 45. 73 42.09 43 .47 43.85 40.67 *39. 96 35.34 35. 43. 91 47.29 42. 51 39.85 38. 08 37.14 37.32 28. 98 41.12 44.38 40.28 40.23 39.95 36.41 39.31 48. 97 53 .99 56 .64 56 .79 39.38 41.82 37.67 39.58 42 SSSD/55034. V01 WO 98/07835 PCT/US97/14885.

458 ATOM 4103 CG ASP 735 45.690 -1.175 32.604 1.00 47.78 ATOM 4104 ODI ASP 735 46.116 -2.355 32.524 1.00 47.92 ATOM 4105 0D2 ASP 735 44.733 -0.803 33.339 1.00 46.75 ATOM 4106 C ASP 735 46.339 2.161 30.881 1.00 37.68 ATOM 4107 0 ASP 735 46. 447 3 .178 31.579 1.00 36.83 ATOM 4108 N CYS 736 46.996 1.967 29.734, 1.00 35.06 ATOM 4109 CA CYS 736 47-858 2.979 29.140 1.00 32.91 ATOM 4110 CB CYS 736 -48.499 2.469 27.848 1.00 27.65 ATOM 4111 SG CYS 736 49.631 1.067 27.989 1.00 31.08 ATOM 4112 C CYS 736 47.054 4.232 28.828 1.00 35.28 ATOM 4113 0 CYS 736 47.595 5.334 28.810 1.00 35.52 ATOM 4114 N TRP 737 45.742 4.078 28.677 1.00 38.73 ATOM 4115 CA TRP 737 44.885 5.217 28.352 1.00 41.10 ATOM 4116 CB TRP 737 43.890 4.816 27.266 1.00 41.22 ATOM 4117 CG TRP 737 44.535 4.362 25.994 1.00 40.65 ATOM 4118 CD2 TRP 737 43.976 3.465 25.026 1.00 41.90 ATOM 4119 CE2 TRP 737 44.932 3.325 23.990 1.00 41.02 ATOM 4120 CE3 TRP 737 42.763 2.764 24.930 1.00 40.44 ATOM 4121 CD1 TRP 737 45.766 4.721 25.5.7 1.00 39.14 ATOM 4122 NEl TRP 737 46.011 4.103 24.316 1.00 37.93 ATOM 4123 CZ2 TRP 737 44.708 2.512 22.875 1.00 40.92 ATOM 4124 CZ3 TRP 737 42.549 1.956 23.820 1.00 38.42 ATOM 4125 CH2 TRP 737 43.518 1.837 22.812 1.00 36.49 ATOM 4126 C TRP 737 44.159 5.847 29.538 1.00 41.39 ATOM 4127 0 TRP 737 43.163 6.551 29.366 1.00 40.86 ATOM 4128 N HIS 738 44.685 5.643 30.743 1.00 43.61 ATOM 4129 CA HIS 738 44.059 6.197 31.941 1.00 44.35 ATOM 4130 CB HIS 738 44.698 5.596 33.183 1.00 45.31 ATOM 4131 CG HIS 738 43.970 5.922 34.446 1.00 50.87 ATOM 4132 CD2 HIS 738 43.685 7.111 35.026 1.00 49.13 ATOM 4133 ND1 HIS 738 43.401 4.961 35.252 1.00 52.48 ATOM 4134 CEl HIS 738 42.798 5.541 36.275 1.00 55.70 ATOM 4135 NE2 HIS 738 42.955 6.848 36.159 1.00 51.42 ATOM 4136 C HIS 738 44.202 7.714 31.969 1.00 44.15 ATOM 4137 0 HIS 738 45.294 8.223 31.787 1.00 43.14 ATOM 4138 N ALA 739 43.115 8.428 32.272 1.00 45.42 ATOM 4139 CA ALA 739 43.141 9.895 32.318 1.00 47.29 ATOM 4140 CB ALA 739 41.792 10.426 32.752 1.00 49.75 ATOM 4141 C ALA 739 44.240 10.454 33.223 1.00 48.73 ATOM 4142 0 ALA 739 44.921 11.415 32.868 1.00 49.32 ATOM 4143 N VAL 740 44.331 9.893 34.425 1.00 50.51 ATOM 4144 CA VAL 740 45.332 10.262 35.424 1.00 51.32 ATOM 4145 CB VAL 740 44.861 9.880 36.842 1.00 52.29 ATOM 4146- CG1 VAL 740 45.905 10.254 37.869 1.00 53.73 ATOM 4147 CG2 VAL 740 43.551 10.575 37.152 1.00 53.54 ATOM 4148 C VAL 740 46.656 9.535 35.121 1.00 51.06 ATOM 4149 0 VAL 740 46.780 8.320 35.348 1.00 50.81 ATOM 4150 N PRO 741 47.670 10.280 34.657 1.00 50.12 ATOM 4151 CD PRO 741 47.595 11.738 34.454 1.00 50.19 ATOM 4152 CA PRO 741 49.003 9.775 34.294 1.00 51.10 ATOM 4153 CB PRO 741 49.790 11.060 34.024 1.00 50.35 ATOM 4154 CG PRO 741 48.731 11.978 33.492 1.00 50.13 SSSD/55034. V01 WO 99/07835 WO 98/7835PUS97I14885 459

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

4155 4156 4157 4158 4159 4160 4161 4162 4163 4164 4165 4166 4167 4168 4169 4170 4171 4172 4173 4174 4175 4176 4177 4178 4179 4180 4181 4182 4183 4184 4185 4186 4187 4188 4189 4190 4191 4192 4193 4194 4195 4196 4197 4198 4199 4200 4201 4202 4203 4204 4205 4206 C PRO 0 PRO N SER CA SER CB SER OG SER C SER 0 SER N GLN CA GLN CB GLN CG GLN CD GLN OE1 GLN NE2 GLN C GLN O GLN N ARG CA ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NrHl ARG NH2 ARG C ARG 0 ARG N PRO CD PRO CA PRO CE PRO CG PRO C PRO 0 PRO N THR CA THR CB THR OGi THR CG2 TER C TER O TER N PE CA PE CB PE CG PE CD1 PE CD2 PE CEl PE CE2 PHE CZ PHE C PE 741 741 742 742 742 742 742 742 743 743 743 743 743 743 743 743 743 744 744 744 744 744 744 744 744 744 744 744 745 745 745 745 745 745 745 746 746 746 746 746 746 746 747 747 747 747 747 747 747 747 747 747 49.687 50.374 49.482 50 .079 49.921 48 .572 49.479 50.074 48.286 47.616 46 .108 45.506 46.269 46.910 46.199 47.963 47.629 48.605 49.010 49.478 48.433 48.991 48.034 48.352 49.622 47.382 50.153 50.833 50.319 49.444 51.414 51.004 50 .251 52 .744 52 .807 53 .812 55.135 56 .113 56.439 55.489 55.687 55.228 56.649 57.267 58.305 57.702 57.060 57.749 56.469 57.150 56 .518 57.901 8 .902 7 .941 9 .228 8 .474 9 .245 9 .629 7 .077 6 .189 6 .897 5.613 5 .827 5 .374 5 .887 5 .114 7 .194 4 .690 3 .499 5 .241 4 .437 5.330 6 .300 7. 178 8 .218.

