WO2009033183A2 - Compounds and methods for treatment of hcv and conditions associated with cd81 binding - Google Patents

Abstract

The invention features compositions and methods that are useful for treating or preventing HCV infection and associated conditions. In addition, the invention provides methods for identifying compounds useful for treatment of HCV infection and associated conditions.

Description

Date or Deposit: ieptemoer 8, zuua

COMPOUNDS AND METHODS FOR TREATMENT OF HCV AND CONDITIONS ASSOCIATED WITH CD81 BINDING

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application No. 60/970,951, filed September 8, 2007, the contents of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Hepatitis C viral (HCV) infection is a common cause of chronic liver disease and a major public health problem. Except for symptomatic control and replacement therapy, there is currently no effective treatment available for subjects having HCV infection; the current combination therapy with interferon α (IFN) and Ribavirin is only partially effective.

New compounds and methods for the treatment of HCV infection, and for generally for conditions associated with binding of proteins to CD81, would be beneficial.

SUMMARY OF THE INVENTION

The invention features compositions and methods that are useful for treating and/or preventing conditions associated with CD81 binding (including, without limitation, Hepatitis C viral (HCV) infection and conditions or symptoms related to HCV infection; multiple sclerosis; and malaria infection and conditions or symptoms related to malaria infection) and methods for identifying compounds useful for such treatment. In one aspect, the invention provides a method of treating or preventing a condition associated with CD81 binding in a subject in need of such treatment. The method includes administering to the subject a compound capable of binding to a binding site in a CD81 protein, said binding site comprising one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acids) of CD81 selected from Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Asp 189, under conditions such that the condition associated with CD81 binding is treated (or prevented). In certain embodiments, the condition associated with CD81 binding is selected from HCV infection, multiple sclerosis, and malaria. In certain embodiments, the condition associated with CD81 binding is HCV infection. In certain embodiments, compound is a compound selected from the compounds of Tables 1 and 2.

In another aspect, the invention provides a method of treating HCV infection in a subject in need of such treatment, the method comprising administering to the subject a compound capable of reducing the level of hepatitis C virus in the subject under conditions such that HCV infection is treated or ameliorated.

In a further aspect, the invention provides a method of treating a condition related to or associated with HCV infection in a subject in need of such treatment, the method comprising administering to the subject a compound capable of disrupting NS3 helicase or RNA-dependent RNA polymerase NS5B under conditions such that a condition related to or associated with HCV infection is treated or ameliorated.

In another aspect, the invention provides a method of inhibiting viral replication (e.g., HCV replication) in a cell, the method comprising contacting the cell with a compound capable of inhibiting HCV helicase or polymerase activity.

In yet another aspect, the invention provides a method of inhibiting HCV NS3 helicase in a cell, the method comprising contacting the cell with a compound capable of inhibiting HCV NS3 helicase activity under conditions such that HCV NS3 is partially or wholly inhibited.

In yet another aspect, the invention provides a method of inhibiting HCV NS5B RNA polymerase in a cell, the method comprising contacting the cell with a compound capable of inhibiting HCV NS5B RNA polymerase under conditions such that HCV NS5B RNA polymerase is partially or wholly inhibited.

In a still further aspect, the invention provides a method for treating a subject diagnosed as having HCV infection, the method comprising administering to the subject a pharmaceutically effective amount of a compound capable of inhibiting HCV helicase or polymerase activity in the subject.

In one aspect, the invention provides a method of treating HCV infection (or a condition associated with CD81) in a subject in need of such treatment, the method comprising administering to the subject a compound capable of blocking interaction between CD81 and a protein such as HCV E2 (e.g., viral entry inhibitors), thereby treating HCV infection (or a condition associated with CD81), e.g., by disrupting or inhibiting interaction between CD81 and an endogenous or exogenous protein, e.g., thereby preventing entry of virus into a cell of the subject and/or preventing HCV infection in the subject and/or reducing the level of hepatitis C virus in the subject under conditions such that HCV infection (or the condition associated with CD81) is treated, ameliorated or prevented (e.g., entry of virus into a cell is inhibited or prevented and/or the level of hepatitis C virus in the subject is reduced).

In another aspect, the invention provides a pharmaceutical composition comprising a compound capable of inhibiting HCV helicase or polymerase activity, or a compound capable of blocking, inhibiting and/or reducing an interaction between CD81 and a protein (such as HCV E2), or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable vehicle.

In another aspect, the invention provides an oral dosage form comprising a compound capable of inhibiting HCV helicase or polymerase activity, or a compound capable of blocking, inhibiting and/or reducing an interaction between CD81 and a protein (such as HCV E2), or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable vehicle.

In a further aspect, the invention provides a kit for the treatment of HCV infection in a sample or subject, the kit comprising an effective amount of a compound capable of inhibiting HCV helicase or polymerase activity, and instructions for administering the compound capable of inhibiting HCV helicase or polymerase activity to a subject to treat HCV infection.

In a further aspect, the invention provides a kit for the treatment of a condition associated with CD81 binding (including, e.g., HCV) in a sample or subject, the kit comprising an effective amount of a compound capable of inhibiting an interaction between CD81 and a protein, and instructions for administering the compound capable of inhibiting an interaction between CD81 and a protein to a subject to treat a condition associated with CD 81 binding.

In any of the above methods, pharmaceutical compositions, oral dosage forms, or kits of the invention, the compound can be a compound identified by computational screening, and/or can be a compound selected from the following: methyl 5-amino-l- (4-chloro-2-methyl-phenyl)triazole-4-carboxylate, 3-anilinophenol, 2-(4-oxochromen- 3-yl)-l,3-thiazolidine-4-carboxylic acid, 2-benzothiophen-3-yl-7-methyl-8H-l,8- naphthyridin-4-one, 3-(5-oxo-l-phenyl-2-sulfanylidene-imidazolidin-4-yl)propanoic acid, 3-(2-furylmethylideneamino)-2-methyl-quinazolin-4-one, 3-[(4S)-5-oxo-l- phenyl-2-sulfanylidene-imidazolidin-4-yl]propanamide, ethyl 4- [(2- methylphenyl)amino]-2-methylsulfanyl-pyrimidine-5-carboxylate, 2-Methoxy-5H- pyrido(3',2':5,6)(l,4)thiazino(2,3-b)quinoxaline, 3-phenyl-5-(2-methylpropyl)-2- sulfanylidene-imidazolidin-4-one, 3-chloro-4-methylphenylphosphinic acid, A-

(diethylamino)phenyl-phosphinic acid, Hydroxy(phenyl)methyl-phosphinic acid, 1- Amino-3-(methylthio)propyl-phosphinic acid, 2-amino- 1 -(4-methoxybenzyl)ethyl- phosphonic acid, 2,2,2-Trichloro- 1 -((hydroxy(oxido)amino)methyl)ethyl phenylcarbamate, l-(3-Chlorophenoxy)-2,4-dinitrobenzene, Ethyl 3-(3,5-dioxo-4- phenyl- l,2,4-triazolidin-l-yl)-5-methyl-2-oxotetrahydrofuran-3-carboxylate, 2-amino- 7-methoxy-6,10-dihydro-5aH-pyrido[2,3-b]pyrimido[4,5-e]thiazin-4-ol, 2-(((l- carboxy-2-(lH-imidazol-4-yl)ethyl)amino)carbonyl)-benzoic acid, 1,1,3,4- tetrabromo-4-cyclohexylbutan-2-one, 2,3,4-Triphenyl-l,2,4-oxadiazolidin-5-one, N- methylbenzanilide, N-(triphenylmethyl) pyridin-2-amine, N-carbamoyl-2- (phenylmethyl)butanamide, 5-phenyl-[l,2,5]oxadiazolo[3,4-e]pyrimidin-7-amine, N- (2,6-dimethylphenyl)-l-(4-nitrophenyl)methanimine, NSC269216; or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the compound is methyl 5-amino-l-(4-chloro-2-methyl-phenyl)triazole-4-carboxylate, 3- anilinophenol, 2-(4-oxochromen-3-yl)-l,3-thiazolidine-4-carboxylic acid, 2- benzothiophen-3-yl-7-methyl-8H-l,8-naphthyridin-4-one, 3-(5-oxo-l-phenyl-2- sulfanylidene-imidazolidin-4-yl)propanoic acid, 3-(2-furylmethylideneamino)-2- methyl-quinazolin-4-one, 3-[(4S)-5-oxo-l-phenyl-2-sulfanylidene-imidazolidin-4- yl]propanamide, ethyl 4-[(2-methylphenyl)amino]-2-methylsulfanyl-pyrimidine-5- carboxylate, 2-Methoxy-5H-pyrido(3',2':5,6)(l,4)thiazino(2,3-b)quinoxaline, 3- phenyl-5-(2-methylpropyl)-2-sulfanylidene-imidazolidin-4-one, 3-chloro-4- methylphenylphosphinic acid, 4-(diethylamino)phenyl-phosphinic acid, Hydroxy(phenyl)methyl-phosphinic acid, 1 - Amino-3-(methylthio)propyl-phosphinic acid, 2-amino- l-(4-methoxybenzyl)ethyl-phosphonic acid, 2,2,2-Trichloro- 1- ((hydroxy(oxido)amino)methyl)ethyl phenylcarbamate, 1 -(3-Chlorophenoxy)-2,4- dinitrobenzene, Ethyl 3-(3,5-dioxo-4-phenyl-l,2,4-triazolidin-l-yl)-5-methyl-2- oxotetrahydrofuran-3-carboxylate, 2-amino-7-methoxy-6,10-dihydro-5aH-pyrido[2,3- b]pyrimido[4,5-e]thiazin-4-ol, 2-(((l-carboxy-2-(lH-imidazol-4- yl)ethyl)amino)carbonyl)-benzoic acid; or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the compound is l,l,3,4-tetrabromo-4- cyclohexylbutan-2-one, 2,3,4-Triphenyl-l,2,4-oxadiazolidin-5-one, N- methylbenzanilide, N-(triphenylmethyl) pyridin-2-amine, N-carbamoyl-2- (phenylmethyl)butanamide, 5-phenyl-[l,2,5]oxadiazolo[3,4-e]pyrimidin-7-amine, N- (2,6-dimethylphenyl)-l-(4-nitrophenyl)methanimine, or NSC269216; or a pharmaceutically acceptable salt or solvate thereof.

Also provided are methods, including computational screening methods, for identifying compounds which can bind to an HCV replication enzyme, and compounds which can inhibit replication of HCV enzymes (e.g., HCV polymerase, HCV helicase, HCV protease). Also provided are methods, including computational screening methods, for identifying compounds which can bind to, or inhibit the binding of a protein to, CD81.

In one aspect, the invention provides a computer for producing a three- dimensional representation of a) a molecule or molecular complex, wherein said molecule or molecular complex comprises a binding site in the HCV NS3 or HCV NS5B enzyme; or b) a three-dimensional representation of a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than about 2.0 (more preferably not more than 1.5) angstroms, wherein said computer comprises: (i) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises the structure coordinates of structure coordinates of amino acid residues in the HCV NS3 or HCV NS5B protein; (ii) a working memory for storing instructions for processing said machine-readable data; (iii) a central-processing unit coupled to said working memory and to said machine-readable data storage medium for processing said machine readable data into said three-dimensional representation; and (iv) a display coupled to said central-processing unit for displaying said three-dimensional representation.

In one aspect, the invention provides a computer for producing a three- dimensional representation of a) a molecule or molecular complex, wherein said molecule or molecular complex comprises a binding site in the CD81 protein which binds to proteins (including HCV E2 protein) including at least one of amino acids Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Aspl89; or b) a three-dimensional representation of a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of amino acids Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Aspl89 of CD81 of not more than about 2.0 (more preferably not more than 1.5) angstroms, wherein said computer comprises: (i) a machine -readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises the structure coordinates of structure coordinates of one or more amino acid residues selected from Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Aspl89 of the human CD81 protein; (ii) a working memory for storing instructions for processing said machine-readable data; (iii) a central-processing unit coupled to said working memory and to said machine- readable data storage medium for processing said machine readable data into said three-dimensional representation; and (iv) a display coupled to said central-processing unit for displaying said three-dimensional representation.

In another aspect, the invention provides a method for evaluating the potential of a chemical entity to associate with a) a molecule or molecular complex comprising a binding pocket defined by structure coordinates of HCV NS3 or HCV NS5B protein, or b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 2.0 (more preferably 1.5) angstroms, the method comprising the steps of: i) employing computational means to perform a fitting operation between the chemical entity and a binding pocket of the molecule or molecular complex; and ii) analyzing the results of the fitting operation to quantify the association between the chemical entity and the binding pocket.

In another aspect, the invention provides a method for evaluating the potential of a chemical entity to bind with a) a molecule or molecular complex comprising a binding pocket defined by structure coordinates of one or more of amino acid residues Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Asp 189 of the CD81 protein, or b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 2.0 (more preferably 1.5) angstroms, the method comprising the steps of: i) employing computational means to perform a fitting operation between the chemical entity and a binding pocket of the molecule or molecular complex; and ii) analyzing the results of the fitting operation to quantify the association between the chemical entity and the binding pocket. In another aspect, the invention provides a method for preventing HCV infection (or a condition associated with binding of a protein to CD81) in a subject, the method comprising administering to the subject an effective amount of a compound capable of disrupting binding of a protein with CD81 protein, such that a condition associated with CD81 binding (including HCV) is prevented in the subject. In certain embodiments, the compound is a compound capable of binding to CD81 at or about a binding pocket defined by structure coordinates of one or more of amino acid residues Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Aspl89 of the CD81 protein. In certain embodiments, the compound is a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method of treating or preventing liver damage in a subject suffering from HCV infection, the method comprising administering to the subject a compound capable of inhibiting HCV helicase (e.g., NS3) or HCV polymerase (e.g., NS5B) in the subject under conditions such that liver damage in the subject is treated, ameliorated or prevented.

In another aspect, wherein the method further comprises the step of identifying the subject as suffering from HCV infection-related liver damage prior to the step of administering to the subject the compound capable of inhibiting HCV helicase or HCV polymerase. In certain embodiments, the method further comprises the step of determining the efficacy of administration to the subject of the compound capable of inhibiting HCV helicase or HCV polymerase. In certain embodiments, the step of determining the efficacy of administration to the subject of the compound comprises testing liver function of the subject before and after administration of the compound, and comparing the liver function determined before administration of the compound and after administration of the compound.

In another aspect, the invention provides a method of preserving liver function in a subject suffering from HCV infection, the method comprising administering to the subject a compound capable of inhibiting HCV helicase or HCV polymerase under conditions such that liver function in the subject is preserved. In another aspect, the invention provides a packaged pharmaceutical formulation for the treatment or prevention of liver damage in a subject suffering from HCV infection, the packaged pharmaceutical formulation comprising: an effective amount of the amount of a compound capable of inhibiting HCV helicase or HCV polymerase; and instructions for administering the compound capable of inhibiting HCV helicase or HCV polymerase to a subject suffering from HCV infection for the treatment or prevention of liver damage in the subject.

In another aspect, the invention provides a packaged pharmaceutical formulation for preserving liver function in a subject suffering from HCV infection, the packaged pharmaceutical formulation comprising: an effective amount of the amount of a compound capable of inhibiting HCV helicase or HCV polymerase; and instructions for administering the compound capable inhibiting HCV helicase or HCV polymerase to a subject suffering from HCV infection for the preservation of liver function in the subject.

Other aspects and embodiments of the invention are described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a scheme illustrating the computational docking approach used to identify compounds according to the invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions By "reduces" or "increases" is meant a negative or positive alteration, respectively, of at least 10%, 25%, 50%, 75%, or 100%.

The term "treating" or "treated" refers to administering a compound described herein to a subject with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a disease or condition, the symptoms of the disease or condition or the predisposition toward the disease or condition.

The term "condition associated with CD81 binding in a subject" refers to a disease or condition in which the symptoms or progress of the disease or condition is associated with or related to binding of a protein (including either an endogenous protein or an exogenous protein (e.g., viral protein or a malarial protein)) to CD81 in a subject. For example, a condition associated with CD81 binding in a subject can include HCV infection, malaria infection (see, e.g., Dijstra et al., Neurobiology of Disease, 31:413-421 (2008) or multiple sclerosis (MS) (see, e.g., Silvie et al., Cellular Microbiology 8(7):1134-1146 (2006)). "An effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of a compound described herein may range from about 1 mg/Kg to about 5000 mg/Kg body weight. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.

Compounds of the Invention

It has been found that certain compounds are capable of binding to a binding site in the CD81 protein, said binding site comprising one or more amino acids of CD81 selected from Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Aspl89 of CD81, and thereby modulating the activity of CD81 and/or the ability of proteins (including, e.g., HCV proteins involved in viral entry into host cells, or malarial proteins SPECT-I and/or SPECT-2) to bind to CD81. In certain embodiments, a compound of the invention can prevent, inhibit, or disrupt (e.g., reduce by at least 10%, 25%, 50%, 75%, or 100%) the binding of an endogenous or exogenous protein to CD81 (e.g., in a host cell).

Without wishing to be bound by theory, it is believed that compounds capable of binding to the binding site of CD81 may have one or more of the following structural features: (i) an aromatic ring, (ii) an oxygen atom(s) that likely interact with elements at the base of the structural pocket of CD81. For example, the oxygen atoms in active compounds may be capable of interaction with non-carbon atoms in Cysl57, Serl59, Thrl66 and Asnl84 residues at the base of the structural pocket. As a further example, the aromatic ring in the active compounds may be capable of interaction with carbon atoms in Thrl63, Thrl66 and Thrl67, Ilel81 and Leul85.

Thus, in certain embodiments, a compound of this invention includes at least one aromatic ring (such as a phenyl ring, or a heteroaromatic ring such as a pyridyl ring, a triazole ring, a furanyl ring, a pyrimidinyl ring or an imidazolyl ring) or a fused aromatic ring system such as quinazolinyl, pyrido[2,3-b]pyrimido[4,5-e]thiazinyl. In certain embodiments, a compound of this invention includes at least one oxygen atom, e.g., an oxygen atom(s) capable of interaction with non-carbon atoms in Cysl57, Serl59, Thrl66 and Asnl84. In certain embodiments, the compound includes a carboxylic, phosphonic, or phosphinic acid or ester group. It has further been found that certain compounds are capable of modulating

(e.g., inhibiting) proteins that participate in the HCV viral replication cascade. Such compounds are sometimes referred to herein as "HCV polymerase", "HCV helicase" or "HCV inhibitor" compounds. In certain embodiments, a compound of the invention can bind to enzymes that are relevant in HCV replication, and thereby interfere with proliferation or replication of HCV.

In certain embodiments, a compound of the invention can prevent, inhibit, or disrupt (e.g., reduce by at least 10%, 25%, 50%, 75%, or 100%) the activity of HCV helicase or HCV polymerase.

In certain embodiments, a compound of the invention is a non-polymeric (e.g., small molecule) compound having a molecular weight less than about 1000 daltons, less than 800, less than 600, less than 500, less than 400, or less than about 300 daltons. In certain embodiments, an active compound can increase the amount (e.g., from or in a cell) of a stably-folded and/or physiologically active mutant protein by at least 10%, 15%, 20%, 25%, 50%, 75%, or 100% compared to an untreated control cell or protein.

Examples of compounds of the invention include the compounds of Table 1, Table 2 and Table 3, and pharmaceutically acceptable salts and solvates thereof.

As used herein, the term "pharmaceutically acceptable salt," is a salt formed from an acid and a basic group of one of the compounds of the invention (e.g., of Tables 1-3). Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i. e. , 1,1 '-methylene- bis-(2-hydroxy-3-naphthoate)) salts.

The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of the invention (e.g., of Tables 1-3) having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)- amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)- amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound disclosed herein, e.g., a compound of Tables 1-3, having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid. Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, andp-toluenesulfonic acid.

Methods of the Invention

In certain aspects, the present invention features methods, compounds, and compositions useful for treating or preventing a condition associated with CD81 binding in a subject in need of such treatment.

In these aspects, the invention is generally based on the discovery that certain compounds can be used to inhibit the binding of proteins (such as HCV protease, or malarial proteins SPECT-I and/or SPECT-2) to CD81. Without wishing to be bound by any particular theory, these compounds are believed to prevent entry of infectious particles into cells (in the case of HCV and malaria) or modulating cellular infiltration or immune response (in the case of multiple sclerosis (MS)).

In certain aspects, the method includes administering to the subject a compound capable of binding to a binding site in the CD81 protein, said binding site comprising one or more amino acids of CD81 selected from Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Aspl89 of CD81, under conditions such that a condition associated with CD81 binding is treated. In certain embodiments, the condition associated with CD81 binding is selected from HCV infection, multiple sclerosis, and malaria. In certain embodiments, the condition associated with CD81 binding is HCV infection. In certain embodiments, the compound is a compound selected from the compounds of Tables 1 and 2.

The invention also features compositions and methods that are useful for inhibiting HCV helicase or HCV polymerase proteins in vitro or in vivo and for treatment of conditions associated with HCV infection. This aspect of the invention is generally based on the discovery that certain compounds can be used to inhibit HCV helicase or HCV polymerase proteins in a cell, or inhibit the binding of HCV E2 to CD81. Without wishing to be bound by any particular theory, these compounds are believed to prevent viral replication (in the case of HCV helicase or HCV polymerase inhibitors) or prevent entry of HCV into cells (in the case of compounds capable of disrupting binding of, or interaction between, HCV E2 to CD81).

In one aspect, the invention provides a method of treating HCV infection, or a condition related HCV infection, in a subject in need of such treatment, the method comprising administering to the subject a compound capable of inhibiting HCV helicase or HCV polymerase in a subject under conditions such that the HCV infection, or a condition related to HCV infection, is treated or ameliorated.

Conditions related to HCV infection include conditions related to the presence and/or proliferation of HCV levels in a subject, and include, for example, liver damage, and liver diseases such as chronic hepatitis, cirrhosis, and liver cancer (e.g., hepatocellular carcinoma).

In a still further aspect, the invention provides a method for treating a subject diagnosed as having HCV infection (e.g., by diagnosis, identification of marker, etc.), the method comprising administering to the subject a pharmaceutically effective amount of a compound capable of inhibiting HCV helicase or HCV polymerase activity in the subject.

In another aspect, the invention provides a method for preventing HCV infection in a subject, the method comprising administering to the subject an effective amount of a compound capable of disrupting binding of HCV E2 protein with CD81 protein, such that HCV infection is prevented in the subject. In effect, administration of a compound capable of disrupting binding of HCV E2 protein with CD81 protein prevents entry of HCV into cells, preventing (in whole or in part) the establishment of HCV infection. In this aspect, the compound can be administered until the HCV viral particles are cleared from subject's body, e.g., by the immune system. The administration of a compound in this way is analogous to "passive" vaccination in that infection is inhibited or prevented by administration of a compound which prevents establishment of infection (e.g., by inhibiting viral entry into a cell) but does not itself promote an immune response to the virus. In certain embodiments, the compound is a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method for preventing malaria infection in a subject, the method comprising administering to the subject an effective amount of a compound capable of disrupting binding of a malarial protein (such as SPECT-I and/or SPECT-2)with CD81 protein, such that HCV infection is prevented in the subject. In effect, administration of a compound capable of disrupting binding of HCV E2 protein with CD81 protein prevents entry of HCV into cells, preventing (in whole or in part) the establishment of HCV infection. In this aspect, the compound can be administered until the HCV viral particles are cleared from subject's body, e.g., by the immune system. The administration of a compound in this way is analogous to "passive" vaccination in that infection is inhibited or prevented by administration of a compound which prevents establishment of infection (e.g., by inhibiting viral entry into a cell) but does not itself promote an immune response to the virus. In certain embodiments, the compound is a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. The compounds delineated herein can be used alone or in combination with one or more additional compounds to treat or prevent conditions associated with HCV infection, for example, cirrhosis or liver damage.

Pharmaceutical Compositions The present invention features pharmaceutical preparations comprising compounds together with pharmaceutically acceptable carriers, where the compounds provide for the treatment, prevention or amelioration of HCV infection. Such preparations have both therapeutic and prophylactic applications. In one embodiment, a pharmaceutical composition includes compound capable of inhibiting HCV helicase or HCV polymerase (e.g., a compound of Table 3) or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a pharmaceutical composition includes compound capable of inhibiting an interaction between CD81 and a protein (such as HCV E2 protein) (e.g., a compound of Table 1 or Table 2) or a pharmaceutically acceptable salt or solvate thereof. Compounds of the invention may be administered as part of a pharmaceutical composition.

The compositions should be sterile and contain a therapeutically effective amount of the active compound in a unit of weight or volume suitable for administration to a subject. The compositions and combinations of the invention can be part of a pharmaceutical pack, where each of the compounds is present in individual dosage amounts.

The phrase "pharmaceutically acceptable" refers to those compound of the inventions of the present invention, compositions containing such compounds, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

In another aspect, the invention provides a pharmaceutical composition comprising a compound capable of inhibiting HCV helicase or HCV polymerase, or a pharmaceutically acceptable salt or solvate thereof, in a pharmaceutically acceptable vehicle.

In another aspect, the invention provides an oral dosage form comprising a compound capable of inhibiting an interaction between CD81 and a protein (such as HCV E2 protein) , or a pharmaceutically acceptable salt or solvate thereof, in a pharmaceutically acceptable vehicle.

In another aspect, the invention provides an oral dosage form comprising a compound capable of inhibiting HCV helicase or HCV polymerase, or a pharmaceutically acceptable salt or solvate thereof, in a pharmaceutically acceptable vehicle. Pharmaceutical compositions of the invention to be used for prophylactic or therapeutic administration should be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 μm membranes), by gamma irradiation, or any other suitable means known to those skilled in the art. Therapeutic compound compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. These compositions ordinarily will be stored in unit or multi-dose containers, for example, sealed ampoules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution.

The compounds may be combined, optionally, with a pharmaceutically acceptable excipient. The term "pharmaceutically-acceptable excipient" as used herein means one or more compatible solid or liquid filler, diluents or encapsulating substances that are suitable for administration into a human. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate administration. The components of the pharmaceutical compositions also are capable of being co-mingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction that would substantially impair the desired pharmaceutical efficacy. Compounds of the present invention can be contained in a pharmaceutically acceptable excipient. The excipient preferably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetate, lactate, tartrate, and other organic acids or their salts; tris- hydroxymethylaminomethane (TRIS), bicarbonate, carbonate, and other organic bases and their salts; antioxidants, such as ascorbic acid; low molecular weight (for example, less than about ten residues) polypeptides, e.g., polyarginine, polylysine, polyglutamate and polyaspartate; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone (PVP), polypropylene glycols (PPGs), and polyethylene glycols (PEGs); amino acids, such as glycine, glutamic acid, aspartic acid, histidine, lysine, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, sucrose, dextrins or sulfated carbohydrate derivatives, such as heparin, chondroitin sulfate or dextran sulfate; polyvalent metal ions, such as divalent metal ions including calcium ions, magnesium ions and manganese ions; chelating agents, such as ethylenediamine tetraacetic acid (EDTA); sugar alcohols, such as mannitol or sorbitol; counterions, such as sodium or ammonium; and/or nonionic surfactants, such as polysorbates or poloxamers. Other additives may be included, such as stabilizers, anti-microbials, inert gases, fluid and nutrient replenishers (i.e., Ringer's dextrose), electrolyte replenishers, and the like, which can be present in conventional amounts.

The compositions, as described above, can be administered in effective amounts. The effective amount will depend upon the mode of administration, the particular condition being treated and the desired outcome. It may also depend upon the stage of the condition, the age and physical condition of the subject, the nature of concurrent therapy, if any, and like factors well known to the medical practitioner. For therapeutic applications, it is that amount sufficient to achieve a medically desirable result. Generally, doses of the compounds of the present invention would be from about 0.01 mg/kg per day to about 1000 mg/kg per day, e.g., from about 0.1 mg/kg per day to about 100 mg/kg per day. It is expected that doses ranging from about 1 to about 1000 mg/kg will be suitable. Lower doses may be used with certain forms of administration, such as intravenous administration. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of a composition of the present invention.

A variety of administration routes are available. The methods of the invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. In one embodiment, a composition of the invention is administered orally. Oral administration may provide certain advantages, e.g., for treatment or prevention of liver damage, oral administration can provide a high concentration of the drug to hepatic circulation and thus to the liver. Other modes of administration include rectal, topical, intraocular, buccal, intravaginal, intracisternal, intracerebroventricular, intratracheal, nasal, transdermal, within/on implants, or parenteral routes. The term "parenteral" includes subcutaneous, intrathecal, intravenous, intramuscular, intraperitoneal, or infusion. Compositions comprising a composition of the invention can be added to a physiological fluid, such as to the intravitreal humor. For CNS administration, a variety of techniques are available for promoting transfer of the therapeutic across the blood brain barrier including disruption by surgery or injection, drugs which transiently open adhesion contact between the CNS vasculature endothelial cells, and compounds that facilitate translocation through such cells. Oral administration can be preferred for prophylactic treatment because of the convenience to the patient as well as the dosing schedule. Oral administration is also beneficial because of the first passage effect on the liver, which may reduce the systemic side effects.

Pharmaceutical compositions of the invention can optionally further contain one or more additional proteins as desired, including plasma proteins, proteases, and other biological material, so long as it does not cause adverse effects upon administration to a subject. Suitable proteins or biological material may be obtained from human or mammalian plasma by any of the purification methods known and available to those skilled in the art; from supernatants, extracts, or lysates of recombinant tissue culture, viruses, yeast, bacteria, or the like that contain a gene that expresses a human or mammalian plasma protein which has been introduced according to standard recombinant DNA techniques; or from the fluids (e.g., blood, milk, lymph, urine or the like) or transgenic animals that contain a gene that expresses a human plasma protein which has been introduced according to standard transgenic techniques.

Pharmaceutical compositions of the invention can comprise one or more pH buffering compounds to maintain the pH of the formulation at a predetermined level that reflects physiological pH, such as in the range of about 5.0 to about 8.0. The pH buffering compound used in the aqueous liquid formulation can be an amino acid or mixture of amino acids, such as histidine or a mixture of amino acids such as histidine and glycine. Alternatively, the pH buffering compound is preferably an agent which maintains the pH of the formulation at a predetermined level, such as in the range of about 5.0 to about 8.0, and which does not chelate calcium ions. Illustrative examples of such pH buffering compounds include, but are not limited to, imidazole and acetate ions. The pH buffering compound may be present in any amount suitable to maintain the pH of the formulation at a predetermined level.

Pharmaceutical compositions of the invention can also contain one or more osmotic modulating agents, i.e., a compound that modulates the osmotic properties (e.g., tonicity, osmolality and/or osmotic pressure) of the formulation to a level that is acceptable to the blood stream and blood cells of recipient individuals. The osmotic modulating agent can be an agent that does not chelate calcium ions. The osmotic modulating agent can be any compound known or available to those skilled in the art that modulates the osmotic properties of the formulation. One skilled in the art may empirically determine the suitability of a given osmotic modulating agent for use in the inventive formulation. Illustrative examples of suitable types of osmotic modulating agents include, but are not limited to: salts, such as sodium chloride and sodium acetate; sugars, such as sucrose, dextrose, and mannitol; amino acids, such as glycine; and mixtures of one or more of these agents and/or types of agents. The osmotic modulating agent(s) may be present in any concentration sufficient to modulate the osmotic properties of the formulation.

Pharmaceutical compositions of the invention can also be a non-aqueous liquid formulation. Any suitable non-aqueous liquid may be employed, provided that it provides stability to the active agents (s) contained therein. Preferably, the nonaqueous liquid is a hydrophilic liquid. Illustrative examples of suitable non-aqueous liquids include: glycerol; dimethyl sulfoxide (DMSO); polydimethylsiloxane (PMS); ethylene glycols, such as ethylene glycol, diethylene glycol, Methylene glycol, polyethylene glycol ("PEG") 200, PEG 300, and PEG 400; and propylene glycols, such as dipropylene glycol, tripropylene glycol, polypropylene glycol ("PPG") 425, PPG 725, PPG 1000, PPG 2000, PPG 3000 and PPG 4000.