9 .454 9.814 10.349 3 .498 3.741 2 .365 1 .737 1 .470 0 .132 0 .515 1 .956 2 .654 1 .626 2 .020 2 .132 0 .824 2 .990 1. 036 -0.103 1 .482 0 .599 1 .350 2 .123 1 .455 3 .510 2 .154 4 .216 3 .535 -0.593 35.340 34.998 36.613 37. 708 39.020 39.237 37.851 38.464 37.305 37.390 37. 505 38. 838 40. 046 40.752 40.290 36.229 36.246 35.202 34.044 32 .894 32.360 31.254 30.932 30.542 3 0. 40 C 30.350 34.472 35.474 33.765 32 .763 34.157 33.532 32.335 33 .612 32.602 34.316 33.886 35.091 35.600 36.195 32.852 32.772 32.043 31.055 30.226 29.103 28.059 29.080 27.025 28.047 27.018 31.732 1.00 52.02 1.00 50.79 1.00 53.75 1.00 54.58 1.00 57.25 1.00 61.69 1.00 53.33 1.00 52.98 1.00 52.97 1.00 52.15 1.00 56.12 1.00 60.50 1.00 64.45 1.00 65.64 1.00 67.99 1.00 49.54 1.00 50.07 1.00 46.93 1.00 44.51 1.00 39.30 1.00 32.53 1.00 25.50 1.00 32.16 1.00 34.35 1.00 30.49 1.,00 32.23 1.00 44.61 1.00 47.68 1.00 43.21 1.00 42.00 1.00 40.11 1.00 37.54 1.00 36.49 1.00 39.15 1.00 40.56 1.00 37.77 1.00 37.61 1.00 39.14 1.00 35.16 1.00 36.82 1.00 36.75 1.00 32.89 1.00 36.56 1.00 33.79 1.00 28.85 1.00 30.71 1.00 26.42 1.00 28.73 1.00 26.56 1.00 28.97 1.00 28 1.00 34.64 SSSD/55034. V01 WO 98/07835 PCTIIJS97/14885 460 ATOM 4207 0 PHE 747 58.008 -1.667 31.156 1.00 31.47 ATOM 4208 N LYS 748 58.328 -0.399 32.972 1.00 38.86 ATOM 4209 CA LYS 748 58.920 -1.480 33.727 1.00 39.79 ATOM 4210 CB LYS 748 59.529 -0.952 35.026 1.00 43.68 ATOM 4211 CG LYS 748 60.200 -2.047 35.838 1.00 48.11 ATOM 4212 CD LYS 748 60.917 -1.515 37.064 1.00 51.33 ATOM 4213 CE LYS 748 61.353 -2.660 37.973 1.00 51.17 ATOM 4214 NZ LYS 748 62.135 -2.141 39.127 1.00 56.55 ATOM 4215 C LYS 748 57.813 -2.503 34.008 1.00 41.14 ATOM 4216 0 LYS 748 58.025 -3.706 33.848 1.00 38.24 ATOM 4217 N GLN 749 56.622 -2.008 34.383 1.00 41.20 ATOM 4218 CA GLN 749 55.454 -2.856 34.669 1.00 40.49 ATOM 4219 CB GLN 749 54.254 -2.015 35.134 1.00 45.70 ATOM 4220 CG GLN 749 54.378 -1.368 36.500 1.00 50.61 ATOM 4221 CD GLN 749 53.203 -0.441 36-:797 1.00 55.26 ATOM 4222 OE1 GLN 749 53 .392' 0.727 37.123 1.00 58.00 ATOM 4223 NE2 GLN 749 51.988 -0.951 36.665 1.00 59.25 ATOM 4224 C GLN 749 55.049 -3.588 33.397 1.00 37.42 ATOM 4225 0 GLN 749 54.964 -4.810 33.369 1.00 36.00 ATOM 4226 N LEU 750 54.810 -2.817 32.340 1.00 36.76 ATOM 4227 CA LEU 750 54.409 -3.355 31.033 1.00 35.39 ATOM 4228 CB LEU 750 54.358 -2.241 29.984 1.00 30.97 ATOM 4229 CG LEU 750 53.369 -1.091 30.177 1.00 27.36 ATOM 4230 CD1 LEU 750 53.745 0.037 29.217 1.00 29.15 ATOM 4231 CD2 LEU 750 51.941 -1.578 29.934 1.00 29.22 ATOM 4232 C LEU 750 55.369 -4.437 30.557 1.00 35.16 ATOM 4233 0 LEU 750 54.934 -5.449 30.014 1.00 34.45 ATOM 4234 N VAL 751 56.673 -4.212 30.721 1.00 38.76 ATOM 4235 CA VAL 751 57.656 -5.217 30.312 1. 00 38.69 ATOM 4236 CE VAL 751 59.129 -4.724 30.485 1.00 33.81 ATOM 4237 CG1 VAL "751 60.092 -5.836 30.120 1.00 32.04 ATOM 4238 CG2 VAL 751 59.415 -3.535 29.598 1.00 30.67 ATOM 4239 C VAL 751 57.428 -6.493 31.131 1.00 41.68 ATOM 4240 0 VAL 751 57.492 -7.599 30.594 1.00 39.92 ATOM 4241 N GLU 752 57.109 -6.338 32.414 1.00 44.22 ATOM 4242 CA GLU 752 56.854 -7.501 33.266 1.00 47.43 ATOM 4243 CB GLU 752 56.779 -7.078 34.743 1.00 49.29 ATOM 4244 CG GLU 752 58.093 -6.448 35.212 1.00 53.53 ATOM 4245 CD GLU 752 58.215 -6.249 36.707 1.00 53.05 ATOM 4246 OE1 GLU 752 58.554 -5.123 37.136 1.00 53.63 ATOM 4247 0E2 GLU 752 58.021 -7.228 37.452 1.00 56.18 ATOM 4248 C GLU 752 55.594 -8.256 32.809 1.00 46.90 ATOM 4249 0 GLU 752 55.646 -9.464 32.551 1.00 43.85 ATOM 4250 N ASP 753 54.490 -7.529 32.640 1.00 48.05 ATOM 4251 CA ASP 753 53.232 -8.128 32.193 1.00 48.46 ATOM 4252 CE ASP 753 52.119 -7.090 32.118 1.00 51.25 ATOM 4253 CG ASP 753 51.579 -6.707 33.467 1.00 54.20 ATOM 4254 ODi ASP 753 51.440 -7.589 34.330 1.00 57.31 ATOM 4255 0D2 ASP 753 51.281 -5.513 33.659 1.00 55.58 ATOM 4256 C -ASP 753 -53.371 -8.771 '30.837 1.00 48.59 ATOM 4257 0 ASP 753 53.001 -9.930 30.649 1.00 49.69 ATOM 4258 N LEt) 754 53.903 -8.009 29.889 1.00 47.21 SSSD/55034. VOl WO 98/07835 PCT/US97/14885 461

ATOM

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

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ATOM

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ATOM

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ATOM

4259 4260 4261 4262 4263 4264 4265 4266 4267 4268 4269 4270 4271 4272 4273 4274 4275 4276 4277 4278 4279 4280 4281 4282 4283 4284 4285 4286 4287 4288 4289 4290 4291 4292 4293 4294 4295 4296 4297 4298 4299 4300 4301 4302 4303 4304 4305 4306 4307 4308 4309 4310 CA LEU CB LEU ICG LEU CD1 LEU CD2 LEU C LEU 0 LEIJ N ASP CA -ASP CB ASP CG ASP ODi ASP 0D2 ASP C ASP 0 ASP N ARG CA ARG CE ARG CG ARG CD ARG NE ARG CZ ARG NH1 ARG NI{2 ARG C ARG O ARG N ILE CA ILE CB ILE CG2 ILE CG1 ILE CD1 ILE C ILE 0 ILE N VAL CA VAL CB VAL CGl VAL CG2 VAL C VAL O VAL N ALA CA ALA CB ALA C ALA 0 ALA N LEU CA LEU CE LEU CG LEU CD1 LEU CD2 LEU 754 754 754 754 754 754 754 755 755 755 755 755 755 755 755 756 756 756 756 756 756 756 756 756 756 756 757 757 757 757 757 757 757 757 758 758 758 758 758 758 758 759 759 759 759 759 760 760 760 760 760 760 54 .102 54 .664 53 .621 54 .296 52 .514 55 .004 54 .818 55 .969 56 .890 57 .883 59. 009 59 .694 59.223 56 .059 56 .119 55 .237 54 .362 53 .635 52 .459 51 .815 51 .417 50. 366 49.598 50 .061 53 .361 .53 .267 52 .645 51.656 50.919 49. 923 50.202 49.481 52.251 51 .643 53 .440 54 .102 55. 543 56. 198 55.493 54.249 54 .043 54 .622 54 .825 55.406 53. 524 53 .487 52.452 51. 151 50.280 50.808 49. 917 50. 899 -2 -2

-J

-J

-J

-J

-J

-1 -2 -2

-I

-1 -a -1 -1 -2.

-1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -2.