Pharmaceutical compositions of the invention can also be a mixed aqueous/non-aqueous liquid formulation. Any suitable non-aqueous liquid formulation, such as those described above, can be employed along with any aqueous liquid formulation, such as those described above, provided that the mixed aqueous/non-aqueous liquid formulation provides stability to the compound contained therein. Preferably, the non- aqueous liquid in such a formulation is a hydrophilic liquid. Illustrative examples of suitable non-aqueous liquids include: glycerol; DMSO; PMS; ethylene glycols, such as PEG 200, PEG 300, and PEG 400; and propylene glycols, such as PPG 425, PPG 725, PPG 1000, PPG 2000, PPG 3000 and PPG 4000.

Suitable stable formulations can permit storage of the active agents in a frozen or an unfrozen liquid state. Stable liquid formulations can be stored at a temperature of at least -70°C, but can also be stored at higher temperatures of at least O⁰C, or between about 0.1⁰C and about 42⁰C, depending on the properties of the composition. It is generally known to the skilled artisan that proteins and polypeptides are sensitive to changes in pH, temperature, and a multiplicity of other factors that may affect therapeutic efficacy.

In certain embodiments a desirable route of administration can be by pulmonary aerosol. Techniques for preparing aerosol delivery systems containing polypeptides are well known to those of skill in the art. Generally, such systems should utilize components that will not significantly impair the biological properties of the antibodies, such as the paratope binding capacity (see, for example, Sciarra and Cutie, "Aerosols," in Remington's Pharmaceutical Sciences, 18th edition, 1990, pp 1694-1712; incorporated by reference). Those of skill in the art can readily modify the various parameters and conditions for producing polypeptide aerosols without resorting to undue experimentation.

Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of compositions of the invention, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as polylactides (U.S. Pat. No. 3,773,919; European Patent No. 58,481), poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acids, such as poly-D-(-)-3-hydroxybutyric acid (European Patent No. 133, 988), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate

(Sidman, K.R. et al., Biopolymers 22: 547-556), poly (2-hydroxyethyl methacrylate) or ethylene vinyl acetate (Langer, R. et al., J. Biomed. Mater. Res. 15:267-277; Langer, R. Chem. Tech. 12:98-105), and polyanhydrides.

Other examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules.

Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono- di- and tri-glycerides; hydrogel release systems such as biologically-derived bioresorbable hydrogel (i.e., chitin hydrogels or chitosan hydrogels); sylastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like. Specific examples include, but are not limited to: (a) erosional systems in which the agent is contained in a form within a matrix such as those described in U.S. Patent Nos. 4,452,775, 4,667,014, 4,748,034 and 5,239,660 and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer such as described in U.S. Patent Nos. 3,832,253, and 3,854,480.

Another type of delivery system that can be used with the methods and compositions of the invention is a colloidal dispersion system. Colloidal dispersion systems include lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Liposomes are artificial membrane vessels, which are useful as a delivery vector in vivo or in vitro. Large unilamellar vessels (LUV), which range in size from 0.2 - 4.0 μm, can encapsulate large macromolecules within the aqueous interior and be delivered to cells in a biologically active form (Fraley, R., and Papahadjopoulos, D., Trends Biochem. Sci. 6: 77-80).

Liposomes can be targeted to a particular tissue by coupling the liposome to a specific ligand such as a monoclonal antibody, sugar, glycolipid, or protein. Liposomes are commercially available from Gibco BRL, for example, as LIPOFECTIN™ and LIPOFECTACE™, which are formed of cationic lipids such as N-[l-(2, 3 dioleyloxy)-propyl]-N, N, N-trimethylammonium chloride (DOTMA) and dimethyl dioctadecylammonium bromide (DDAB). Methods for making liposomes are well known in the art and have been described in many publications, for example, in DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. (USA) 77:4030-4034 (1980); EP 52,322; EP 36,676; EP 88, 046; EP 143,949; EP 142,641; Japanese Pat. Appl. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Liposomes also have been reviewed by Gregoriadis, G., Trends Biotechnol., 3: 235-241).

Another type of vehicle is a biocompatible microparticle or implant that is suitable for implantation into the mammalian recipient. Exemplary bioerodible implants that are useful in accordance with this method are described in PCT

International application no. PCT/US/03307 (Publication No. WO 95/24929, entitled "Polymeric Gene Delivery System"). PCT/US/03307 describes biocompatible, preferably biodegradable polymeric matrices for containing an exogenous gene under the control of an appropriate promoter. The polymeric matrices can be used to achieve sustained release of the exogenous gene or gene product in the subject.

The polymeric matrix preferably is in the form of a microparticle such as a microsphere (wherein an agent is dispersed throughout a solid polymeric matrix) or a microcapsule (wherein an agent is stored in the core of a polymeric shell). Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Patent 5,075,109. Other forms of the polymeric matrix for containing an agent include films, coatings, gels, implants, and stents. The size and composition of the polymeric matrix device is selected to result in favorable release kinetics in the tissue into which the matrix is introduced. The size of the polymeric matrix further is selected according to the method of delivery that is to be used. Preferably, when an aerosol route is used the polymeric matrix and composition are encompassed in a surfactant vehicle. The polymeric matrix composition can be selected to have both favorable degradation rates and also to be formed of a material, which is a bioadhesive, to further increase the effectiveness of transfer. The matrix composition also can be selected not to degrade, but rather to release by diffusion over an extended period of time. The delivery system can also be a biocompatible microsphere that is suitable for local, site-specific delivery. Such microspheres are disclosed in Chickering, D.E., et al., Biotechnol. Bioeng., 52: 96-101; Mathiowitz, E., et al., Nature 386: 410-414. Both non-biodegradable and biodegradable polymeric matrices can be used to deliver the compositions of the invention to the subject. Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired, generally in the order of a few hours to a year or longer. Typically, release over a period ranging from between a few hours and three to twelve months is most desirable. The polymer optionally is in the form of a hydrogel that can absorb up to about 90% of its weight in water and further, optionally is cross- linked with multivalent ions or other polymers.

Exemplary synthetic polymers which can be used to form the biodegradable delivery system include: polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, poly-vinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, cellulose sulphate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), polyφhenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly( vinyl alcohols), polyvinyl acetate, poly vinyl chloride, polystyrene, polyvinylpyrrolidone, and polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), and poly(lactide-cocaprolactone), and natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen, chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, copolymers and mixtures thereof. In general, these materials degrade either by enzymatic hydrolysis or exposure to water in vivo, by surface or bulk erosion. Nanoparticles are a colloidal carrier system that has been shown to improve the efficacy of the encapsulated drug by prolonging the serum half-life. Polyalkylcyanoacrylates (PACAs) nanoparticles are a polymer colloidal drug delivery system that is in clinical development, as described by Stella et al., J. Pharm. ScL, 2000. 89: p. 1452-1464; Brigger et al., Int. J. Pharm., 2001. 214: p. 37-42; Calvo et al., Pharm. Res., 2001. 18: p. 1157-1166; and Li et al., Biol. Pharm. Bull., 2001. 24: p. 662-665. Biodegradable poly (hydroxyl acids), such as the copolymers of poly (lactic acid) (PLA) and poly (lactic-co-glycolide) (PLGA) are being extensively used in biomedical applications and have received FDA approval for certain clinical applications. In addition, PEG-PLGA nanoparticles have many desirable carrier features including (i) that the agent to be encapsulated comprises a reasonably high weight fraction (loading) of the total carrier system; (ii) that the amount of agent used in the first step of the encapsulation process is incorporated into the final carrier (entrapment efficiency) at a reasonably high level; (iii) that the carrier have the ability to be freeze-dried and reconstituted in solution without aggregation; (iv) that the carrier be biodegradable; (v) that the carrier system be of small size; and (vi) that the carrier enhance the particles persistence.

Nanoparticles are synthesized using virtually any biodegradable shell known in the art. In one embodiment, a polymer, such as poly (lactic-acid) (PLA) or poly (lactic-co-glycolic acid) (PLGA) is used. Such polymers are biocompatible and biodegradable, and are subject to modifications that desirably increase the photochemical efficacy and circulation lifetime of the nanoparticle. In one embodiment, the polymer is modified with a terminal carboxylic acid group (COOH) that increases the negative charge of the particle and thus limits the interaction with negatively charge nucleic acid aptamers. Nanoparticles are also modified with polyethylene glycol (PEG), which also increases the half-life and stability of the particles in circulation. Alternatively, the COOH group is converted to an N- hydroxysuccinimide (NHS) ester for covalent conjugation to amine-modified aptamers. Biocompatible polymers useful in the composition and methods of the invention include, but are not limited to, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetage phthalate, carboxylethyl cellulose, cellulose triacetate, cellulose sulphate sodium salt, poly(methyl methacrylate), poly(ethylmethacrylate), poly(butylmethacrylate), poly(isobutylmethacrylate), poly(hexylmethacrylate), poly(isodecylmethacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly( vinyl alcohols), poly( vinyl acetate, poly vinyl chloride polystyrene, polyvinylpyrrolidone, polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutylmethacrylate), poly(hexylmethacrylate), poly(isodecl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and combinations of any of these. In one embodiment, the nanoparticles of the invention include PEG-PLGA polymers. Compositions of the invention may also be delivered topically. For topical delivery, the compositions are provided in any pharmaceutically acceptable excipient that is approved for topical delivery.

Those of skill in the art will recognize that the best treatment regimens for using compounds of the present invention to treat, prevent or ameliorate HCV infection can be straightforwardly determined. This is not a question of experimentation, but rather one of optimization, which is routinely conducted in the medical arts. In vivo studies in nude mice often provide a starting point from which to begin to optimize the dosage and delivery regimes. The frequency of injection will initially be once a week, as has been done in some mice studies. However, this frequency might be optimally adjusted from one day to every two weeks to monthly, depending upon the results obtained from the initial clinical trials and the needs of a particular patient.

Human dosage amounts can initially be determined by extrapolating from the amount of compound used in mice, as a skilled artisan recognizes it is routine in the art to modify the dosage for humans compared to animal models. In certain embodiments it is envisioned that the dosage may vary from between about 1 mg compound/Kg body weight to about 2000 mg compound/Kg body weight; or from about 5 mg/Kg body weight to about 1000 mg/Kg body weight or from about 10 mg/Kg body weight to about 5000 mg/Kg body weight; or from about 50 mg/Kg body weight to about 200 mg/Kg body weight; or from about 100 mg/Kg body weight to about 1000 mg/Kg body weight; or from about 150 mg/Kg body weight to about 500 mg/Kg body weight. In other embodiments this dose may be about 0.1, 1, 5, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg/Kg body weight. In other embodiments, it is envisaged that doses may be in the range of about 5 mg compound/Kg body to about 20 mg compound/Kg body. Of course, this dosage amount may be adjusted upward or downward, as is routinely done in such treatment protocols, depending on the results of the initial clinical trials and the needs of a particular patient.

SCREENING METHODS AND SYSTEMS In another aspect, the invention provides a machine readable storage medium which comprises the structural coordinates of an HCV enzyme or protein (e.g., HCV helicase, HCV polymerase, HCV E2 protein) or the structural coordinates of a CD81 binding site identified herein, (e.g., a binding site of CD81 which includes at least one (more preferably at least 2, 3, 4, 5 or 6) amino acid(s) selected from Serl60,Thrl63, Alal64, Thrl67, Ilel81, Leul85 and Aspl89 of CD81. Such storage medium encoded with these data are capable of displaying a three-dimensional graphical representation of a molecule or molecular complex which comprises such binding pockets on a computer screen or similar viewing device. The invention also provides methods for designing, evaluating and identifying compounds which bind to the aforementioned binding pockets. Such compounds are potential inhibitors of HCV helicase or HCV polymerase activity or inhibitors of an interaction between CD 81 and HCV E2.

According to another aspect, the invention provides a computer for producing a) a three-dimensional representation of a molecule or molecular complex, wherein said molecule or molecular complex comprises a binding site of CD81 which includes one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acids) of CD81 selected from Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, ϋel81, Asnl84, Leul85 and Aspl89 more preferably 2, 3, 4 or more amino acids); or b) a three-dimensional representation of a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than about 2.0 (more preferably not more than 1.5) angstroms, wherein said computer comprises: (i) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises the structure coordinates of structure coordinates of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acids) of CD81 selected from Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Aspl89 (more preferably 2, 3, 4 or more amino acids);

(ii) a working memory for storing instructions for processing said machine- readable data; (iii) a central-processing unit coupled to said working memory and to said machine-readable data storage medium for processing said machine readable data into said three-dimensional representation; and

(iv) a display coupled to said central-processing unit for displaying said three- dimensional representation.

According to another aspect, the invention provides a computer for producing a) a three-dimensional representation of a molecule or molecular complex, wherein said molecule or molecular complex comprises a binding site of CD81 which includes one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acids) of CD81 selected from Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Aspl89 (more preferably 2, 3, 4 or more amino acids); or b) a three-dimensional representation of a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than about 2.0 (more preferably not more than 1.5) angstroms, wherein said computer comprises:

(i) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises the structure coordinates of structure coordinates of a binding site of HCV polymerase NS5B; (ii) a working memory for storing instructions for processing said machine- readable data;

(iii) a central-processing unit coupled to said working memory and to said machine-readable data storage medium for processing said machine readable data into said three-dimensional representation; and (iv) a display coupled to said central-processing unit for displaying said three- dimensional representation.

Thus, the computer produces a three-dimensional graphical structure of a molecule or a molecular complex which comprises a binding site.

In another embodiment, the invention provides a computer for producing a three-dimensional representation of a molecule or molecular complex defined by structure coordinates of all of the HCV enzyme amino acids or of CD81, or a three- dimensional representation of a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 2.0 (more preferably not more than 1.5) angstroms

In exemplary embodiments, the computer or computer system can include components which are conventional in the art, e.g., as disclosed in U.S. Patent No. 5,978,740 and/or 6,183,121 (incorporated herein by reference). For example, a computer system can includes a computer comprising a central processing unit ("CPU"), a working memory (which may be, e.g., RAM (random- access memory) or "core" memory), a mass storage memory (such as one or more disk drives or CD- ROM drives), one or more cathode-ray tube (CRT) or liquid crystal display (LCD) display terminals, one or more keyboards, one or more input lines, and one or more output lines, all of which are interconnected by a conventional system bus.

Machine-readable data of this invention may be inputted to the computer via the use of a modem or modems connected by a data line. Alternatively or additionally, the input hardware may include CD-ROM drives, disk drives or flash memory. In conjunction with a display terminal, a keyboard may also be used as an input device.

Output hardware coupled to the computer by output lines may similarly be implemented by conventional devices. By way of example, output hardware may include a CRT or LCD display terminal for displaying a graphical representation of a binding pocket of this invention using a program such as QUANTA or PYMOL. Output hardware might also include a printer, or a disk drive to store system output for later use.

In operation, the CPU coordinates the use of the various input and output devices, coordinates data accesses from the mass storage and accesses to and from working memory, and determines the sequence of data processing steps. A number of programs may be used to process the machine-readable data of this invention, including commercially- available software.

A magnetic storage medium for storing machine-readable data according to the invention can be conventional. A magnetic data storage medium can be encoded with a machine-readable data that can be carried out by a system such as the computer system described above. The medium can be a conventional floppy diskette or hard disk, having a suitable substrate which may be conventional, and a suitable coating , which may also be conventional, on one or both sides, containing magnetic domains whose polarity or orientation can be altered magnetically. The medium may also have an opening (not shown) for receiving the spindle of a disk drive or other data storage device.

The magnetic domains of the medium are polarized or oriented so as to encode in manner which may be conventional, machine readable data such as that described herein, for execution by a system such as the computer system described herein.

An optically-readable data storage medium also can be encoded with machine- readable data, or a set of instructions, which can be carried out by a computer system. The medium can be a conventional compact disk read only memory (CD-ROM) or a rewritable medium such as a magneto-optical disk which is optically readable and magneto-optically writable.