-1 -1 -1 -8.489 28.523 -7.385 27.625 -6.366 27.152 -5.272 26.343 -7.070 26.349 -9.703 28.481 10.590 27.659 -9.755 29.385 10.876 29.487 LO.586 30.615 L1.589 30.702 L1.608 31.746 L2.346 29.728 L2.117 29.817 13.150 29.138 L1.958 30.844 L3.009 31.328 -2.519 32.582 .3.358 33.027 .2.727 34.255 .1.335 34.026 .0.960 33.301 .1.866 32.721 9.676 33.183 .3.440 30.260 .4.622 29.960 .2.483 29.673 .2.789 28.644 1i.532 28.125 .1.923 27.062 .0.830 29.277 9 .551 28.920 3.528 27.454 4.469 26.959 3.111 27.014 3.745 25.874 3.177 25.609 3.920 24.456 1.714 25.262 5.232 26.149 6.055 25.258 5.550 27.386 6.925 27.814 6.949 29.212 7.717 27.777 8.849 27.296 7.13.2 28.271 7.760 28.295 7.149 29;*388 7.323 30.812 6.603 31.815 8.799 31.138 1.00- 46.37 1.00 44.16 1.00 46.35 1.00 45.11 1.00 42.89 1.00 47.08 1.00 45.02 1.00 49.68 1.00 51.62 1.00 54.90 1.00 59.00 1.00 63.70 1.00 60.31 1.00 51.50 1.00 47.11 1.00 51.81 1.00 51.44 1.00 54.52 1.00 55.00 1.00 59.54 1.00 64.01 1.00 65.76 1.00 63.56 1.00 66.59 1.00 50.03 1.00 49.98 1.00 46.87 1.00 44.28 1.00 40.46 1.00 38.44 1.00 39.74 1.00 40.68 1.00 44.20 1.00 40.28 1.00 47.56 1.00 48.90 1.00 47.01 1.00 44.38 1.00 47.85 1.00 51.79 1.00 49.80 1.00 54.80 1.00 57.15 1.00 56.77 1.00 60.83 1.00 63.59 1.00 61.74 1.00 61.29 1.00 60.41 1.00 58.68 1.00 59.64 1.00 57.84 SSSD/55034. V01 WO 98/07835 PCTIUS97/14889 462 ATOM 4311 C LEU 760 50.439 -17.706 26.951 1.00 63.42 ATOM 4312 0 LEU 760 49.282 -18.121 26.842 1.00 63.68 ATOM 4313 N THR 761 51.113 -17.200 25.924 1.00 66.71 ATOM 4314 CA THR 761 50.512 -17.109 24.586 1.00 68.48 ATOM 4315 CB THR 761 50.794 -15.734 23.922 1.00 68.21 ATOM 4316 OGi THR 761 50.193 -14.695 24.701 1.00 70.34 ATOM 4317 CG2 THR 761 50.202 -15.684 22.530 1.00 64.45 ATOM 4318 C TER 761 51.030 -18.225 23.688 1.00 69.65 ATOM 4319 0 THR 761 52.230 -18.492 23.623 1.00 70.43 ATOM 4320 SG CYS 2603 18.668 -9.074 20.131 0.50 30.57 ATOM 4321 CG MET 534 69.414 12.079 23.224 0.50 36.86 ATOM 4322 SD MET 534 69.162 13.149 24.646 0.50 40.20 ATOM 4323 CE MET 534 70.204 12.299 25.912 0.50 41.95 ATOM 4324 SG CYS 603 56.218 -8.072 16.341 0.50 37.35 ATOM 4325 0112 TIP 1 71.863 25.340 2.719 1.00 24.40 ATOM 4326 0112 TIP 2 39.671 4.177 15.837 1.00 36.87 ATOM 4327 0112 TIP 3 83.765 19.802 10.549 1.00 26.81 ATOM 4328 0H2 TIP 4 83.844 20.193 7.757 1.00 30.07 ATOM 4329 0112 TIP 5 75.192 16.430 6.693 1.00l 26.76 ATOM 4330 0112 TIP 6 86.579 19.662 9.323 1.00 36.11 ATOM 4331 0H2 TIP 7 52.204 10.911 24.392 1.00 36.83 ATOM 4332 0112 TIP 8 55.174 9.435 22.514 1.00 21.93 ATOM 4333 0112 TIP 9 57.077 4.556 32.580 1.00 25.17 ATOM 4334 0112 TIP 10 52.281 4.737 13.300 1.00 20.79 ATOM 4335 0H2 TIP 11 41.402 5.304 22.893 1.00 39.17 ATOM 4336 0112 TIP 12 45.088 8.857 21.604 1.00 35.14 ATOM 4337 0H2 TIP 13 64.519 -2.772 28;799 1.00 47.52 ATOM 4338 0112 TIP 14 77.327 12.960 23.832 1.00 34.47 ATOM 4339 0H2 TIP 15 79.366 17.021 18.247 1.00 47.49 ATOM 4340 0112 TIP 16 83.087 11.573 15.986 1.00 22.80 ATOM 4341 0H2 TIP 17 13.977 9.804 0.222 1.00 24.88 ATOM 4342 0112 TIP 18 38.451 0.155 5.081 1.00 41.03 ATOM 4343 0112 TIP 20 27.109 6.286 4.902 1.00 27.69 ATOM 4344 0112 TIP 21 34.379 1.750 16.771 1.00 47.69 ATOM 4345 0112 TIP 22 20.394 2.449 27.821 1.00 54.32 ATOM 4346 0112 TIP 23 50.587 -11.642 38.062 1.00 45.31 ATOM 4347 0H2 TIP 24 17.137 5.949 -1.716 1.00 27.63 ATOM '4348 0H2 TIP 25 27.604 7.961 15.119 1.00 47.19 ATOM 4349 0112 TIP 26 31.446 0.136 6.605 1.00 29.98 ATOM 4350 0112 TIP 27 27.030 -13.047 27.803 1.00 28.86 ATOM 4351 0H2 TIP 28 28.477 -17.191 13.067 1.00 37.44 ATOM 4352 0112 TIP 29 88.748 14.279 8.091 1.00 32.72 ATOM 4353 0112 TIP 30 -2.392 -3.684 11.343 1.00 41.86 ATOM 4354 0H2 TIP 31 34.968 -4.221 18.549 1.00 40.51 ATOM 4355 0H2 TIP 32 80.581 17.982 9.655 1.00 27.85 ATOM 4356 0112 TIP 33 5.522 3.773 10.805 1.00 24.60 ATOM 4357 0112 TIP 34 -10.747 5.416 11.174 1.00 29.27 ATOM 4358 0112 TIP 35 29.049 -8.816 19.978 1.00 35.24 ATOM 4359 0112 TIP 36 5.871 3.463 13.481 1.00 26.62 ATOM 4360 0112 TIP 37 31.834 2.899 0.207 1.00 49.70 ATOM 4361 0112 TIP 38 19.799 2.012 -3.941 1.00 29.67 ATOM 4362 0H2 TIP 39 62.060 2.679 32.659 1.00 54.86 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 463 ATOM 4363 OH2 TIP 40 21.100 -6.883 -4.054 1.00 22.33 ATOM 4364 OH2 TIP 41 -15.675 8.744 22.559 1.00 44.54 ATOM 4365 OH2 TIP 42 40.066 2.225 8.567 1.00 57.00 ATOM 4366 OH2 TIP 43 19.477 11.293 -0.049 1.00 37.77 ATOM 4367 OH2 TIP 44 67.060 9.047 17.334 1.00 25.14 ATOM 4368 OH2 TIP 45 87.829 18.937 '18.529 1.00 45.92 ATOM 4369 OH2 TIP 46 74.741 16.956 3.987 1.00 40.33 ATOM 4370 OH2 TIP 47 29.411 16.888 10.525 1.00 38.41 ATOM 4371 OH2 TIP 48 66.592 7.020 15.108 1.00 36.15 ATOM 4372 OH2 TIP 49 85.071 21.432 5.755 1.00 19.89 ATOM 4373 OH2 TIP 50 -4.842 3.281 3.118 1.00 28.22 ATOM 4374 OH2 TIP 51 19.454 5.250 4.876 1.00 34.86 ATOM 4375 0H2 TIP 53 34.785 5.433 24.743 1.00 30.40 ATOM 4376 OH2 TIP 54 34.792 -17.150 13.665 1.00 35.81 ATOM 4377 OH2 TIP 55 59.956 7.380 27.941 1.00 36.76 ATOM 4378 OH2 TIP 56 -7.327 -1.518 6.428 1.00 39.13 ATOM 4379 OH2 TIP 57 55.164 12.120 25.338 1.00 38.87 ATOM 4380 OH2 TIP 58 68.637 6.832 16.698 1.00 54.96 ATOM 4381 OH2 TIP 59 73.778 20.869 19.031 1.00 35.01 ATOM 4382 OH2 TIP 60 3.582 -8.363 -8.103 1.00 16.71 ATOM 4383 OH2 TIP 61 38.051 10.933 5.487 1.00 32.85 ATOM 4384 OH2 TIP 62 29.727 -9.630 -1.370 1.00 30.92 ATOM 4385 OH2 TIP 64 49.186 1.253 12.066 1.00 42.67 ATOM 4386 OH2 TIP 65 41.375 3.989 28.951 1.00 37.95 ATOM 4387 0H2 TIP 66 10.798 -13.119 1.125 1.00 38.26 ATOM 4388 OH2 TIP 67 -1.079 -4.386 21.428 1.00 27.92 ATOM 4389 OH2 TIP 68 30.327 16.346 13.295 1.00 53.21 ATOM 4390 OH2 TIP 69 8.319 4.437 3.449 1.00 23.63 ATOM 4391 OH2 TIP 70 73.152 18.809 22.631 1.00 36.45 ATOM 4392 OH2 TIP 71 -7.984 -3.476 25.048 1.00 33.16 ATOM 4393 OH2 TIP 72 66.529 -4.720 28.421 1.00 66.32 ATOM 4394 OH2 TIP 73 21.577 -20.723 4.868 1.00 48.14 ATOM 4395 OH2 TIP 74 59.417 -6.760 4.957 1.00 48.73 ATOM 4396 OH2 TIP 75 16.509 -13.306 -2.942 1.00 41.02 ATOM 4397 OH2 TIP 76 -15.064 7.473 4.275 1.00 26.77 ATOM 4398 OH2 TIP 77 33.118 2.917 13.384 1.00 41.38 ATOM 4399 OH2 TIP 78 0.112 -2.913 10.809 1.00 27.49 ATOM 4400 OH2 TIP 79 17.448 2.562 5.507 1.00 16.32 ATOM 4401 OH2 TIP 81 27.445 3.796 6.134 1.00 29.83 ATOM 4402 OH2 TIP 82 -8.708 6.231 9.598 1.00 27.66 ATOM 4403 OH2 TIP 83 1.565 -1.998 8.758 1.00 33.46 ATOM 4404 OH2 TIP 84 -4.774 -3.153 7.049 1.00 36.59 ATOM 4405 OH2 TIP 85 17.443 3.105 1.795 1.00 20.39 ATOM 4406 OH2 TIP 86 20.120 3.387 2.918 1.00 30.35 ATOM 4407 OH2 TIP 87 0.466 -2.238 22.190 1.00 20.30 ATOM 4408 OH2 TIP 88 19.749 -6.018 -1.687 1.00 21.33 ATOM 4409 0112 TIP 89 10.505 -15.695 6.861 1.00 38.80 ATOM 4410 OH2 TIP 90 4.223 -12.113 11.774 1.00 34.18 ATOM 4411 OH2 TIP 91 6.297 1.090 -3.192 1.00 24.40 ATOM 4412 OH2 TIP 92 -13.540 1.554 5.413 1.00 34.94 ATOM 4413 OH2 TIP 93 15.607 -7.315 0.017 1.00 26.30 ATOM 4414 OH2 TIP 94 -1.868 -5.461 3.839 1.00 37.12 SSSD/55034. V01 WO 98/07835 PCTIUS97/14888 464 ATOM 4415 0112 TIP 95 12.718 5.095 -4.401 1.00 40.61 ATOM 4416 0112 TIP 96 69.849 27.233 2.056 1.00 41.42 ATOM 4417 0112 TIP 97 24.374 -13.311 0.143 1.00 52.75 ATOM 4418 0112 TIP 98 60.424 -4.582 34.237 1.00 42.02 ATOM 4419 0112 TIP 99 10.589 5.757 3.485 1.00 61.53 ATOM 4420 0112 TIP 100 -9.564 -3.999 4.718 1.00 29.02 ATOM 4421 0H2 TIP 101 73.085 -1.967 10.565 1.00 59.23 ATOM 4422 0112 TIP 102 -3.172 5.701 30.623 1.00 30.51 ATOM 4423 0112 TIP 103 36.672 0.620 11.780 1.00 53.77 ATOM 4424 0H2 TIP 104 21.408 6.462 16.955 1.00 27.62 ATOM 4425 0H2 TIP 105 31.224 0.791 19.345 1.00 77.65 ATOM 4426 0112 TIP 106 5.660 -8.451 22.197 1.00 49.50 ATOM 4427 0112 TIP 1.07 -12.988 8.471 17.441 1.00 31.69 ATOM 4428 0H2 TIP 108 26.733 -10.524 0.894 1.00 25.26 ATOM 4429 0112 TIP 109 24.182 2.026 18.156 1.00 35.87 ATOM 4430 0H2 TIP 110 -1.822 12.848 3.561 1.00 35.44 ATOM 4431 0H2 TIP ill 59.584 13.491 33.225 1.00 40.47 ATOM 4432 0112 TIP 112 4.402 -10.813 1.929 1.00 47.07 ATOM 4433 0H2 TIP 113 8.032 2.916 0.940 1.00 40.79 ATOM 4434 0112 TIP 1.14 75.905 1.522 25.912 1.00 55.51 ATOM 4435 0H2 TIP 115 48.960 15.737 14.249 1.00 38.97 ATOM 4436 0H2 TIP 116 2.333 -11.271 9.174 1.00 29.12 ATOM 4437 0H2 TIP 117 83.062 26.404 12.925 1.00 41.17 ATOM 4438 OH2 TIP 118 8.816 6.440 -3.424 1.00 48.26 ATOM 4439 0112 TIP 119 -8'.594 4.575 ,4.258 1.00 32.68 ATOM 4440 0H2 TIP 120 7.695 -13.769 8.481 1.00 39.22 ATOM 4441 0112 TIP 121 51.500. 6.285 10.369 1.00 25.18 ATOM 4442 0112 TIP 122 20.720 3.849 15.625 1.00 22.46 ATOM 4443 0H2 TIP 123 73.111 3.718 20.617 1.00 28.26 ATOM 4444 0112 TIP 124 5.312 -11.608 22.516 1.00 32.74 ATOM 4445 0112 TIP 125 34.207 2.437 16.601 1.00 65.04 ATOM 4446 0112 TIP 126 9.535 -11.998 7.085 1.00 25.13 ATOM 4447 0H2 TIP 127 8.227 3.912 -1.495 1.00 43.73 ATOM 4448 0H2 TIP 129 -7.312 7.072 2.922 1.00 47.65 ATOM 4449 0112 TIP 130 35.824 -1.660 0.135 1.00 30.43 ATOM 4450 0112 TIP 131 44.723 10.285 11.144 1.00 32.74 ATOM 4451 0112 TIP 132 27.941 -13.172 18.733 1.00 58.65 ATOM 4452 0H2 TIP 133 45.301 11.497 21.408 1.00 35.00 ATOM 4453 0112 TIP 134 57.705 -10.824 14.202 1.00 69.18 ATOM 4454 0112 TIP 135 -3.108 15.385 16.685 1.00 38.07 ATOM 4455 0H2 TIP 136 85.884 11.182 9.044 1.00 32.04 ATOM 4456 0H2 TIP 137 1.2.840 -2.444 1.983 1.00 30.08 ATOM 4457 0112 TIP 138 75.645 3.496 20.607 1 .00 33.94 ATOM 4458 0112 TIP 139 13.020 7.518 -2.510 1.00 40.68 ATOM 4459 0112 TIP 140 11.245 -10.070 0.729 1.00 26.02 ATOM 4460 0H2 TIP 141 59.563 10.829 14.466 1.00 71.34 ATOM 4461 0H2 TIP 142 13.671 -16.214 3.489 1.00 39.47 ATOM 4462 0112 TIP 143 -6.358 -3.421 16.520 1.00 37.08 ATOM 4463 0112 TIP 144 25.629 -12.764 3.534 1.00 50.51 ATOM 4464 0H2 TIP 145 -16.459 10.869 .6.524 1.00 38.40 ATOM .4465 0112 TIP 146 86.598 12.840 7.028 1.00 47.80 ATOM 4466 0112 TIP 147 32.139 -4.674 1.757 1.00 32.43 SSSD/55034. V01 WO 98/07835 PCT/US97/14885 465 ATOM 4467 OH2 TIP 148 44.890 7.505 11.806 1.00 32.46 ATOM 4468 OH2 TIP 149 80.781 12.432 16.562 1.00 47.77 ATOM 4469 OH2 TIP 150 3.017 -7.101 -1.917 1.00 40.92 ATOM 4470 OH2 TIP 151 31.784 -6.139 20.968 1.00 38.23 ATOM 4471 OH2 TIP 152 74.835 -2.597 12.290 1.00 48.89 ATOM 4472 OH2 TIP 153 7.509 6.768 -1.083 1.00 46.02 ATOM 4473 OH2 TIP 154 71.732 5.360 21.908 1.00 33.30 ATOM 4474 OH2 TIP 155 68.150 -5.075 8.794 1.00 39.31 ATOM 4475 OH2 TIP 156 0.148 -9.544 6.872 1.00 41.37 ATOM 4476 OH2 TIP 157 67.878 18.204 10.861 1.00 51.19 ATOM 