In the case of CD-ROM, as is well known, a disk coating is reflective and is impressed with a plurality of pits to encode the machine-readable data. The arrangement of pits is read by reflecting laser light off the surface of the coating. A protective coating, which preferably is substantially transparent, is provided on top of the reflective coating.

In the case of a magneto-optical disk, as is well known, a data-recording coating has no pits, but has a plurality of magnetic domains whose polarity or orientation can be changed magnetically when heated above a certain temperature, as by a laser. The orientation of the domains can be read by measuring the polarization of laser light reflected from the coating. The arrangement of the domains encodes the data as described above.

Structure data, when used in conjunction with a computer programmed with software to translate those coordinates into the 3-dimensional structure of a molecule or molecular complex comprising a binding pocket may be used for a variety of purposes, such as drug discovery.

For example, the structure encoded by the data may be computationally evaluated for its ability to associate with chemical entities. Chemical entities that associate with a binding site of an HCV protein may inhibit HCV helicase or HCV polymerase, and are potential drug candidates. Alternatively, the structure encoded by the data may be displayed in a graphical three-dimensional representation on a computer screen. This allows visual inspection of the structure, as well as visual inspection of the structure's association with chemical entities.

Thus, according to another embodiment, the invention relates to a method for evaluating the potential of a chemical entity to associate with a) a molecule or molecular complex comprising a binding pocket defined by structure coordinates of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acids) of CD81 selected from Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, ϋel81, Asnl84, Leul85 and Aspl89 (more preferably 2, 3, 4 or more amino acids), as described herein, or b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 2.0 (more preferably 1.5) angstroms.

This method comprises the steps of: i) employing computational means to perform a fitting operation between the chemical entity and a binding pocket of the molecule or molecular complex; and ii) analyzing the results of the fitting operation to quantify the association between the chemical entity and the binding pocket. This embodiment relates to evaluating the potential of a chemical entity to associate with or bind to a binding site of CD81.

Thus, according to another embodiment, the invention relates to a method for evaluating the potential of a chemical entity to associate with a) a molecule or molecular complex comprising a binding pocket defined by structure coordinates of at least one (more preferably 2, 3, 5, 10, 20, or 30) amino acids of HCV NS5B, as described herein, or b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 2.0 (more preferably 1.5) angstroms.

This method comprises the steps of: i) employing computational means to perform a fitting operation between the chemical entity and a binding pocket of the molecule or molecular complex; and ii) analyzing the results of the fitting operation to quantify the association between the chemical entity and the binding pocket. This embodiment relates to evaluating the potential of a chemical entity to associate with or bind to a binding site of HCV protein.

The term "chemical entity", as used herein, refers to chemical compounds, complexes of at least two chemical compounds, and fragments of such compounds or complexes. In certain embodiments, the method evaluates the potential of a chemical entity to associate with a molecule or molecular complex defined by structure coordinates of all of the amino acids of HCV NS5B, as described herein, or a homologue of said molecule or molecular complex having a root mean square deviation from the backbone atoms of said amino acids of not more than 2.0 (more preferably not more than 1.5) angstroms.

In certain embodiments, the method evaluates the potential of a chemical entity to associate with a molecule or molecular complex defined by structure coordinates of all of the amino acids of CD81, as described herein, or a homologue of said molecule or molecular complex having a root mean square deviation from the backbone atoms of said amino acids of not more than 2.0 (more preferably not more than 1.5) angstroms.

In a further embodiment, the structural coordinates one of the binding pockets described herein can be utilized in a method for identifying a potential agonist or antagonist of a molecule comprising an HCV protein binding site. This method comprises the steps of: a) using the atomic coordinates of all or a portion of HCV NS5B or CD81; b) employing the three-dimensional structure to design or select the potential agonist or antagonist. The method further includes the optional steps of c) synthesizing the agonist or antagonist; and d) contacting the agonist or antagonist with the molecule to determine the ability of the potential agonist or antagonist to interact with the molecule.

In another embodiment, the invention provides a method for identifying a potential agonist or antagonist of HCV enzyme, the method comprising the steps of: a) using the atomic coordinates of all or a portion of HCV NS5B or CD81; b) employing the three-dimensional structure to design or select the potential agonist or antagonist.

The present inventors' elucidation of heretofore unknown binding sites of HCV proteins (or binding of a protein, such as an HCV protein, such as HCV E2, to CD81), provides the necessary information for designing new chemical entities and compounds that may interact with HCV proteins, in whole or in part, and may therefore modulate (e.g., inhibit) the activity of HCV proteins, or modulate the binding of a protein, including an HCV protein, to CD81. The design of compounds that bind to binding sites according to this invention generally involves consideration of several factors. First, the entity must be capable of physically and structurally associating with parts or all of the binding site. Non- covalent molecular interactions important in this association include hydrogen bonding, van der Waals interactions, hydrophobic interactions and electrostatic interactions. Second, the entity must be able to assume a conformation that allows it to associate with the binding site(s) directly. Although certain portions of the entity will not directly participate in these associations, those portions of the entity may still influence the overall conformation of the molecule. This, in turn, may have a significant impact on potency. Such conformational requirements include the overall three-dimensional structure and orientation of the chemical entity in relation to all or a portion of the binding pocket, or the spacing between functional groups of an entity comprising several chemical entities that directly interact with the binding pocket or homologues thereof. The potential inhibitory or binding effect of a chemical entity on a protein binding site may be analyzed prior to its actual synthesis and testing by the use of computer modeling techniques. If the theoretical structure of the given entity suggests insufficient interaction and association between it and the target binding pocket, testing of the entity is obviated. However, if computer modeling indicates a strong interaction, the molecule may then be synthesized and tested for its ability to bind to a binding site. This may be achieved, e.g., by testing the ability of the molecule to inhibit HCV enzyme activity (e.g., replication activity, viral entry, etc.), e.g., using assays described herein or known in the art. In this manner, synthesis of inoperative compounds may be avoided. A potential inhibitor of an HCV enzyme binding site may be computationally evaluated by means of a series of steps in which chemical entities or fragments are screened and selected for their ability to associate with the HCV enzyme binding site.

One skilled in the art may use one of several methods to screen chemical entities or fragments for their ability to associate with an a binding site. This process may begin by visual inspection of, for example, a binding site on the computer screen based on the an protein structure coordinates described herein, or other coordinates which define a similar shape generated from the machine-readable storage medium. Selected fragments or chemical entities may then be positioned in a variety of orientations, or docked, within that binding site as defined supra. Docking may be accomplished using software such as Quanta and DOCK, followed by energy minimization and molecular dynamics with standard molecular mechanics force fields, such as CHARMM and AMBER.

Specialized computer programs (e.g., as known in the art and/or commercially available and/or as described herein) may also assist in the process of selecting fragments or chemical entities.

Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound or complex. Assembly may be preceded by visual inspection of the relationship of the fragments to each other on the three-dimensional image displayed on a computer screen in relation to the structure coordinates of the target binding site.

Instead of proceeding to build an inhibitor of a binding pocket in a step-wise fashion one fragment or chemical entity at a time as described above, inhibitory or other binding compounds may be designed as a whole or "de novo" using either an empty binding site or optionally including some portion(s) of a known inhibitor(s). There are many de novo ligand design methods known in the art, some of which are commercially available (e.g., LeapFrog, available from Tripos Associates, St. Louis, Mo.).

Other molecular modeling techniques may also be employed in accordance with this invention (see, e.g., N. C. Cohen et al., "Molecular Modeling Software and Methods for Medicinal Chemistry, J. Med. Chem., 33, pp. 883-894 (1990); see also, M. A. Navia and M. A. Murcko, "The Use of Structural Information in Drug Design", Current Opinions in Structural Biology, 2, pp. 202-210 (1992); L. M. Balbes et al., "A Perspective of Modern Methods in Computer- Aided Drug Design", in Reviews in Computational Chemistry, Vol. 5, K. B. Lipkowitz and D. B. Boyd, Eds., VCH, New York, pp. 337-380 (1994); see also, W. C. Guida, "Software For Structure-Based Drug Design", Curr. Opin. Struct. Biology,, 4, pp. 777-781 (1994)).

Once a compound has been designed or selected, the efficiency with which that entity may bind to a binding pocket may be tested and optimized by computational evaluation.

Specific computer software is available in the art to evaluate compound deformation energy and electrostatic interactions. Examples of programs designed for such uses include: AMBER; QUANTA/CHARMM (Accelrys, Inc., Madison, WI) and the like. These programs may be implemented, for instance, using a commercially-available graphics workstation. Other hardware systems and software packages will be known to those skilled in the art.

Another technique involves the in silico screening of virtual libraries of compounds, e.g., as described herein (see, e.g., Examples 1 and T). Many thousands of compounds can be rapidly screened and the best virtual compounds can be selected for further screening (e.g., by synthesis and in vitro testing). Small molecule databases can be screened for chemical entities or compounds that can bind, in whole or in part, to a protein or enzyme binding site. In this screening, the quality of fit of such entities to the binding site may be judged either by shape complementarity or by estimated interaction energy.

Screening Assays

As discussed herein, useful compounds inhibit HCV enzymes and their activity or the binding of proteins to CD81. Any number of methods are available for carrying out screening assays to identify such compounds. In one approach, a HCV enzyme protein is expressed in a cell (e.g., a cell in vitro or in vivo); the cell is contacted with a candidate compound; and the effect of the compound on the inhibition of HCV enzyme and functional activity is assayed using any method known in the art or described herein. Useful compounds decrease the amount of HCV enzyme or polymerization by at least 10%, 15%, or 20%, or preferably by 25%, 50%, or 75%; or most preferably by at least 100%, 200%, 300% or even 400%.

Test Compounds and Extracts

In general, compounds capable of inhibiting HCV proliferation in a cell are identified from large libraries of either natural product or synthetic (or semi-synthetic) extracts or chemical libraries according to methods known in the art. Those skilled in the field of drug discovery and development will understand that the precise source of test extracts or compounds is not critical to the screening procedure(s) of the invention. Accordingly, large numbers of chemical extracts or compounds can be screened using the methods described herein. Examples of such extracts or compounds include, but are not limited to, plant-, fungal-, prokaryotic- or animal- based extracts, fermentation broths, and synthetic compounds, as well as modification of existing compounds. Numerous methods are also available for generating random or directed synthesis (e.g., semi-synthesis or total synthesis) of any number of chemical compounds, including, but not limited to, saccharide-, lipid-, peptide-, and nucleic acid-based compounds. Synthetic compound libraries are commercially available from Brandon Associates (Merrimack, N. H.) and Aldrich Chemical (Milwaukee, Wis.). Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant, and animal extracts are commercially available from a number of sources, including Biotics (Sussex, UK), Xenova (Slough, UK), Harbor Branch Oceangraphics Institute (Ft. Pierce, FIa.), and PharmaMar, U.S.A. (Cambridge, Mass.). In addition, natural and synthetically produced libraries are produced, if desired, according to methods known in the art, e.g., by standard extraction and fractionation methods. Furthermore, if desired, any library or compound is readily modified using standard chemical, physical, or biochemical methods.

Combination Therapies

Compositions of the invention useful for the treatment of HCV inhibition (or conditions related to protein binding to CD81) can optionally be combined with additional therapies. For example, interferons (such as interferon- alpha, and nucleoside antimetabolite antiviral compounds such as ribavirin can be used in combination with a compound according to this invention.

Kits

The invention provides kits for the treatment or prevention of HCV infection or conditions associated with binding to CD81, or symptoms thereof.

In one embodiment, the kit includes a pharmaceutical pack comprising an effective amount of a compound of the invention for prevention or treatment of HCV infection. Preferably, the compositions are present in unit dosage form. In some embodiments, the kit comprises a sterile container which contains a therapeutic or prophylactic composition; such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art. Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments. In certain embodiments, the kit further comprises a second compound for treatment of HCV infection, e.g., interferon-alfa or ribavirin.

If desired compositions of the invention or combinations thereof are provided together with instructions for administering them to a subject having or at risk of developing HCV infection. The instructions will generally include information about the use of the compounds for the treatment or prevention of HCV infection. In other embodiments, the instructions include at least one of the following: description of the compound or combination of compounds; dosage schedule and administration for treatment of HCV infection or symptoms thereof; precautions; warnings; indications; counter- indications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references. The instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container. The following examples are provided to illustrate the invention, not to limit it.

EXAMPLES

Example 1. Identification of CD81 binding inhibitors The crystal structure of CD81 provided the basis for selection of potential small molecule inhibitors.

RESEARCH DESIGNAND METHODS

Database Preparation The National Cancer Institute/Developmental Therapeutics Program

(NCI/DTP) maintains a repository of approximately 220,000 samples (the plated compound set) which are non-proprietary and offered to the extramural research community for the discovery and development of new agents for the treatment of cancer, AIDS, or opportunistic infections afflicting patients with cancer or AIDS (Monga and Sausville 2002). The three-dimensional coordinates for the NCI/DTP plated compound set was obtained in the MDL SD format and converted to the mol2 format by the DOCK utility program SDF2MOL2 (UCSF). Partial atomic charges, solvation energies and van der Waals parameters for the ligands were calculated using SYBDB (Tripos, Inc.) and added to the plated compound set mol2 file.

Molecular Docking

Docking calculations were performed with the October 15, 2002, development version of DOCK, v5.1.0 (Charifson et al. 1999; Ewing et al. 2001). The general features of DOCK include rigid orienting of ligands to receptor spheres, AMBER energy scoring, GB/SA solvation scoring, contact scoring, internal non-bonded energy scoring, ligand flexibility and both rigid and torsional simplex minimization (Gschwend et al.; Good et al. 1995). Unlike previously distributed versions, this release incorporates automated matching, internal energy (used in flexible docking), scoring function hierarchy and new minimizer termination criteria.

To identify molecules that would specifically interact with CD81, the crystal structure of the human form of CD81 was used (PDB code 1G8Q, accessed at http://www.rcsb. org/pdb/explore.do?structureId=lG8Q) (see Appendix A for the sequence/PDB file for 1G8Q, which is incorporated herein by reference), combined with information on the residues thought to bind HCV through mutagenesis data. The residues of interest included Serl60,Thrl63, Alal64, Thrl67, Ilel81, Leul85 and Aspl89. When these residues were mapped on to the CD81 structure, they appeared to form part of a structural pocket with characteristics favorable to small molecule binding. Approximately 20,000 druglike molecules (that follow the Lipinski rules) that are in the NCI/DTP repository of compounds were computational docked using a supercomputer. The top scoring molecules were obtained and tested for activity.

To prepare the site for docking, all water molecules were removed. Protonation of receptor residues was performed with Sybyl (Tripos, St. Louis, MO). The structure was explored using sets of spheres to describe potential binding pockets. The number of orientations per molecule was 100. Intermolecular AMBER energy scoring (vdw + columbic), contact scoring and bump filtering were implemented in DOCK5.1.0 (Gschwend et al.). SETOR (Evans 1993) and GRASP (Petrey and Honig 2003) were used to generate molecular graphic images. The approach is generally illustrated in Figure 1. Compounds identified using virtual screening are shown in Table 1.

Table 1. CD 81 binding inhibitors

An additional round of molecular docking using DOCK6, with improved scoring functions. This round of scoring resulted in identification of additional compounds; the top ten scoring molecules are shown in Table 2 (note that the energy scores in Table 2 are not directly comparable to the energy scores of Table 1).

Table 2. Additional CD 81 binding inhibitors

Example 2. Identification of HCV polymerase inhibitors

The crystal structure of NS5B provided the basis for selection of potential small molecule inhibitors HCV polymerase inhibitors. The coordinates for the crystal structure of NS5B (see, e.g., Love, R.A., et al., J.Virol. (2003) 77:7575-7581, incorporated herein by reference), were used in the molecular docking calculations. The atomic positions of the amino acid residues of the NS5B protein were used for the site selected for molecular docking, with the aim of inhibiting HCV polymerase activity with small molecules. The site consists of residues in the crystal structure of PDB code 1OS5 (accessed at http://www.rcsb.org/pdb/explore.do?structureId=lOS5).