4477 OH2 TIP 158 3.652 8.829 4.428 1.00 31.24 ATOM 4478 OH2 TIP 159 52.100 11.362 18.433 1.00 40.73 ATOM 4479 OH2 TIP 161 -10.357 6.783 4.861 1.00 35.13 ATOM 4480 OH2 TIP 162 76.471 1.562 -0.853 1.00 59.17 ATOM 4481 OH2 TIP 163 10.073 -12.056 17.071 1.0044.69 ATOM 4482 OH2 TIP 164 34.163 14.271 18.254 1.00 39.59 ATOM 4483 OH2 TIP 165 2.320 -7.990 16.820 1.00 38.19 ATOM 4484 OH2 TIP 166 29.696 1.908 6.098 1.00 38.02 ATOM 4485 OH2 TIP 167 32.626 -17.410 11.766 1.00 48.15 ATOM 4486 OH2 TIP 168 42.244 18.049 11.043 1.00 50.95 ATOM 4487 OH2 TIP 169 87.907 10.574 5.721 1.00 60.28 ATOM 4488 OH2 TIP 170 70.313 3.998 25.141 1.00 72.64 ATOM 4489 OH2 TIP 171 77.603 5.679 23.952 1.00 43.23 ATOM 4490 OH2 TIP 172 -0.942 -8.153 4.508 1.00 55.10 ATOM 4491 OH2 TIP 173 34.297 15.574 1.690 1.00 34.19 ATOM 4492 OH2 TIP 174 -9.643 7.829 7.414 1.00 50.48 ATOM 4493 OH2 TIP 175 11.618 5.655 7.455 1.00 43.37 ATOM 4494 OH2 TIP 176 -8.705 13.841 13.642 1.00 72.49 ATOM 4495 OH2 TIP 177 32.0C9 3.416 18.257 1.00 44.16 ATOM 4496 OH2 TIP 178 -8.651 10.180 24.352 1.00 44.85 ATOM 4497 OH2 TIP 179 -1.15'3 -6.532 15.548 1.00 32.90 ATOM 4498 OH2 TIP 180 80.235 0.749 15.508 1.00 34.75 ATOM 4499 OH2 TIP 181 67.222 20.490 -1.574 1.00 40.76 ATOM 4500 OH2 TIP 182 -0.471 4.367 1.248 1.00 36.58 ATOM 4501 OH2 TIP 183 0.149 6.517 2.578 1.00 40.12 ATOM 4502 OH2 TIP 184 -1.186 8.867 1.311 1.00 44.77 ATOM 4503 OH2 TIP 185 -5.093 9.260 2.252 1.00 52.07 ATOM 4504 OH2 TIP 186 -7.235 10.227 3.913 1.00 58.53 ATOM 4505 OH2 TIP 187 2.724 7.169 0.879 1.00 47.77 ATOM 4506 0112 TIP 188 5.527 11.031 8.519 1.00 34.40 ATOM 4507 OH2 TIP 189 63.927 12.721 22.689 1.00 40.75 ATOM 4508 OH2 TIP 190 79.264 1.066 18.321 1.00 41.34 ATOM 4509 OH2 TIP 191 59.247 -11.825 7.256 1.00 79.86 ATOM 4510 OH2 TIP 192 13.994 -0.972 -4.310 1.00 31.15 ATOM 4511 OH2 TIP 193 59.546 3.024 33.227 1.00 40.34 ATOM 4512 OH2 TIP 194 .32.179 13.637 19.964 1.00 48.25 ATOM 4513 OH2 TIP 195 72.178 16.188 22.879 1.00 42.72 ATOM 4514 OH2 TIP 196 0.898 -8.663 14.348 1.00 41.76 ATOM 4515 OH2 TIP 197 -0.490 5.455 30.574 1.00 38.30 ATOM 4516 OH2 TIP 199 -1.277 -4.244 27.691 1.00 56.27 ATOM 4517 OH2 TIP- 200 81.605 15.360 17.272 1.00 42.05 ATOM 4518 OH2 TIP 201 -17.534 4.081 23.779 1.00 59.65 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 466 ATOM 4519 0H2 TIP 202 27.748 10.634 14.595 1.00 49.97 ATOM 4520 0H2 TIP 203 34.891 4.468 27.604 1.00 60.26 ATOM 4521 0H2 TIP 204 -3.460 -4.448 9.045 1.00 44.70 ATOM 4522 0H2 TIP 205 42.705 7.590 22.526 1.00 35.77 ATOM 4523 OH2 TIP 206 52.983 11.950 21.969 1.00 35.12 ATOM 4524 OH2 TIP 207 26.871 14.098 19.820 1.00 53.04 ATOM 4525 0H2 TIP 208 -7.184 9.323 6.370 1.00 37.49 ATOM 4526 0H2 TIP 209 86.676 5.553 15.911 1.00 72.92 ATOM 4527 0H2 TIP 210 55.080 15.928 20.414 1.00 68.75 ATOM 4528 0H2 TIP 211 51.512 19.264 22.672 1.00 54.72 ATOM 4529 0H2 TIP 212 19.988 7.127 6.976 1.00 45.55 ATOM 4530 0H2 TIP 213 28.905 2.021 -3.430 1.00 48.55 ATOM 4531 0H2 TIP 214 26.446 2.593 -4.753 1.00 55.04 ATOM 4532 0H2 TIP 215 36.539 2.911 18.446 1.00 38.50 ATOM 4533 0H2 TIP 216 16.807 -20.725 14.119 1.00 56.03 ATOM 4534 0H2 TIP 217 28.203 -14.485 6.172 1.00 62.90 ATOM 4535 0H2 TIP 218 31.519 1.503 -2.010 1.00 56.19 ATOM 4536 0H2 TIP 219 10.014 -16.571 15.451 1.00 46.37 ATOM 4537 0H2 TIP 220 7.126 -11.922 5.526 1.00 56.89 ATOM 4538 0H2 TIP 221 -12.414 14.643 10.965 1.00 67.36 ATOM 4539 0H2 TIP 222 10.978 9.734 -1.436 1.00 38.81 ATOM 4540 0H2 TIP 223 1.1.293 12.362 -1.306 1.00 52.56 ATOM 4541 0H2 TIP 224 34.011 13.162 -1.255 1.00 52.58 ATOM 4542 0H2 TIP 225 31.195 17.923 8.021 1.00 75.88 ATOM 4543 0H2 TIP 226 36.957 11.949 -1.947 1.00 50.99 ATOM 4544 0H2 TIP 227 35.179 3.114 10.888 1.00 58.55 ATOM 4545 0H2 TIP 228 64.027 13.281 26.577 1.00 51.98 ATOM 4546 0H2 TIP 229 36.514 6.155 15.292 1.00 45.57 ATOM 4547 0112 TIP 230 90.627 4.3 39 6.386 1.00 56.65 ATOM 4548 0112 TIP 231 49.907 -11.937 10.792 1.00 53.49 ATOM 4549 0112 TIP 232 60.296 -10.212 16.610 1.00 79.85 ATOM 4550 0112 TIP 233 18.154 -21.314 7.018 1.00 53.60 ATOM 4551 0112 TIP 234 66.186 -1.068 30.882 1.00 56.92 ATOM 4552 0H2 TIP 235 75.153 18.983 20.700 1.00 34.22 ATOM 4553 0H2 TIP 236 -2.885 10.207 3.295 1.00 68.34 ATOM 4554 0H2 TIP 237 5.834 -3.507 25.370 1.00 34.75 ATOM 4555 0H2 TIP 238 35.910 6.163 12.569 1.00 37.31 ATOM -4556 0112 TIP 239 -5.494 16.637 14.033 1.00 65.17 ATOM 4557 0112 TIP 240 46.332 -11.698 26.865 1.00 55.30 ATOM 4558 0112 TIP 241 6.179 6.434 13.895 1.00 45.92 ATOM 4559 0112 TIP 242 -3.869 -4.958 20.821 1.00 41.96 ATOM 4560 0112 TIP 243 1.690 -3.598 -0.200 1.00 41.42 ATOM 4561 0H2 TIP 244 86.181 11.454 23.000 1.00 56.22 ATOM 4562 0112 TIP 245 10.501 7.621 5.627 1.00 77.40 ATOM 4563 0112 TIP 246 5.007 8.485 2.181 1.00 89. 31 ATOM 4564 0112 TIP 247 64.552 -8.093 20.595 1.00 45.86 ATOM 4565 0112 TIP 248 11.243 -17.828 13.332 1.00 65.30 ATOM 4566 0H2 TIP 249 42.226 -6.785 14.857 1.00 81.78 ATOM 4567 0112 TIP 250 2.875 -4.176 22.032 1.00 53.45 ATOM 4568 0112 TIP 251 72.048 1.134 -2.037 1.00 38.85 ATOM 4569 0112 TIP 252 50.357 -3.142 32.88-7 1.00 67.13 ATOM 4570 0H2 TIP 254 57.772 9.500 11.808 1.00 40.03 SSSD/55034. V01 WO 98/07835 WO 9807835PCT/US97/14885 467

ATOM

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4571 4572 4573 4574 4575 4576 4577 4578 4579 4580 4581.

4582 4583 4584 4585 4586 4587 4588 4589 4590 4591 4592 4593 4594 4595 4596 4597 4598 4599 4600 4601 4602 4603 4604 4605 4606 4607 4608 4609 4610 4611 4612 4613 4614 4615 4616 4617 4618 4619 4620 4621 4622 0H2 0H2 0H2 0H2 0H2 0H2 0H2 0H2 0H2 0H2 Cl C2 N3 C4 Cs C6 C7 C8 Cl 0 Cil 012 C13 C14 C15 C16 C1 7 C18 Ni19 C2 0 C2 1 C2 2 N2 3 C2 4 025 C2 6 Cl C2 N3 C4 Cs C6 C7 C8 dlo Cil 012 C13 C14 C15S C16 C1 7 C18

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MON

255 256 257 258 261 262 263 264 265 266 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1001 1001 1001 1001 1001 1001 1001 1001 1001 1001 1001 1001 1001 1001 1001 1001 1001 43.306 67.064 87.612 21.095 71.914 25.727 -18.738 30.524 22.211 29.755 67.458 67.015 67.367 66.127 65.620 *66 .041 66.948 65.933 66.745 65.043 66.862 64.4'79 63.459 62.923 63.379 64.96 0 64.418 62.848 63.429 61.888 61. 085 61. 868 62.562 61.481 62.001 5.458 6.049 5.935 6.857.

7.121 6.543 5.722 7.250 6.647 8.138 6.735 8.918 9.913 10.654 10.435 8.670 9.416 20.459 16. 514 21 .648 9. 853 28 .544 -8 .133 10.877 11 .543 -16 .242 9. 037 4 .500 3 958 2 .732 4 .618 5 .919 6 .508 5 809 3 759 2 518 4 .051 1. 516 2. 990 3 .330 2 333 0 .956 1 .637 0 .642 025 -1 .407 0 .343 -0 .818 -2 .035 -2 .492 -2 .328 -2 .670 3 .340 3 .475 2 .580 4 .573 5 .641 5 .548 4 .412 4 .340 3 .023 5 .242 2.426 4 .783 S .641 5 .224 3 .935 3 .508 3 .095 30.366 15 .765 5 .147 -9.308 7 .912 27.190 12.767 16.329 -2.763 18.396 11.935 10 .687 10.160 9.793 10 .125 11.380 12.276 8.668 8 .922 7.483 8.241 6.570 5.617 4.727 4 .754 6.605 5 .713 3.880 3 .816 2.786 2 .152 1.930 3.133 -0.389 0.659 18.422 19.718 20.763 20.124 19.202 17.877 17.489 21. 477 21.886 22.302 22.943 23.509 24 .091 25.253 25.881 24.123 25.285 1. 00 1.00 '1.00 1.00 1.00 1. 00 1. 00 1. 00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00o 1,.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1. 00 1.00 1.00 1.00 1.00 00 1.00 47.59 57.51 70.52 78. 97 83.90 54 .87 71.80 46 .98 55.17 67.93 0. 00 0. 00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0. 00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0. 00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0. 00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 SSSD/55034. V01 WO 98/07835 PCTIUS97/14885 468 ATOM 4623 N19 MON 1001 11.168 3.525 27.023 1.00 0.00 ATOM 4624 C20 MON 1001 10.831 2.255 27.749 1.00 0.00 ATOM 4625 C21 MON 1001 12.107 4.463 27.725 1.00 0.00 ATOM 4626 C22 MON 1001 13.125 3.821 28.698 1.00 0.00 ATOM 4627 N23 MON 1001 12.570 2.742 29.518 1.00 0.00 ATOM 4628 C24 MON 1001 11.902 1.711 28.725 1.00 0.00 ATOM 4629 025 MON 1001 13.118 3.569 31.669 1.00 0.00 ATOM 4630 C26 MON 1001 12.610 2.731 30.944 1.00 0.00 SSSD/55034. V01

Claims (64)

1. A crystalline form comprising a polypeptide wherein said polypeptide consists of a catalytic domain of a protein tvrosine kinase wherein said protein tvrosine kinase is a non-insulin receptor protein tyrosine kinase.

2. The crystalline form of claim 1, wherein said non-insulin receptor protein ivrosine kinase is selected from the group consisting of FGF-R. EGF-R. PDGF-R. FLK. CCK4. MET. TRKA. AXL. TIE. EPH. RYK. DDR. ROS. RET. LTK. RORI. and N IUSK.

3. The crystalline form of claim 1, where said non-insulin receptor protein tyrosine kinase is selected from the group consisting of FGF-R, PDGF-R. DDR. and RET.

4. The crystalline form of claim 1. wherein said protein tvrosine kinase is a non- receptor protein tyrosine kinase. he crystalline form of claim 4. wherein said non-receptor protein tvrosine iinase is selected from a group consisting of SRC. BRK. BTK. CSK. ABL. ZAP70. FES. IFA-K. JAK. and ACK.

6. The crystalline form of claim 1. comprising one or more heavy metal atoms. 7 The crystalline form of claim 1. wherein said non-insulin receptor [R:\LIBFF]03757.doc:mrr WO 98/07835 PCT/US97/14885 470 protein tyrosine kinase is FGFR.

8. The crystalline form of claim 7, wherein said FGFR is FGFR1.

9. The crystalline form of claim 8, defined by atomic structural coordinates set forth in Table 1. The crystalline form of claim 7, comprising at least one compound.

11. The crystalline form of claim 10, wherein said compound is a nucleotide analog.

12. The crystalline form of claim 11, wherein said nucleotide analog is AMP-PCP.

13. The crystalline form of claim 12, defined by atomic structural coordinates set forth in Table 2.

14. The crystalline form of claim 10, wherein said compound is an indolinone compound. The crystalline form of claim 14, wherein said indolinone compound has a structure set forth in formula I or II: WO 98/07835 PCT/US97/14885 471 R3' R4 /R2 Rs R21 R 4 CR3 R 6 R 6 (I) A RR R7 R1 14 CR 3 A 2 A II R2 R7 R (II) or a pharmaceutically acceptable salt, isomer, metabolite, ester, amide, or prodrug thereof, wherein A 2 A 3 and A 4 are independently carbon or nitrogen; R, is hydrogen or alkyl; R 2 is oxygen in the case of an oxindolinone or sulfur in the case of a thiolindolinone; R 3 is hydrogen; R 4 Rs, R 6 and R, are optionally present and are WO 98/07835 PCTIUS97/14885 472 either independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO 2 NRR'I, SO 3 R, SR, NO 2 NRR'-, OH, CN, C OC (0)R, NHC(O)R, (CH 2 )nCO 2 R, and CONRR' or (ii) any two adjacent R 4 R5, and R 7 taken together form a fused ring with the aryl portion of the oxindole-based portion of the indolinone; (f R 2 R 3 R, I, R 5 and R 6 1 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO 2 NRRI, SO 3 R, SR, NO 2 NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH 2 1 ,CO 2 R, and CONRR'; nis 0, 1, 2, or 3; R is hydrogen, alkyl or aryl; R' is hydrogen, alkyl or aryl; and A is a five membered heteroaryl ring selected from the group consisting of thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, furan, 1,2,3- oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4- oxadiazole, l, 2 ,3,4-oxatriazole, l, 2 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3, 4-thiadiazole, 1,2,3,4 -thiatriazole, 1,2,3,5- thiatriazole, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO 2 NRR', SO 3 R, SR, NO 2 NRR', OH, CN, C(O)R, OC(O)R, NHC (CH 2 ),,CO 2 R or CONRR'I. 16 The crystalline form of claim 15, wherein said indolinone compound is 3-[(3-(2-carboxyethyl)-4- methylpyrrol-2-yl)methylene]-2-indolinone.