The location of the allosteric site on NS5B is approximately 35 A from the active site in the "thumb" domain. The domain arrangement of NS5B and other polymerases has been referred to as the "fingers," "palm," and "thumb" of a right hand. Known small molecule inhibitors were previously characterized in an allosteric site near the second to last helix in the C-terminal region of the thumb subdomain. The characterized inhibitors were bound in a wedge manner to a largely hydrophobic pocket. Although this pocket is relatively shallow, the characterized inhibitors form hydrogen bonds, hydrophobic and van der Waals interactions with NS5B. We have utilized the chemical and geometric characteristics of this site on NS5B by conducting dynamic molecular docking simulations (DOCK, UCSF) of 140,000 small molecules (available through the NCI/DTP) interacting with this site (100 orientations for each compound) using the atomic coordinates provided by NS5B/inhibitor crystal structures. Through this preliminary study, we have identified several compounds that exhibit strong binding activity in this region (Table 3). One of the top compounds, N- methylbenzanilide (CuH₁₃NO), showed inhibitory activity against HCV in replicon cell culture (see below). We then modeled this compound in the context of NS5B structure and found that this compound is located in the active site of NS5B.

Table 3. HCV polymerase inhibitors

Example 3

We first tested five compounds (the top five compounds in Table 3) on HCV NS5B enzymatic activity in vitro. Among all the compounds tested, all of them showed inhibitory effect on NS5B activity (data not shown). To further test the effectiveness of these compounds on HCV RNA replication in a cell culture system, we incubated varying doses of the compounds with the GSB cell line, which contains a subgenomic replicon in Huh7 cells (Lohmann V. et al., , Science (1999) 285:110-3; Blight KJ, et al., Science (2000) 290:1972-4). Our previous studies have shown the feasibility of this cell culture system on evaluation of antiviral agents (see, e.g., Zhu H et al., Hepatology (2003) 37:1180-8). IFN-treated cells serve as a positive control (IFN exhibits dose-dependent, anti-HCV activity in GSB cells). The compounds were incubated with the cells for 48 hours. Two of the five compounds (N- methylbenzanilide and N-(triphenylmethyl) pyridin-2-amine) exhibited antiviral effect. The inhibitory effect is dose-dependent.

As discussed above, two compounds showed antiviral activity in cell culture. We next tested whether these two compounds have any toxicity on liver cells. We incubated the compounds with Huh7 cells and GSB cells for 48 hours. The cells were fixed and stained with DAPI and examined under a microscope. In this test, N- methylbenzanilide did not appear to cause cell apoptosis, while N-(triphenylmethyl) pyridin-2-amine induced up to 30% of the cells undergoing apoptosis. The data suggest that N-(triphenylmethyl) pyridin-2-amine is toxic at certain concentrations, and its antiviral effect could be due, at least in part, to cell toxicity. The apparent lack of cell toxicity of N-methylbenzanilide suggests that this compound could be an effective viral inhibitor. Other Embodiments

From the foregoing description, it will be apparent that variations and modifications may be made to the invention described herein to adopt it to various usages and conditions. Such embodiments are also within the scope of the following claims.

All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and individually indicated to be incorporated by reference. From the above description, one skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Thus, other embodiments are also within the scope of the following claims.

APPENDIX A

HEADER IMMUNE SYSTEM 20-NOV-OO 1G8Q

TITLE CRYSTAL STRUCTURE OF HUMAN CD81 EXTRACELLULAR DOMAIN, A TITLE 2 RECEPTOR FOR HEPATITIS C VIRUS

COMPND MOLJD: 1 ;

COMPND 2 MOLECULE: CD81 ANTIGEN, EXTRACELLULAR DOMAIN;

COMPND 3 CHAIN: A, B;

COMPND 4 FRAGMENT: EXTRACELLULAR DOMAIN; COMPND 5 SYNONYM: CD81 , TARGET OF ANTIPROLIFERATIVE ANTIBODY 1 , 26

COMPND 6 KDA CELL SURFACE PROTEIN TAPA-1 ;

COMPND 7 ENGINEERED: YES

SOURCE MOLJD: 1 ;

SOURCE 2 ORGANISM_.SCIENTIFIC: HOMO SAPIENS; SOURCE 3 ORGANISM_COMMON: HUMAN;

SOURCE 4 EXPRESSION_SYSTEM: ESCHERICHIA COLI;

SOURCE 5 EXPRESSION_SYSTEMJ3OMMON: BACTERIA;

SOURCE 6 EXPRESSION_SYSTEM_VECTOR_TYPE: PLASMID;

SOURCE 7 EXPRESSION-SYSTEMJ³LASMID: PEZZ18 KEYWDS ALPHA HELICAL

EXPDTA X-RAY DIFFRACTION

AUTHOR K-KITADOKORO₁M-BOLOGNESI₁D-BORDO₁CGRANDI₁CGALLI,

AUTHOR 2 R.PETRACCA,F.FALUGI

REVDAT 1 21-FEB-01 1G8Q O JRNL AUTH K-KITADOKORO₁D-BORDO₁CGALLI₁R-PETRACCA₁F-FALUGI,

JRNL AUTH 2 S.ABRIGNANI.CGRANDI.M.BOLOGNESI

JRNL TITL CD81 EXTRACELLULAR DOMAIN 3D STRUCTURE: INSIGHT

JRNL TITL 2 INTO THE TETRASPANIN SUPERFAMILY STRUCTURAL MOTIFS.

JRNL REF EMBO J. V. 20 12 2001 JRNL REFN ASTM EMJODG UK ISSN 0261-4189

REMARK 1

REMARK 2

REMARK 2 RESOLUTION. 1.60 ANGSTROMS.

REMARK 3 REMARK 3 REFINEMENT.

REMARK 3 PROGRAM : REFMAC

REMARK 3 AUTHORS : MURSHUDOV, VAGIN, DODSON

REMARK 3

REMARK 3 DATA USED IN REFINEMENT. REMARK 3 RESOLUTION RANGEHIGH (ANGSTROMS) I IeO

REMARK 3 RESOLUTION RANGE LOW (ANGSTROMS) : 20.00

REMARK 3 DATA CUTOFF (SIGMA(F)) : 0.000

REMARK 3 COMPLETENESSFORRANGE (%) : 93.0 REMARK 3 NUMBER OF REFLECTIONS : 23143

REMARK 3

REMARK 3 FIT TO DATA USED IN REFINEMENT.

REMARK 3 CROSS-VALIDATION METHOD : THROUGHOUT

REMARK 3 FREE R VALUE TEST SET SELECTION : RANDOM REMARK 3 RVALUE (WORKING + TEST SET) : NULL

REMARK 3 RVALUE (WORKING SET) : 0.188

REMARK 3 FREERVALUE : 0.238

REMARK 3 FREE R VALUE TEST SET SIZE (%) : 4.800

REMARK 3 FREERVALUETESTSETCOUNT : 1104 REMARK 3

REMARK 3 NUMBER OF NON-HYDROGEN ATOMS USED IN REFINEMENT.

REMARK 3 PROTEINATOMS : 1356

REMARK 3 NUCLEICACIDATOMS : 0

REMARK 3 HETEROGEN ATOMS : 0 REMARK 3 SOLVENT ATOMS : 194

REMARK 3

REMARK 3 BVALUES.

REMARK 3 FROM WILSON PLOT (A**2) : 26.30

REMARK 3 MEAN B VALUE (OVERALL, A**2) : NULL REMARK 3 OVERALL ANISOTROPIC B VALUE.

REMARK 3 B11 (A**2) : NULL

REMARK 3 B22 (A**2) : NULL

REMARK 3 B33 (A**2) : NULL

REMARK 3 B12(A**2): NULL REMARK 3 B13 (A**2) : NULL

REMARK 3 B23 (A**2) : NULL

REMARK 3

REMARK 3 ESTIMATEDOVERALLCOORDINATEERROR.

REMARK 3 ESU BASEDON RVALUE (A): NULL REMARK 3 ESU BASED ON FREE R VALUE (A): NULL

REMARK 3 ESU BASED ON MAXIMUM LIKELIHOOD (A): NULL

REMARK 3 ESU FOR B VALUES BASED ON MAXIMUM LIKELIHOOD (A**2): NULL

REMARK 3

REMARK 3 RMS DEVIATIONS FROM IDEALVALUES. REMARK 3 DISTANCE RESTRAINTS. RMS SIGMA REMARK 3 BOND LENGTH (A) : NULL ; NULL

REMARK 3 ANGLE DISTANCE (A) : NULL ; NULL

REMARK 3 INTRAPLANAR 1-4 DISTANCE (A) : NULL ; NULL

REMARK 3 H-BOND OR METAL COORDINATION (A) : NULL ; NULL REMARK 3

REMARK 3 PLANE RESTRAINT (A) : NULL ; NULL

REMARK 3 CHIRAL-CENTER RESTRAINT (A**3) : NULL ; NULL

REMARK 3

REMARK 3 NON-BONDED CONTACT RESTRAINTS. REMARK 3 SINGLE TORSION (A) : NULL ; NULL

REMARK 3 MULTIPLE TORSION (A) : NULL ; NULL

REMARK 3 H-BOND (X...Y) (A) : NULL ; NULL

REMARK 3 H-BOND (X-H...Y) (A) : NULL ; NULL

REMARK 3 REMARK 3 CONFORMATIONAL TORSION ANGLE RESTRAINTS.

REMARK 3 SPECIFIED (DEGREES) : NULL ; NULL

REMARK 3 PLANAR (DEGREES) : NULL ; NULL

REMARK 3 STAGGERED (DEGREES) : NULL ; NULL

REMARK 3 TRANSVERSE (DEGREES) : NULL ; NULL REMARK 3

REMARK 3 ISOTROPIC THERMAL FACTOR RESTRAINTS. RMS SIGMA

REMARK 3 MAIN-CHAIN BOND (A**2) : NULL ; NULL

REMARK 3 MAIN-CHAIN ANGLE (A**2) : NULL ; NULL

REMARK 3 SIDE-CHAIN BOND (A**2) : NULL ; NULL REMARK 3 SIDE-CHAIN ANGLE (A**2) : NULL ; NULL

REMARK 3

REMARK 3 OTHER REFINEMENT REMARKS: NULL

REMARK 4

REMARK 4 1G8Q COMPLIES WITH FORMAT V. 3.0, 1-DEC-2006 REMARK 4

REMARK 4 THIS IS THE REMEDIATED VERSION OF THIS PDB ENTRY.

REMARK 4 REMEDIATED DATA FILE REVISION 3.100 (2007-03-17)

REMARK 100

REMARK 100 THIS ENTRY HAS BEEN PROCESSED BY RCSB . REMARK 100 THE RCSB ID CODE IS RCSB012373.

REMARK 200

REMARK 200 EXPERIMENTAL DETAILS

REMARK 200 EXPERIMENT TYPE : X-RAY DIFFRACTION

REMARK 200 DATE OF DATA COLLECTION : 19-NOV-1999 REMARK 200 TEMPERATURE (KELVIN) : 100.0 REMARK 200 PH : 6.00

REMARK 200 NUMBER OF CRYSTALS USED : 1

REMARK 200

REMARK 200 SYNCHROTRON (Y/N) : Y REMARK 200 RADIATION SOURCE : ESRF

REMARK 200 BEAMLINE : NULL

REMARK 200 X-RAY GENERATOR MODEL : NULL

REMARK 200 MONOCHROMATIC OR LAUE (M/L) : M

REMARK 200 WAVELENGTH OR RANGE (A) : 0.93 REMARK 200 MONOCHROMATOR : SAGITALLY FOCUSING GE(220)

REMARK 200 AND A MULTILAYER

REMARK 200 OPTICS : NULL

REMARK 200

REMARK 200 DETECTOR TYPE : CCD REMARK 200 DETECTOR MANUFACTURER : MARRESEARCH

REMARK 200 INTENSITY-INTEGRATION SOFTWARE : DENZO

REMARK 200 DATA SCALING SOFTWARE : SCALEPACK

REMARK 200

REMARK 200 NUMBER OF UNIQUE REFLECTIONS : 21557 REMARK 200 RESOLUTION RANGE HIGH (A) : 1.600

REMARK 200 RESOLUTION RANGE LOW (A) : 50.000

REMARK 200 REJECTION CRITERIA (SIGMA(I)) : 1.000

REMARK 200

REMARK 200 OVERALL. REMARK 200 COMPLETENESS FOR RANGE (%) : 98.0

REMARK 200 DATA REDUNDANCY : 6.900

REMARK 200 R MERGE (I) : 0.03800

REMARK 200 R SYM (I) : NULL

REMARK 200 <I/SIGMA(I)> FOR THE DATA SET : 5.2000 REMARK 200

REMARK 200 IN THE HIGHEST RESOLUTION SHELL.

REMARK 200 HIGHEST RESOLUTION SHELL, RANGE HIGH (A) : 1.60

REMARK 200 HIGHEST RESOLUTION SHELL, RANGE LOW (A) : 1.66

REMARK 200 COMPLETENESS FOR SHELL (%) : 98.0 REMARK 200 DATA REDUNDANCY IN SHELL : 2.00

REMARK 200 R MERGE FOR SHELL (I) : 0.30300

REMARK 200 R SYM FOR SHELL (I) : 0.31400

REMARK 200 <I/SIGMA(I)> FOR SHELL : NULL

REMARK 200 REMARK 200 DIFFRACTION PROTOCOL: SINGLE WAVELENGTH REMARK 200 METHOD USED TO DETERMINE THE STRUCTURE: MIR

REMARK 200 SOFTWARE USED: SHARP

REMARK 200 STARTING MODEL: NULL

REMARK 200

REMARK 200 REMARK: NULL

REMARK 280

REMARK 280 CRYSTAL

REMARK 280 SOLVENT CONTENT, VS (%): 45.28

REMARK 280 MATTHEWS COEFFICIENT, VM (ANGSTROMS**3/DA): 2.25

REMARK 280

REMARK 280 CRYSTALLIZATION CONDITIONS: PEG 4000, MES, NACL, PH 6.0, VAPOR

REMARK 280 DIFFUSION, SITTING DROP, TEMPERATURE 298K

REMARK 290

REMARK 290 CRYST ALLOGRAPHIC SYMMETRY

REMARK 290 SYMMETRY OPERATORS FOR SPACE GROUP: P 1 21 1

REMARK 290

REMARK 290 SYMOP SYMMETRY

REMARK 290 NNNMMM OPERATOR

REMARK 290 1555 X,Y,Z

REMARK 290 2555 -X,1/2+Y,-Z

REMARK 290

REMARK 290 WHERE NNN -> OPERATOR NUMBER

REMARK 290 MMM -> TRANSLATION VECTOR

REMARK 290

REMARK 290 CRYST ALLOGRAPHIC SYMMETRY TRANSFORMATIONS

REMARK 290 THE FOLLOWING TRANSFORMATIONS OPERATE ON THE

ATOM/H ETATM

REMARK 290 RECORDS IN THIS ENTRY TO PRODUCE CRYSTALLOGRAPHICALLY

REMARK 290 RELATED MOLECULES.

REMARK 290 SMTRY1 1 1.000000 0.000000 0.000000 0.00000

REMARK 290 SMTRY2 1 0.000000 1.000000 0.000000 0.00000

REMARK 290 SMTRY3 1 0.000000 0.000000 1.000000 0.00000

REMARK 290 SMTRY1 2 -1.000000 0.000000 0.000000 0.00000

REMARK 290 SMTRY2 2 0.000000 1.000000 0.000000 38.58600

REMARK 290 SMTRY3 2 0.000000 0.000000 -1.000000 0.00000

REMARK 290

REMARK 290 REMARK: NULL

REMARK 300

REMARK 300 BIOMOLECULE: 1

REMARK 300 THIS ENTRY CONTAINS THE CRYSTALLOGRAPHIC ASYMMETRIC UNIT REMARK 300 WHICH CONSISTS OF 2 CHAIN(S). SEE REMARK 350 FOR

REMARK 300 INFORMATION ON GENERATING THE BIOLOGICAL MOLECULE(S).

REMARK 350

REMARK 350 GENERATING THE BIOMOLECULE REMARK 350 COORDINATES FOR A COMPLETE MULTIMER REPRESENTING THE

KNOWN

REMARK 350 BIOLOGICALLY SIGNIFICANT OLIGOMERIZATION STATE OF THE

REMARK 350 MOLECULE CAN BE GENERATED BY APPLYING BIOMT

TRANSFORMATIONS REMARK 350 GIVEN BELOW. BOTH NON-CRYSTALLOGRAPHIC AND

REMARK 350 CRYST ALLOGRAPHIC OPERATIONS ARE GIVEN.

REMARK 350

REMARK 350 BIOMOLECULE: 1

REMARK 350 APPLY THE FOLLOWING TO CHAINS: A, B REMARK 350 BIOMT1 1 1.000000 0.000000 0.000000 0.00000

REMARK 350 BIOMT2 1 0.000000 1.000000 0.000000 0.00000

REMARK 350 BIOMT3 1 0.000000 0.000000 1.000000 0.00000

REMARK 465

REMARK 465 MISSING RESIDUES REMARK 465 THE FOLLOWING RESIDUES WERE NOT LOCATED IN THE

REMARK 465 EXPERIMENT. (M=MODEL NUMBER; RES=RESIDUE NAME; C=CHAIN

REMARK 465 IDENTIFIER; SSSEQ=SEQUENCE NUMBER; I=INSERTION CODE.)

REMARK 465

REMARK 465 M RES C SSSEQI REMARK 465 ASP B 238

REMARK 465 ASP B 239

REMARK 465 ALA B 240

REMARK 465 ASN B 241

REMARK 470 REMARK 470 MISSING ATOM

REMARK 470 THE FOLLOWING RESIDUES HAVE MISSING ATOMS(M=MODEL

NUMBER;

REMARK 470 RES=RESIDUE NAME; C=CHAIN IDENTIFIER; SSEQ=SEQUENCE

NUMBER; REMARK 470 I=INSERTION CODE):

REMARK 470 M RES CSSEQI ATOMS

REMARK 470 SER B 279 CB OG

REMARK 500

REMARK 500 GEOMETRY AND STEREOCHEMISTRY REMARK 500 SUBTOPIC: CLOSE CONTACTS IN SAME ASYMMETRIC UNIT REMARK 500

REMARK 500 THE FOLLOWING ATOMS ARE IN CLOSE CONTACT.

REMARK 500

REMARK 500 ATM1 RES C SSEQI ATM2 RES C SSEQI REMARK 500 OD2 ASP A 138 O HOH 118 1.91

REMARK 500 OD2 ASP A 155 O HOH 158 2.03

REMARK 500 O HIS A 202 O HOH 33 2.08

REMARK 500 NZ LYS B 271 O HOH 154 2.10

REMARK 500 O HOH 134 O HOH 168 2.12 REMARK 500 CG GLN B 229 O HOH 194 2.17

REMARK 500 O HOH 44 O HOH 134 2.19

REMARK 500

REMARK 500 GEOMETRY AND STEREOCHEMISTRY

REMARK 500 SUBTOPIC: CLOSE CONTACTS REMARK 500

REMARK 500 THE FOLLOWING ATOMS THAT ARE RELATED BY CRYST ALLOGRAPHIC

REMARK 500 SYMMETRY ARE IN CLOSE CONTACT. AN ATOM LOCATED WITHIN 0.15

REMARK 500 ANGSTROMS OF A SYMMETRY RELATED ATOM IS ASSUMED TO BE ON

A REMARK 500 SPECIAL POSITION AND IS, THEREFORE, LISTED IN REMARK 375

REMARK 500 INSTEAD OF REMARK 500. ATOMS WITH NON-BLANK ALTERNATE

REMARK 500 LOCATION INDICATORS ARE NOT INCLUDED IN THE CALCULATIONS.

REMARK 500

REMARK 500 DISTANCE CUTOFF: REMARK 500 2.2 ANGSTROMS FOR CONTACTS NOT INVOLVING HYDROGEN ATOMS

REMARK 500 1.6 ANGSTROMS FOR CONTACTS INVOLVING HYDROGEN ATOMS

REMARK 500

REMARK 500 ATM1 RES C SSEQI ATM2 RES C SSEQI SSYMOP DISTANCE

REMARK 500 CZ PHE B 213 O HOH 173 1655 0.78 REMARK 500 OD1 ASP A 138 O HOH 180 2646 1.37

REMARK 500 CE1 PHE B 213 O HOH 173 1655 1.43

REMARK 500 CE2 PHE B 213 O HOH 173 1655 1.66

REMARK 500 C ILE B 282 O HOH 141 2556 1.83

REMARK 500 CG2 ILE B 282 O HOH 141 2556 1.87 REMARK 500 CE2 PHE B 213 O HOH 47 1655 2.15

REMARK 500 O HOH 82 O HOH 143 1455 2.15

REMARK 500 O ILE B 282 O HOH 141 2556 2.17

REMARK 500 CB ILE B 282 O HOH 141 2556 2.17

REMARK 500 REMARK 500 GEOMETRY AND STEREOCHEMISTRY REMARK 500 SUBTOPIC: COVALENT BOND LENGTHS

REMARK 500

REMARK 500 THE STEREOCHEMICAL PARAMETERS OF THE FOLLOWING RESIDUES

REMARK 500 HAVE VALUES WHICH DEVIATE FROM EXPECTED VALUES BY MORE REMARK 500 THAN 6*RMSD (M=MODEL NUMBER; RES=RESIDUE NAME; C=CHAIN

REMARK 500 IDENTIFIER; SSEQ=SEQUENCE NUMBER; I=INSERTION CODE).

REMARK 500

REMARK 500 STANDARD TABLE:

REMARK 500 FORMAT: (1OX,I3,1X,2(A3,1X,A1 ,I4,A1 ,1X,A4,3X),F6.3) REMARK 500

REMARK 500 EXPECTED VALUES: ENGH AND HUBER, 1991

REMARK 500

REMARK 500 M RES CSSEQI ATM1 RES CSSEQI ATM2 DEVIATION

REMARK 500 ASP A 138 CB ASP A 138 CG 0.291 REMARK 500 SER B 277 C GLY B 278 N 0.352

REMARK 500

REMARK 500 GEOMETRY AND STEREOCHEMISTRY

REMARK 500 SUBTOPIC: COVALENT BOND ANGLES

REMARK 500 REMARK 500 THE STEREOCHEMICAL PARAMETERS OF THE FOLLOWING RESIDUES

REMARK 500 HAVE VALUES WHICH DEVIATE FROM EXPECTED VALUES BY MORE

REMARK 500 THAN 6*RMSD (M=MODEL NUMBER; RES=RESIDUE NAME; C=CHAIN

REMARK 500 IDENTIFIER; SSEQ=SEQUENCE NUMBER; I=INSERTION CODE).

REMARK 500 REMARK 500 STANDARD TABLE:

REMARK 500 FORMAT: (1OX,I3,1X,A3,1X,A1 ,I4,A1 ,3(1X,A4,2X),12X,F5.1)

REMARK 500

REMARK 500 EXPECTED VALUES: ENGH AND HUBER, 1991

REMARK 500 REMARK 500 M RES CSSEQI ATM 1 ATM2 ATM3

REMARK 500 SER B 277 O - C - N ANGL. DEV. =-92.9 DEGREES

REMARK 525

REMARK 525 SOLVENT

REMARK 525 THE FOLLOWING SOLVENT MOLECULES LIE FARTHER THAN EXPECTED

REMARK 525 FROM THE PROTEIN OR NUCLEIC ACID MOLECULE AND MAY BE

REMARK 525 ASSOCIATED WITH A SYMMETRY RELATED MOLECULE (M=MODEL

REMARK 525 NUMBER; RES=RESIDUE NAME; C=CHAIN IDENTIFIER;

SSEQ=SEQUENCE REMARK 525 NUMBER; I=INSERTION CODE): REMARK 525

REMARK 525 M RES CSSEQI

REMARK 525 HOH 110 DISTANCE = 8.01 ANGSTROMS REMARK 525 HOH 163 DISTANCE = 5.25 ANGSTROMS REMARK 525 HOH 171 DISTANCE = 6.32 ANGSTROMS REMARK 525 HOH 175 DISTANCE = 5.32 ANGSTROMS DBREF 1G8Q A 113 202 UNP P60033 CD81JHUMAN 113 202 DBREF 1G8Q B 213 302 UNP P60033 CD81JHUMAN 113 202 SEQADV 1G8Q HIS A 202 UNP P60033 LEU 202 CONFLICT SEQADV 1G8Q HIS B 302 UNP P60033 LEU 202 CONFLICT

SEQRES 1 A 90 PHE VAL ASN LYS ASP GLN ILE ALA LYS ASP VAL LYS GLN SEQRES 2 A 90 PHE TYR ASP GLN ALA LEU GLN GLN ALA VAL VAL ASP ASP SEQRES 3 A 90 ASP ALA ASN ASN ALA LYS ALA VAL VAL LYS THR PHE HIS SEQRES 4 A 90 GLU THR LEU ASP CYS CYS GLY SER SER THR LEU THR ALA SEQRES 5 A 90 LEU THR THR SER VAL LEU LYS ASN ASN LEU CYS PRO SER SEQRES 6 A 90 GLY SER ASN ILE ILE SER ASN LEU PHE LYS GLU ASP CYS SEQRES 7 A 90 HIS GLN LYS ILE ASP ASP LEU PHE SER GLY LYS HIS SEQRES 1 B 90 PHE VAL ASN LYS ASP GLN ILE ALA LYS ASP VAL LYS GLN SEQRES 2 B 90 PHE TYR ASP GLN ALA LEU GLN GLN ALA VAL VAL ASP ASP SEQRES 3 B 90 ASP ALA ASN ASN ALA LYS ALA VAL VAL LYS THR PHE HIS

SEQRES 4 B 90 GLU THR LEU ASP CYS CYS GLY SER SER THR LEU THR ALA SEQRES 5 B 90 LEU THR THR SER VAL LEU LYS ASN ASN LEU CYS PRO SER SEQRES 6 B 90 GLY SER ASN ILE ILE SER ASN LEU PHE LYS GLU ASP CYS SEQRES 7 B 90 HIS GLN LYS ILE ASP ASP LEU PHE SER GLY LYS HIS FORMUL 3 HOH *194(H2 O)

HELIX 1 1 ASN A 115 ASP A 137 1 23

HELIX 2 2 ALA A 140 ASP A 155 1 16

HELIX 3 3 LEU A 162 ALA A 164 5 3

HELIX 4 4 LEU A 165 ASN A 172 1 8 HELIX 5 5 ASN A 180 PHE A 186 1 7

HELIX 6 6 ASP A 189 GLY A 200 1 12

HELIX 7 7 ASN B 215 VAL B 236 1 22

HELIX 8 8 ASN B 242 ASP B 255 1 14

HELIX 9 9 LEU B 262 ASN B 272 1 11 HELIX 10 10 GLY B 278 ASN B 284 1 7

HELIX 11 11 ASP B 289 GLY B 300 1 12

SSBOND 1 CYS A 156 CYS A 190 SSBOND 2 CYS A 157 CYS A 175 SSBOND 3 CYS B 256 CYS B 290 SSBOND 4 CYS B 257 CYS B 275 CRYST1 31.485 77.172 38.462 90.00 107.39 90.00 P 1 21 1 4 ORIGX1 1.000000 0.000000 0.000000 0.00000