17. The crystalline form of claim 15, wherein said indolinone compound is 3-[4-(4-formylpiperazine-l- yl)benzylidenyl]-2-indolinone.

18. The crystalline form of claim 16, defined by the atomic structural coordinates of Table 3.

19. The crystalline form of claim 17, defined by the atomic structural coordinates of Table 4. The crystalline form of claim 1, having monoclinic unit cells.

21. The crystalline form of claim 20, wherein said monoclinic unit cells have dimensions of about a=208.3 A, b=57.8 A, c=65.5 A and (=107.2°.

22. The crystalline form of claim 20, wherein said monoclinic unit cells have dimensions of about a=211.6 A, b=51.3 A, c=66. 1 A and P=107.7°.

23. The crystalline form of claim 10, comprising one or more heavy metal atoms.

24. A polypeptide consisting of a catalytic domain of a protein tyrosine kinase having boundaries consisting of about 20 amino acid residues upstream of the first glycine in the conserved glycine-rich region of the catalytic domain, and about 17 amino acid residues downstream of the 474 conserved arginine located at the C-terminal boundary of the catalytic domain; wherein said protein tyrosine kinase is a non- insulin receptor protein tyrosine kinase. The polypeptide of claim 24, wherein said non- insulin receptor protein tyrosine kinase is selected from the group consisting of FGF-R, EGF-R, PDGF-R, KDR, CCK4, MET, TRKA, AXL, TIE, EPH, RYK, DDR, ROS, RET, LTK, ROR1, and MUSK.

26. The polypeptide of claim 25,wherein said non- insulin receptor protein tyrosine kinase is selected from the group consisting of FGF-R, PDGF-R, KDR, and RET.

27. The polypeptide of claim 24, wherein said protein tyrosine kinase is a non-receptor protein tyrosine kinase.

28. The polypeptide of claim 27, wherein said non- receptor kinase is selected from the group consisting of SRC, BRK, BTK, CSK, ABL, ZAP70, FES, FAK, JAK, and ACK.

29. The.polypeptide of claim 24 having the amino acid sequence shown in SEQ ID NO:4. A method of using the polypeptide of claim 24 to form a crystal, comprising the steps of: mixing a volume of polypeptide solution with a reservoir solution; and incubating the mixture obtained in step over the reservoir solution in a closed container, c^ Sp I WO 98/07835 PCT/US97/14885 475 under conditions suitable for crystallization.

31. A method of obtaining an FGF receptor tyrosine kinase domain polypeptide in crystalline form, comprising the steps of: mixing a volume of polypeptide solution with an equal volume of reservoir solution, wherein said polypeptide solution comprises 1 mg/mL to 60 mg/mL FGF- type tyrosine kinase domain protein, 10 mM to 200 mM buffering agent, 0 mM to 2.0 mM dithiothreitol and has a pH of about 5.5 to about 7.5, and wherein said reservoir solution comprises 10% to 30% polyethylene glycol, 0.1 M to 0.5 M ammonium sulfate, 0% to 20% (w/v) ethylene glycol or glycerol, 10 mM to 200 mM buffering agent and has a pH of about 5.5 to about 7.5; and incubating the mixture obtained in step over said reservoir solution in a closed container at a temperature between 00 and 250 oC until crystals form.

32. The method of claim 31, wherein said polypeptide solution comprises about 10 mg/mL FGF receptor tyrosine kinase domain, about 10 mM sodium chloride, about 2 mM dithiothreitol, about 10 mM Tris- HCI and has a pH of about 8; the reservoir buffer comprises about 16% polyethylene glycol (MW 10000), about 0.3 M ammonium sulfate, about 5% ethylene glycol or glycerol, about 100 mM bis-Tris and has a pH of about 6.5; and the temperature is about 4 0 C.

33. The method of claim 31, wherein said WO 98 07835 PCTIUS97/14885 476 polypeptide solution comprises a compound.

34. A cDNA encoding an FGF receptor tyrosine kinase domain protein, wherein a coding strand of the cDNA has the nucleotide sequence of SEQ ID A method of determining three dimensional structures of protein tyrosine kinases with unknown structure comprising the step of applying structural atomic coordinates set forth in Table 1, Table 2, Table 3, or Table 4.

36. The method of claim 35, comprising the following steps: aligning a first computer representation of an amino acid sequence of a protein tyrosine kinase of unknown structure with a second computer representation of a protein tyrosine kinase of known structure by matching homologous regions of amino acid sequences of said first computer representation and said second computer representation; transferring computer representations of amino acid structures in said protein tyrosine kinase of known structure to computer representations of corresponding amino acid structures in said protein tyrosine kinase with unknown structure; and determining a low energy conformation of the protein tyrosine kinase structure resulting from step (b)

37. The method of claim 35, comprising the WO 98/07835 PCT/US97/14885 477 following steps: aligning the positions of atoms in the unit cell by matching electron diffraction data from two crystals; and determining a low energy conformation of the resulting protein tyrosine kinase structure.

38. The method of claim 35, comprising the following steps: determining the secondary structure of a protein tyrosine kinase structure using NMR data; and simplifying the assignment of through- space interactions of amino acids.

39. The method of any one of claims 35, 36, 37, or 38, wherein said protein tyrosine kinase with or without known structure is a receptor protein tyrosine kinase. The method of claim 39, wherein said receptor protein tyrosine kinase with or without known structure is selected from the group consisting of FGF-R, PDGF-R, FLK, CCK4, MET, TRKA, AXL, TIE, EPH, RYK, DDR, ROS, RET, LTK, ROR1, and MUSK.

41. The method of anyone of claims 35, 36, 37, or 38, wherein said protein tyrosine kinase with or without known structure is a non-receptor protein tyrosine kinase.

42. The method of claim 41, wherein said protein tyrosine kinase with or without known structure is WO98/07835 PCT/US97/14885 478 selected from the group consisting of SRC, BRK, BTK, CSK, ABL, ZAP70, FES, FAK, JAK, and ACK.

43. A method of identifying a potential modulator of protein tyrosine kinase function by docking a computer representation of a structure of a compound with a computer representation of a structure of a cavity formed by the active-site of a protein tyrosine kinase, wherein said structure of said protein tyrosine kinase is defined by atomic structural coordinates set forth in Table 1, Table 2, Table 3, or Table 4.

44. The method of claim 43, comprising the following steps: removing a computer representation of a compound complexed with a protein tyrosine kinase and docking a computer representation of a compound from a computer data base with a computer representation of the active-site of the protein tyrosine kinase; determining a conformation of the complex resulting from step with a favorable geometric fit and favorable complementary interactions; and identifying compounds that best fit said active-site as potential modulators of protein tyrosine kinase function. The method of claim 43, comprising the following steps: modifying a computer representation of compound complexed with a protein tyrosine kinase by the deletion of a chemical group or groups or by the WO 98/07835 PCT/US97/14885 479 addition of a chemical group or groups; determining a conformation of the complex resulting from step with a favorable geometric fit and favorable complementary interactions; and identifying compounds that best fit the protein tyrosine kinase active-site as potential modulators of protein tyrosine kinase function.

46. The method of claim 43, wherein said method comprises the following steps: removing a computer representation of a compound complexed with a protein tyrosine kinase; and searching a data base for data base compounds similar to said compounds using a compound searching computer program or replacing portions of said compound with similar chemical structures from a data base using a compound construction computer program.

47. The method of any one of claims 43, 44, 45, or 46, wherein said protein tyrosine kinase is a receptor protein tyrosine kinase.

48. The method of claim 47, wherein said receptor protein tyrosine kinase is selected from the group consisting of FGF-R, PDGF-R, FLK, CCK4, MET, TRKA, AXL, TIE, EPH, RYK, DDR, ROS, RET, LTK, ROR1, and MUSK.

49. The method of anyone of claims 43, 44, 45, or 46, wherein said protein tyrosine kinase is a non- receptor protein tyrosine kinase. WO 98/07835 PCT/US97/14885 480 The method of claim 49, wherein said protein tyrosine kinase is selected from the group consisting of SRC, BRK, BTK, CSK, ABL, ZAP70, FES, FAK, JAK, and ACK.

51. a potential modulator of protein tyrosine kinase function identified by the method of any one of claims 43, 44, 45, or 46.

52. The potential modulator of claim 51, wherein said modulator is selected from a computer data base.

53. The potential modulator of claim 51, wherein said modulator is constructed from chemical groups selected from a computer data base.

54. The potential modulator of protein tyrosine kinase function of claim 51, wherein said modulator is an indolinone compound of formula I or II: R3' R4' y Rs 5 1 (I) WO 98/07835 PCTUS97/14885 481 A R4 4 CR 3 AA 1 I I R2 A 3 Re R( A 4 N R7 R (II) or a pharmaceutically acceptable salt, isomer, metabolite, ester, amide, or prodrug thereof, wherein A 2 A 3 and A 4 are independently carbon or nitrogen; R, is hydrogen or alkyl; R 2 is oxygen in the case of an oxindolinone or sulfur in the case of a thiolindolinone; R 3 is hydrogen; R 4 Rs, R 6 and R, are optionally present and are either independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO 2 NRR', SO 3 R, SR, NO z NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH 2 )nCOR, and CONRR' or (ii) any two adjacent R 4 Rs, R 6 and R, taken together form a fused ring with the aryl portion of the oxindole-based portion of the indolinone; R2', R3', R4', Rs', and Re' are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO 2 NRR', SO 3 R, WO 98/07835 PCTIUS97/14885 482 SR, NO 2 NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH 2 CO 2 R, and CONRR'; n is 0, 1, 2, or 3; R is hydrogen, alkyl or aryl; R' is hydrogen, alkyl or aryl; and A is a five membered heteroaryl ring selected from the group consisting of thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1, 2 ,4-triazole, oxazole, isoxazole, thiazole, isothiazole, furan, 1,2,3- oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4- oxadiazole, 1, 2 3 ,4-oxatriazole, 1, 2 3 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1, 2 1,3,4-thiadiazole, 1, 2 3 ,4-thiatriazole, 1,2,3,5- thiatriazole, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO 2 NRR', S03R, SR, NO 2 NRR', OH, CN, C(O)R, OC(O)R, NHC(0)R, (CH 2 nCOR or CONRR

55. A method of identifying a potential modulator of protein tyrosine kinase function as a modulator of protein tyrosine kinase function, comprising the following steps: administering said potential modulator to cells; comparing the level of protein tyrosine kinase phosphorylation between cells not administered the potential modulator and cells administered said potential,modulator; and identifying said potential modulator as a modulator of protein tyrosine kinase function based on 483 the difference in the level of protein tyrosine kinase phosphorylation.

56. A method of identifying a potential modulator of protein tyrosine kinase function as a modulator of protein tyrosine kinase function, wherein said method comprises the following steps: administering a preparation of said potential modulator to cells; comparing the rate of cell growth between cells not administered the modulator and cells administered the modulator; and identifying said potential modulator as a modulator of protein tyrosine kinase function based on the difference in the rate of cell growth.

57. A method of treating a disease associated with a protein tyrosine kinase with inappropriate activity in a cellular organism, wherein said method comprises the steps of: administering a modulator of protein tyrosine kinase function to the organism, wherein said modulator is in an acceptable pharmaceutical preparation; and activating or inhibiting the protein tyrosine kinase function to treat the disease.

58. A modulator of protein tyrosine kinase function when used in treating a disease associated with a protein tyrosine kinase with inappropriate activity in a cellular organism.

59. The use of a modulator of protein tyrosine kinase function for the 20 manufacture of a medicament for treating a disease associated with a protein tyrosine kinase with inappropriate activity in a cellular organism. The method, modulator or use of any one of claims 55, to 59, wherein said protein tyrosine kinase is a receptor protein tyrosine kinase.

61. The method, modulator or use of claim 60, wherein said receptor protein 25 tyrosine kinase is selected from the group containing FGF-R, PDGF-R, FLK, CCK4, MET, TRKA, AXL, TIE, EPH, RYK, DDR, ROS, RET, LTK, ROR1, and MUSK.

62. The method, modulator or use of any one of claims 55, to 59, wherein said protein tyrosine kinase is a non-receptor protein tyrosine kinase.

63. The method, modulator or use of claim 62, wherein said non-receptor protein tyrosine kinase is selected from a group consisting of SRC, BRK, BTK, VO CSK, ABL, ZAP70, FES, FAK, JAK, and ACK.

64. The crystalline form of claim 1 wherein said catalytic domain has boundaries consisting of about 20 amino acid residues upstream of the first glycine in the conserved glycine-rich region of the catalytic domain, and about 17 amino acid residues downstream of the conserved arginine located at the C-terminal boundary of the catalytic domain. The polypeptide of claim 26, wherein said non-insulin receptor protein tyrosine kinase is FGF-R.

66. The method of claim 30, wherein said reservoir solution comprises to 30% polyethylene glycol, 0.1M to 0.5M ammonium sulfate, 0% to 20% ethylene N:\LIBC\04347.doc glycol or glycerol, 10mM to 200mM buffering agent, and has a pH of about 5.5 to about

67. A crystalline form comprising a polypeptide, wherein said polypeptide consists of a catalytic domain of a protein tyrosine kinase, wherein said protein tyrosine kinase is non-insulin receptor protein tyrosine wherein said crystalline form is prepared by a process comprising the steps of: mixing a volume of polypeptide solution with a reservoir solution; and incubating the mixture obtained in step over the reservoir solution in a closed container, under conditions suitable for crystallisation

68. The crystalline form of claim 67, wherein said reservoir solution comprises 10% to 30% polyethylene glycol, 0.1M to 0.5M ammonium sulfate, 0% to ethylene glycol or glycerol, 10mM to 200mM buffering agent, and has a pH of to about

69. The crystalline form of claim 67, wherein said non-insulin receptor protein tyrosine kinase is selected from the group consisting of FGF-R, EGF-R, PDGF-R, FLK, CCK4, MET, TRKA, AXL, TIE, EPH, RYK, DDR, ROS, RET, LTK, ROR1, and MUSK.

70. The crystalline form of claim 67, wherein said non-insulin receptor protein tyrosine kinase is selected from the group consisting of FGF-R, PDGF-R, 20 KDR, and RET.

71. The crystalline form of claim 70, wherein said non-insulin receptor protein tyrosine kinase is FGF-R.

72. The crystalline form of claim 67, wherein said catalytic domain has boundaries consisting of:- about 20 amino acid residues upstream of the first 25 glycine in the conserved glycine-rich region of the catalytic domain, and about 17 amino acid residues downstream of the conserved arginine located at the C- S terminal boundary of the catalytic domain.

73. A crystalline form comprising a polypeptide wherein said polypeptide consists of a catalytic domain of a protein tyrosine kinase, substantially as hereinbefore described with reference to any one of the examples.

74. A polypeptide consisting of a catalytic domain of a protein tyrosine Skinase, substantially as hereinbefore described with reference to any one of the S examples. A method of forming a crystal, substantially as hereinbefore described with reference to any one of the examples.

76. A method of obtaining an FGF receptor tyrosine kinase domain polypeptide in crystalline form, substantially as hereinbefore described with reference to any one of the examples.

77. A cDNA encoding an FGF receptor tyrosine kinase domain protein, substantially as hereinbefore described with reference to any one of the examples. N:\LIBC\04347.doc 485

78. A method of determining three dimentional structures of protein tyrosine kinases with unknown structure, substantially as hereinbefore described with reference to any one of the examples.

79. A method of identifying a potential modulator of protein tyrosine kinase function, substantially as hereinbefore described with reference to any one of the examples. A potential modulator of protein tyrosine kinase function, substantially as hereinbefore described with reference to any one of the examples. Dated 19 March 1999 SUGEN, INC. Patent Attorneys for the Applicant/Nominated Person SPRUSON&FERGUSON SO S. 0 0 0 S N:LIBC\04347.doc