ORIGX2 0.000000 1.000000 0.000000 0.00000

ORIGX3 0.000000 0.000000 1.000000 0.00000

SCALE 1 0.031761 -0.000001 0.009946 0.00000

SCALE2 0.000000 0.012958 0.000000 0.00000

SCALE3 0.000000 0.000000 0.027245 0.00000

ATOM 1 N PHE A 113 15.167 44.770 -2.797 1.00 39.24 N

ATOM 2 CA PHE A 113 13.708 45.147 -2.958 1.00 34.94 C

ATOM 3 C PHE A 113 13.024 44.596 -1.659 1.00 35.10 C

ATOM 4 O PHE A 113 13.487 43.617 -1.121 1.00 35.93 O

ATOM 5 CB PHE A 113 13.050 44.429 -4.084 1.00 35.75 C

ATOM 6 CG PHE A 113 13.549 44.896 -5.455 1.00 34.69 C

ATOM 7 CD1 PHE A 113 13.430 46.212 ! -5.878 1.00 33.45 C

ATOM 8 CD2 PHE A 113 14.081 43.938 I -6.285 1.00 31.71 C

ATOM 9 CE1 PHE A 113 13.797 46.605 » -7.119 1.00 41.37 C

ATOM 10 CE2 PHE A 113 14.510 44.35' 1 -7.562 1.00 34.14 C

ATOM 11 CZ PHE A 113 14.380 45.642 -7.911 1.00 29.25 C

ATOM 12 N VAL A 114 11.997 45.314 -1.304 1.00 30.58 N

ATOM 13 CA VAL A 114 11.331 44.894 -0.015 1.00 29.62 C

ATOM 14 C VAL A 114 10.546 43.656 -0.280 1.00 34.38 C

ATOM 15 O VAL A 114 9.775 43.436 ■ ■1.243 1.00 39.07 O

ATOM 16 CB VAL A 114 10.340 46.075 0.213 1.00 28.69 C

ATOM 17 CG1 VAL A 114 9.250 45.669 1.193 1.00 38.63 C

ATOM 18 CG2 VAL A 114 11.113 47.339 0.485 1.00 32.13 C

ATOM 19 N ASN A 115 10.625 42.728 0.669 1.00 25.83 N

ATOM 20 CA ASN A 115 9.993 41.447 0.619 1.00 26.00 C

ATOM 21 C ASN A 115 9.027 41.300 1.849 1.00 29.46 C

ATOM 22 O ASN A 115 9.603 40.949 2.880 1.00 29.57 O

ATOM 23 CB ASN A 115 11.110 40.401 0.766 1.00 32.45 C

ATOM 24 CG ASN A 115 10.691 38.98E ) 0.428 1.00 37.56 C

ATOM 25 OD1 ASN A 115 9.537 38.605 i 0.619 1.00 37.64 O

ATOM 26 ND2 ASN A 115 11.677 38.219 -0.112 1.00 41.69 N

ATOM 27 N LYS A 116 7.809 41.729 1.649 1.00 28.35 N

ATOM 28 CA LYS A 116 6.882 41.668 2.805 1.00 31.24 C

ATOM 29 C LYS A 116 6.730 40.323 3.475 1.00 29.73 C

ATOM 30 O LYS A 116 6.713 40.228 4.699 1.00 27.86 O

ATOM 31 CB LYS A 116 5.546 42.199 2.325 1.00 32.44 C

ATOM 32 CG LYS A 116 4.449 42.271 3.367 1.00 42.56 C

ATOM 33 CD LYS A 116 3.441 41.207 2.964 1.00 59.59 C ATOM 34 CE LYS A 116 2.091 41.586 3.570 1.00 54.79 C

ATOM 35 NZ LYS A 116 1.324 40.335 3.706 1.00 44.76 N

ATOM 36 N ASP A 117 6.590 39.253 2.686 1.00 30.24 N

ATOM 37 CA ASP A 117 6.532 37.911 3.325 1.00 30.86 C

ATOM 38 C ASP A 117 7.808 37.647 4.074 1.00 31.67 C

ATOM 39 O ASP A 117 7.619 37.085 5.190 1.00 29.62 O

ATOM 40 CB ASP A 117 6.370 36.796 2.280 1.00 36.10 C

ATOM 41 CG ASP A 117 5.042 36.832 1.557 1.00 42.66 C

ATOM 42 OD1 ASP A 117 4.957 36.194 0.452 1.00 44.88 O

ATOM 43 OD2 ASP A 117 4.130 37.497 2.098 1.00 46.14 O

ATOM 44 N GLN A 118 9.018 37.973 3.673 1.00 27.21 N

ATOM 45 CA GLN A 118 10.205 37.641 4.470 1.00 23.73 C

ATOM 46 C GLN A 118 10.221 38.518 5.768 1.00 25.02 C

ATOM 47 O GLN A 118 10.586 38.025 6.858 1.00 28.58 O

ATOM 48 CB GLN A 118 11.519 37.791 3.721 1.00 33.27 C

ATOM 49 CG GLN A 118 12.351 36.517 3.936 1.00 51.73 C

ATOM 50 CD GLN A 118 11.848 35.378 3.072 1.00 60.56 C

ATOM 51 OE1 GLN A 118 11.324 34.393 3.608 1.00 68.76 O

ATOM 52 NE2 GLN A 118 11.942 35.430 1.742 1.00 56.06 N

ATOM 53 N ILE A 119 9.860 39.753 5.560 1.00 25.35 N

ATOM 54 CA ILE A 119 9.895 40.703 6.722 1.00 23.35 C

ATOM 55 C ILE A 119 8.948 40.174 7.778 1.00 23.36 C

ATOM 56 O ILE A 119 9.315 40.183 9.007 1.00 25.20 O

ATOM 57 CB ILE A 119 9.497 42.128 6.252 1.00 28.02 C

ATOM 58 CG1 ILE A 119 10.556 42.719 5.326 1.00 29.50 C

ATOM 59 CG2 ILE A 119 9.264 43.026 7.517 1.00 23.83 C

ATOM 60 CD1 ILE A 119 10.195 44.036 4.621 1.00 30.12 C

ATOM 61 N ALA A 120 7.709 39.796 7.396 1.00 24.29 N

ATOM 62 CA ALA A 120 6.783 39.332 8.475 1.00 25.45 C

ATOM 63 C ALA A 120 7.284 38.050 9.156 1.00 24.83 C

ATOM 64 O ALA A 120 7.233 37.973 10.395 1.00 25.98 O

ATOM 65 CB ALA A 120 5.371 38.968 7.933 1.00 29.86 C

ATOM 66 N LYS A 121 7.884 37.147 8.322 1.00 25.79 N

ATOM 67 CA LYS A 121 8.445 35.944 8.931 1.00 28.41 C

ATOM 68 C LYS A 121 9.578 36.321 9.881 1.00 24.24 C

ATOM 69 O LYS A 121 9.627 35.796 11.048 1.00 26.75 O

ATOM 70 CB LYS A 121 8.938 35.059 7.745 1.00 32.64 C

ATOM 71 CG LYS A 121 10.364 34.549 7.911 1.00 44.31 C

ATOM 72 CD LYS A 121 11.287 35.259 6.938 1.00 69.09 C

ATOM 73 CE LYS A 121 12.675 34.657 6.834 1.00 57.61 C ATOM 74 NZ LYS A 121 13.589 35.621 6.165 1.00 50.39 N

ATOM 75 N ASP A 122 10.373 37.294 9.564 1.00 23.37 N

ATOM 76 CA ASP A 122 11.501 37.727 10.378 1.00 24.26 C

ATOM 77 C ASP A 122 10.983 38.467 11.667 1.00 24.20 C

ATOM 78 O ASP A 122 11.557 38.256 12.735 1.00 23.00 O

ATOM 79 CB ASP A 122 12.558 38.595 9.757 1.00 22.89 C

ATOM 80 CG ASP A 122 13.357 37.803 8.676 1.00 26.88 C

ATOM 81 OD1 ASP A 122 13.258 36.555 8.568 1.00 32.41 O

ATOM 82 OD2 ASP A 122 14.097 38.531 7.966 1.00 31.40 O

AATTOOMM 8833 NN VVAALL AA 112233 9.959 39.272 11.554 1.00 25.26 N

ATOM 84 CA VAL A 123 9.366 39.889 12.760 1.00 22.33 C

ATOM 85 C VAL A 123 8.835 38.836 13.703 1.00 20.29 C

ATOM 86 O VAL A 123 9.011 38.893 14.920 1.00 22.67 O

ATOM 87 CB VAL A 123 8.275 40.934 12.399 1.00 18.96 C

AATTOOMM 8888 CCGG11 VVAALL AA 112233 7.797 41.561 13.712 1.00 20.18 C

ATOM 89 CG2 VAL A 123 9.055 42.031 11.573 1.00 23.67 C

ATOM 90 N LYS A 124 8.096 37.850 13.096 1.00 21.86 N

ATOM 91 CA LYS A 124 7.557 36.770 14.029 1.00 24.09 C

ATOM 92 C LYS A 124 8.717 36.046 14.718 1.00 25.15 C

AATTOOMM 9933 OO LLYYSS AA 112244 8.683 35.781 15.934 1.00 24.94 O

ATOM 94 CB LYS A 124 6.796 35.780 13.133 1.00 25.89 C

ATOM 95 CG LYS A 124 5.506 36.417 12.615 1.00 25.29 C

ATOM 96 CD LYS A 124 4.836 35.401 11.665 1.00 29.66 C

ATOM 97 CE LYS A 124 3.760 36.151 10.867 1.00 33.26 C

AATTOOMM 9988 NNZZ LLYYSS AA 112244 3.127 35.134 9.944 1.00 31.77 N

ATOM 99 N GLN A 125 9.820 35.785 14.057 1.00 22.36 N

ATOM 100 CA ^ GLN A 125 10.964 35.104 14.641 1.00 25.16 C

ATOM 101 C GLN A 125 11.681 35.921 15.679 1.00 22.14 C

ATOM 102 O GLN A 125 12.014 35.492 16.746 1.00 26.91 O

AATTOOMM 110033 CCEB ! GGLLNN AA 112255 11.945 34.652 13.543 1.00 29.01 C

ATOM 104 CG GLN A 125 13.031 33.807 14.174 1.00 28.57 C

ATOM 105 CC ) GLN A 125 12.622 32.700 15.114 1.00 54.17 C

ATOM 106 OE1 GLN A 125 11.511 32.150 15.215 1.00 49.09 O

ATOM 107 NE2 GLN A 125 13.581 32.238 15.938 1.00 56.90 N

AATTOOMM 110088 NN PPHHEE AA 112266 11.883 37.250 15.397 1.00 21.36 N

ATOM 109 CA ^ PHE A 126 12.391 38.153 16.405 1.00 24.32 C

ATOM 110 C PHE A 126 11.618 38.143 17.688 1.00 22.26 C

ATOM 111 O PHE A 126 12.053 38.072 18.817 1.00 22.96 O

ATOM 112 CE ! PHE A 126 12.368 39.573 15.870 1.00 20.57 C

AATTOOMM 111133 CCGG PPHHEE AA 112266 12.963 40.600 16.766 1.00 22.49 C ATOM 114 CD1 PHE A 126 14.371 40.653 16.807 1.00 24.90 C

ATOM 115 CD2 PHE A 126 12.179 41.436 17.582 1.00 24.61 C

ATOM 116 CE1 PHE A 126 14.990 41.590 17.635 1.00 28.22 C

ATOM 117 CE2 PHE A 126 12.843 42.365 18.366 1.00 21.62 C

ATOM 118 CZ PHE A 126 14.187 42.409 18.445 1.00 27.52 C

ATOM 119 N TYR A 127 10.253 38.186 17.529 1.00 20.08 N

ATOM 120 CA TYR A 127 9.357 38.138 18.709 1.00 20.07 C

ATOM 121 C TYR A 127 9.558 36.810 19.423 1.00 18.65 C

ATOM 122 O TYR A 127 9.654 36.867 20.698 1.00 21.80 O

ATOM 123 CB TYR A 127 7.862 38.220 18.163 1.00 24.10 C

ATOM 124 CG TYR A 127 6.916 38.008 19.347 1.00 22.09 C

ATOM 125 CD1 TYR A 127 6.572 38.938 20.301 1.00 21.15 C

ATOM 126 CD2 TYR A 127 6.387 36.697 19.442 1.00 21.40 C

ATOM 127 CE1 TYR A 127 5.739 38.648 21.380 1.00 17.95 C

ATOM 128 CE2 TYR A 127 5.535 36.347 20.518 1.00 23.42 C

ATOM 129 CZ TYR A 127 5.219 37.313 21.437 1.00 22.63 C

ATOM 130 OH TYR A 127 4.375 36.938 22.472 1.00 22.57 O

ATOM 131 N ASP A 128 9.601 35.711 18.665 1.00 23.53 N

ATOM 132 CA ASP A 128 9.711 34.412 19.441 1.00 22.47 C

ATOM 133 C ASP A 128 11.092 34.261 20.060 1.00 24.09 C

ATOM 134 O ASP A 128 11.163 33.757 21.206 1.00 22.97 O

ATOM 135 CB ASP A 128 9.677 33.281 18.369 1.00 26.18 C

ATOM 136 CG ASP A 128 8.242 33.030 17.920 1.00 30.00 C

ATOM 137 OD1 ASP A 128 8.112 32.186 17.003 1.00 33.09 O

ATOM 138 OD2 ASP A 128 7.285 33.596 18.476 1.00 27.78 O

ATOM 139 N GLN A 129 12.138 34.813 19.426 1.00 22.90 N

ATOM 140 CA GLN A 129 13.445 34.792 20.155 1.00 22.90 C

ATOM 141 C GLN A 129 13.295 35.635 21.407 1.00 22.52 C

ATOM 142 O GLN A 129 13.817 35.218 22.484 1.00 24.95 O

ATOM 143 CB GLN A 129 14.513 35.596 19.319 1.00 25.15 C

ATOM 144 CG GLN A 129 14.765 34.861 18.052 1.00 25.16 C

ATOM 145 CD GLN A 129 15.677 35.679 17.066 1.00 26.58 C

ATOM 146 OE1 GLN A 129 15.971 35.072 16.036 1.00 30.99 O

ATOM 147 NE2 GLN A 129 15.997 36.941 17.458 1.00 31.51 N

ATOM 148 N ALA A 130 12.694 36.840 21.393 1.00 20.21 N

ATOM 149 CA ALA A 130 12.613 37.548 22.651 1.00 19.29 C

ATOM 150 C ALA A 130 11.817 36.889 23.683 1.00 22.30 C

ATOM 151 O ALA A 130 12.037 36.954 24.923 1.00 23.00 O

ATOM 152 CB ALA A 130 12.057 39.015 22.407 1.00 21.56 C

ATOM 153 N LEU A 131 10.662 36.254 23.275 1.00 19.17 N ATOM 154 CA LEU A 131 9.735 35.649 24.274 1.00 21.49 C

ATOM 155 C LEU A 131 10.463 34.445 24.955 1.00 21.26 C

ATOM 156 O LEU A 131 10.319 34.276 26.152 1.00 22.13 O

ATOM 157 CB LEU A 131 8.491 35.143 23.506 1.00 21.78 C

ATOM 158 CG LEU A 131 7.340 34.770 24.524 1.00 26.50 C

ATOM 159 CD1 LEU A 131 6.816 36.103 25.128 1.00 24.46 C

ATOM 160 CD2 LEU A 131 6.210 34.112 23.753 1.00 23.66 C

ATOM 161 N GLN A 132 11.180 33.702 24.131 1.00 22.34 N

ATOM 162 CA GLN A 132 11.877 32.528 24.718 1.00 23.45 C

ATOM 163 C GLN A 132 12.919 32.988 25.683 1.00 22.56 C

ATOM 164 O GLN A 132 13.005 32.390 26.763 1.00 23.72 O

ATOM 165 CB GLN A 132 12.511 31.671 23.583 1.00 22.67 C

ATOM 166 CG GLN A 132 11.360 30.974 22.801 1.00 23.87 C

ATOM 167 CD GLN A 132 11.970 30.208 21.612 1.00 25.58 C

ATOM 168 OE1 GLN A 132 11.931 28.953 21.568 1.00 28.70 O

ATOM 169 NE2 GLN A 132 12.435 30.860 20.528 1.00 25.53 N

ATOM 170 N GLN A 133 13.708 34.060 25.414 1.00 21.29 N

ATOM 171 CA GLN A 133 14.731 34.499 26.352 1.00 21.06 C

ATOM 172 C GLN A 133 14.083 35.143 27.568 1.00 22.06 C

ATOM 173 O GLN A 133 14.476 34.990 28.747 1.00 24.74 O

ATOM 174 CB GLN A 133 15.523 35.627 25.616 1.00 23.19 C

ATOM 175 CG GLN A 133 16.684 36.003 26.552 1.00 25.93 C

ATOM 176 CD GLN A 133 17.644 37.020 25.918 1.00 23.37 C

ATOM 177 OE1 GLN A 133 17.459 37.428 24.795 1.00 29.00 O

ATOM 178 NE2 GLN A 133 18.737 37.244 26.654 1.00 29.97 N

ATOM 179 N ALA A 134 12.951 35.892 27.350 1.00 22.33 N

ATOM 180 CA ALA A 134 12.278 36.527 28.484 1.00 24.62 C

ATOM 181 C ALA A 134 11.792 35.644 29.628 1.00 23.96 C

ATOM 182 O ALA A 134 11.707 35.941 30.837 1.00 28.27 O

ATOM 183 CB ALA A 134 11.055 37.336 27.981 1.00 24.32 C

ATOM 184 N VAL A 135 11.447 34.406 29.258 1.00 22.77 N

ATOM 185 CA VAL A 135 10.919 33.424 30.211 1.00 21.49 C

ATOM 186 C VAL A 135 12.053 32.697 30.814 1.00 25.43 C

ATOM 187 O VAL A 135 11.880 32.230 31.966 1.00 31.77 O

ATOM 188 CB VAL A 135 9.962 32.451 29.523 1.00 31.30 C

ATOM 189 CG1 VAL A 135 8.684 33.113 29.087 1.00 30.27 C

ATOM 190 CG2 VAL A 135 10.510 31.424 28.603 1.00 47.56 C

ATOM 191 N VAL A 136 13.146 32.476 30.096 1.00 30.78 N

ATOM 192 CA VAL A 136 14.200 31.646 30.772 1.00 29.87 C

ATOM 193 C VAL A 136 15.227 32.424 31.468 1.00 31.70 C ATOM 194 O VAL A 136 16.091 31.916 32.217 1.00 35.77 O

ATOM 195 CB VAL A 136 14.689 30.731 29.658 1.00 31.34 C

ATOM 196 CG1 VAL A 136 15.644 31.431 28.729 1.00 28.41 C

ATOM 197 CG2 VAL A 136 15.185 29.397 30.181 1.00 33.24 C

ATOM 198 N ASP A 137 15.515 33.682 31.066 1.00 28.53 N

ATOM 199 CA ASP A 137 16.663 34.476 31.489 1.00 29.09 C

ATOM 200 C ASP A 137 16.141 35.528 32.452 1.00 36.48 C

ATOM 201 O ASP A 137 15.425 36.451 32.034 1.00 36.05 O

ATOM 202 CB ASP A 137 17.245 35.177 30.255 1.00 30.94 C

AATTOOMM 220033 CCGG AASSPP AA 113377 18.518 35.945 30.541 1.00 39.46 C

ATOM 204 OD1 ASP A 137 19.163 36.437 29.580 1.00 33.64 O

ATOM 205 OD2 ASP A 137 18.930 36.186 31.696 1.00 34.86 O

ATOM 206 N ASP A 138 16.497 35.446 33.720 1.00 42.16 N

ATOM 207 CA ASP A 138 16.037 36.353 34.714 1.00 45.68 C

AATTOOMM 220088 CC AASSPP AA 113388 16.515 37.774 34.527 1.00 46.37 C

ATOM 209 O ASP A 138 15.704 38.564 34.947 1.00 45.11 O

ATOM 210 CB ASP A 138 16.249 35.931 36.174 1.00 58.56 C

ATOM 211 CG ASP A 138 14.551 35.422 36.525 0.00 27.18 C

ATOM 212 OD1 ASP A 138 14.174 34.275 36.165 0.00 27.18 O

AATTOOMM 221133 OODD22 AASSPP AA 113388 13.773 36.235 37.082 0.00 27.18 O

ATOM 214 N ASP A 139 17.692 38.042 33.967 1.00 47.83 N

ATOM 215 CA ASP A 139 18.036 39.452 33.855 1.00 48.21 C

ATOM 216 C ASP A 139 17.981 39.832 32.377 1.00 44.90 C

ATOM 217 O ASP A 139 18.711 40.782 32.038 1.00 46.82 O

AATTOOMM 221188 CCBB AASSPP AA 113399 19.266 39.981 34.547 1.00 63.50 C

ATOM 219 CG ASP A 139 20.196 38.861 34.969 1.00 65.14 C

ATOM 220 OD1 ASP A 139 20.797 38.271 34.063 1.00 69.59 O

ATOM 221 OD2 ASP A 139 20.264 38.631 36.185 1.00 56.99 O

ATOM 222 N ALA A 140 17.141 39.123 31.588 1.00 35.51 N

AATTOOMM 222233 CCAA AALLAA AA 114400 17.128 39.654 30.167 1.00 33.37 C

ATOM 224 C ALA A 140 16.152 40.797 30.148 1.00 29.22 C

ATOM 225 O ALA A 140 14.961 40.676 29.731 1.00 28.56 O

ATOM 226 CB ALA A 140 16.553 38.540 29.289 1.00 30.39 C

ATOM 227 N ASN A 141 16.517 41.994 30.622 1.00 29.97 N

AATTOOMM 222288 CCAA AASSNN AA 114411 15.581 43.085 30.732 1.00 30.12 C

ATOM 229 C ASN A 141 15.221 43.641 29.300 1.00 24.22 C

ATOM 230 O ASN A 141 14.013 43.975 29.236 1.00 31.05 O

ATOM 231 CB ASN A 141 16.330 44.259 31.407 1.00 37.38 C

ATOM 232 CG ASN A 141 16.706 43.864 32.830 1.00 58.73 C

AATTOOMM 223333 OODD11 AASSNN AA 114411 15.788 43.782 33.649 1.00 48.24 O ATOM 234 ND2 ASN A 141 18.008 43.643 33.006 1.00 57.88 N

ATOM 235 N ASN A 142 16.216 43.572 28.421 1.00 32.80 N

ATOM 236 CA ASN A 142 15.797 44.049 27.087 1.00 27.16 C

ATOM 237 C ASN A 142 14.791 43.063 26.472 1.00 25.25 C

ATOM 238 O ASN A 142 13.778 43.555 25.867 1.00 26.68 O

ATOM 239 CB ASN A 142 16.939 44.271 26.146 1.00 32.32 C

ATOM 240 CG ASN A 142 17.647 45.608 26.355 1.00 58.15 C

ATOM 241 OD1 ASN A 142 18.860 45.694 26.097 1.00 61.45 O

ATOM 242 ND2 ASN A 142 16.938 46.632 26.824 1.00 61.87 N ATOM 243 N ALA A 143 15.051 41.760 26.595 1.00 23.56 N

ATOM 244 CA ALA A 143 14.043 40.852 25.997 1.00 25.35 C

ATOM 245 C ALA A 143 12.672 40.992 26.542 1.00 24.18 C

ATOM 246 0 ALA A 143 11.602 40.992 25.893 1.00 22.84 O

ATOM 247 CB ALA A 143 14.437 39.381 26.220 1.00 22.46 C ATOM 248 N LYS A 144 12.502 41.187 27.921 1.00 21.61 N

ATOM 249 CA LYS A 144 11.244 41.402 28.521 1.00 20.65 C

ATOM 250 C LYS A 144 10.671 42.724 28.035 1.00 19.70 C

ATOM 251 O LYS A 144 9.482 42.704 27.781 1.00 24.51 O

ATOM 252 CB LYS A 144 11.362 41.380 30.080 1.00 28.93 C ATOM 253 CG LYS A 144 11.844 39.995 30.576 1.00 26.32 C

ATOM 254 CD LYS A 144 12.204 40.227 32.081 1.00 31.73 C

ATOM 255 CE LYS A 144 13.013 39.015 32.563 1.00 48.57 C

ATOM 256 NZ LYS A 144 12.006 37.966 32.970 1.00 44.07 N

ATOM 257 N ALA A 145 11.519 43.763 27.883 1.00 22.86 N ATOM 258 CA ALA A 145 10.873 45.027 27.376 1.00 24.48 C

ATOM 259 C ALA A 145 10.440 44.881 25.892 1.00 21.02 C

ATOM 260 O ALA A 145 9.289 45.361 25.646 1.00 21.56 O

ATOM 261 CB ALA A 145 11.954 46.092 27.435 1.00 24.03 C

ATOM 262 N VAL A 146 11.195 44.081 25.205 1.00 22.42 N ATOM 263 CA VAL A 146 10.683 43.860 23.785 1.00 20.82 C

ATOM 264 C VAL A 146 9.364 43.160 23.740 1.00 19.53 C

ATOM 265 0 VAL A 146 8.396 43.570 23.091 1.00 21.74 O

ATOM 266 CB VAL A 146 11.726 43.079 22.969 1.00 22.25 C ATOM 267 CG1 VAL A 146 11.106 42.475 21.692 1.00 23.53 C ATOM 268 CG2 VAL A 146 12.889 44.018 22.740 1.00 22.40 C

ATOM 269 N VAL A 147 9.239 42.070 24.565 1.00 19.41 N

ATOM 270 CA VAL A 147 7.957 41.314 24.518 1.00 19.37 C

ATOM 271 C VAL A 147 6.838 42.199 25.053 1.00 21.11 C

ATOM 272 O VAL A 147 5.742 42.218 24.524 1.00 22.13 O ATOM 273 CB VAL A 147 8.261 40.138 25.599 1.00 23.01 C ATOM 274 CG1 VAL A 147 7.175 39.622 26.405 1.00 36.11 C

ATOM 275 CG2 VAL A 147 8.919 39.135 24.597 1.00 33.30 C

ATOM 276 N LYS A 148 7.074 42.915 26.186 1.00 19.30 N

ATOM 277 CA LYS A 148 5.965 43.779 26.680 1.00 21.11 C

ATOM 278 C LYS A 148 5.557 44.921 25.703 1.00 20.10 C

ATOM 279 O LYS A 148 4.356 45.113 25.577 1.00 23.49 O

ATOM 280 CB LYS A 148 6.519 44.432 27.966 1.00 26.75 C

ATOM 281 CG LYS A 148 6.576 43.380 29.078 1.00 28.35 C

ATOM 282 CD LYS A 148 6.786 44.050 30.392 1.00 30.73 C

AATTOOMM 228833 CCEE LLYYSS AA 114488 7.984 44.914 30.530 1.00 48.22 C

ATOM 284 NZ LYS A 148 8.157 45.443 31.942 1.00 46.26 N

ATOM 285 N THR A 149 6.510 45.383 24.915 1.00 22.89 N

ATOM 286 CA THR A 149 6.185 46.446 23.968 1.00 24.65 C

ATOM 287 C THR A 149 5.451 45.863 22.786 1.00 21.98 C

AATTOOMM 228888 O0 TTHHRR AA 114499 4.446 46.357 22.351 1.00 22.98 O

ATOM 289 CB THR A 149 7.486 47.002 23.362 1.00 29.44 C

ATOM 290 OG1 THR A 149 8.176 47.740 24.406 1.00 27.47 O

ATOM 291 CG2 THR A 149 7.132 47.985 22.234 1.00 25.81 C

ATOM 292 N PHE A 150 5.840 44.643 22.350 1.00 20.37 N

AATTOOMM 229933 CCAA PPHHEE AA 115500 5.029 43.981 21.297 1.00 20.95 C

ATOM 294 C PHE A 150 3.639 43.743 21.813 1.00 21.53 C

ATOM 295 O PHE A 150 2.635 43.979 21.168 1.00 22.27 O

ATOM 296 CB PHE A 150 5.655 42.615 20.805 1.00 19.63 C

ATOM 297 CG PHE A 150 6.573 42.857 19.630 1.00 19.52 C

AATTOOMM 229988 CCDD11 PPHHEE AA 115500 7.777 43.521 19.819 1.00 23.32 C

ATOM 299 CD2 PHE A 150 6.215 42.274 18.434 1.00 22.00 C

ATOM 300 CE1 PHE A 150 8.645 43.659 18.717 1.00 24.62 C

ATOM 301 CE2 PHE A 150 7.101 42.466 17.310 1.00 25.97 C

ATOM 302 CZ PHE A 150 8.286 43.138 17.494 1.00 26.51 C

AATTOOMM 330033 NN HHIISS AA 115511 3.490 43.159 23.064 1.00 19.53 N

ATOM 304 CA HIS A 151 2.124 42.897 23.515 1.00 20.47 C

ATOM 305 C HIS A 151 1.264 44.156 23.688 1.00 18.01 C

ATOM 306 O HIS A 151 0.095 44.036 23.367 1.00 20.92 O

ATOM 307 CB HIS A 151 2.332 42.200 24.888 1.00 20.82 C

AATTOOMM 330088 CCGG HHIISS AA 115511 2.929 40.811 24.743 1.00 19.15 C

ATOM 309 ND1 HIS A 151 3.427 40.314 25.929 1.00 24.25 N

ATOM 310 CD2 HIS A 151 3.109 39.945 23.781 1.00 21.66 C

ATOM 311 CE1 HIS A 151 3.822 39.078 25.667 1.00 23.06 C

ATOM 312 NE2 HIS A 151 3.720 38.801 24.348 1.00 23.88 N

AATTOOMM 331133 NN GGLLUU AA 115522 1.801 45.274 24.157 1.00 21.42 N ATOM 314 CA GLU A 152 0.991 46.475 24.410 1.00 21.40 C

ATOM 315 C GLU A 152 0.649 47.098 23.021 1.00 25.13 C

ATOM 316 O GLU A 152 -0.536 47.381 22.669 1.00 26.67 O

ATOM 317 CB GLU A 152 1.893 47.394 25.196 1.00 24.42 C

ATOM 318 CG GLU A 152 1.128 48.749 25.464 1.00 34.65 C

ATOM 319 CD GLU A 152 1.913 49.423 26.598 1.00 37.56 C

ATOM 320 OE1 GLU A 152 3.043 49.857 26.265 1.00 64.84 O

ATOM 321 OE2 GLU A 152 1.398 49.543 27.716 1.00 55.50 O

ATOM 322 N THR A 153 1.681 47.044 22.171 1.00 22.11 N

AATTOOMM 332233 CCAA TTHHRR AA 115533 1.552 47.629 20.833 1.00 23.71 C

ATOM 324 C THR A 153 0.537 46.966 19.962 1.00 25.46 C

ATOM 325 O THR A 153 -0.256 47.627 19.283 1.00 27.48 O

ATOM 326 CB THR A 153 2.872 47.940 20.170 1.00 22.71 C

ATOM 327 OG1 THR A 153 3.720 48.793 20.993 1.00 25.38 O

AATTOOMM 332288 CCGG22 TTHHRR AA 115533 2.701 48.567 18.771 1.00 25.64 C

ATOM 329 N LEU A 154 0.586 45.635 19.885 1.00 24.29 N

ATOM 330 CA LEU A 154 -0.281 44.863 19.040 1.00 24.20 C

ATOM 331 C LEU A 154 -1.521 44.276 19.702 1.00 25.11 C

ATOM 332 O LEU A 154 -2.242 43.542 19.024 1.00 31.73 O

AATTOOMM 333333 CCBB LLEEUU AA 115544 0.471 43.693 18.386 1.00 23.92 C

ATOM 334 CG LEU A 154 1.721 44.169 17.720 1.00 23.37 C

ATOM 335 CD1 LEU A 154 2.494 42.937 17.204 1.00 28.56 C

ATOM 336 CD2 LEU A 154 1.402 45.022 16.462 1.00 27.60 C

ATOM 337 N ASP A 155 -1.645 44.486 20.999 1.00 23.85 N

AATTOOMM 333388 CCAA AASSPP AA 115555 -2.803 43.999 21.759 1.00 26.72 C

ATOM 339 C ASP A 155 -2.836 42.476 21.723 1.00 31.14 C

ATOM 340 O ASP A 155 -3.738 41.901 21.132 1.00 30.16 O

ATOM 341 CB ASP A 155 -4.086 44.605 21.165 1.00 29.88 C

ATOM 342 CG ASP A 155 -5.284 44.202 22.046 1.00 62.82 C

AATTOOMM 334433 OODD11 AASSPP AA 115555 -6.416 44.204 21.488 1.00 39.28 O

ATOM 344 OD2 ASP A 155 -5.071 43.903 23.251 1.00 34.83 O

ATOM 345 N CYS A 156 -1.733 41.821 22.173 1.00 25.43 N

ATOM 346 CA CYS A 156 -1.687 40.326 22.076 1.00 25.93 C

ATOM 347 C CYS A 156 -0.778 39.856 23.222 1.00 26.10 C

AATTOOMM 334488 O0 CCYYSS AA 115566 -0.272 40.683 24.015 1.00 26.38 O

ATOM 349 CB CYS A 156 -1.081 39.823 20.712 1.00 27.65 C

ATOM 350 SG CYS A 156 0.624 40.431 20.467 1.00 24.42 S

ATOM 351 N CYS A 157 -0.841 38.498 23.386 1.00 26.16 N

ATOM 352 CA CYS A 157 -0.019 37.979 24.534 1.00 27.59 C

AATTOOMM 335533 CC CCYYSS AA 115577 0.313 36.537 24.102 1.00 24.85 C ATOM 354 O CYS A 157 -0.512 35.605 23.948 1.00 27.75 O

ATOM 355 CB CYS A 157 -0.963 37.941 25.755 1.00 33.15 C

ATOM 356 SG CYS A 157 -0.198 37.066 27.122 1.00 32.82 S

ATOM 357 N GLY A 158 1.574 36.270 23.768 1.00 23.57 N

ATOM 358 CA GLY A 158 1.986 34.979 23.277 1.00 23.42 C

ATOM 359 C GLY A 158 1.869 34.744 21.807 1.00 25.49 C

ATOM 360 O GLY A 158 1.349 35.496 20.998 1.00 31.29 O

ATOM 361 N SER A 159 2.414 33.581 21.339 1.00 23.29 N

ATOM 362 CA SER A 159 2.359 33.220 19.919 1.00 24.98 C

AATTOOMM 336633 CC SSEERR AA 115599 1.881 31.744 19.739 1.00 29.71 C

ATOM 364 O SER A 159 2.048 30.954 20.649 1.00 28.92 O

ATOM 365 CB SER A 159 3.592 33.368 19.048 1.00 38.22 C

ATOM 366 OG SER A 159 4.674 32.685 19.718 1.00 33.40 O

ATOM 367 N SER A 160 1.533 31.533 18.480 1.00 29.16 N

AATTOOMM 336688 CCAA SSEERR AA 116600 1.006 30.167 18.156 1.00 31.53 C

ATOM 369 C SER A 160 2.124 29.147 18.136 1.00 30.90 C

ATOM 370 O SER A 160 1.872 27.967 18.164 1.00 41.00 O

ATOM 371 CB SER A 160 0.219 30.309 16.840 1.00 29.50 C

ATOM 372 OG SER A 160 0.984 30.787 15.768 1.00 39.90 O

AATTOOMM 337733 NN TTHHRR AA 116611 3.375 29.476 17.923 1.00 29.06 N

ATOM 374 CA THR A 161 4.554 28.637 17.920 1.00 32.53 C

ATOM 375 C THR A 161 4.973 28.367 19.379 1.00 28.69 C

ATOM 376 O THR A 161 5.909 27.498 19.535 1.00 30.18 O

ATOM 377 CB THR A 161 5.743 29.318 17.183 1.00 33.24 C

AATTOOMM 337788 OOGG11 TTHHRR AA 116611 5.878 30.621 17.769 1.00 30.51 O

ATOM 379 CG2 THR A 161 5.579 29.437 15.695 1.00 30.20 C

ATOM 380 N LEU A 162 4.410 29.011 20.350 1.00 25.65 N

ATOM 381 CA LEU A 162 4.843 28.891 21.737 1.00 27.51 C

ATOM 382 C LEU A 162 3.727 28.800 22.731 1.00 26.68 C

AATTOOMM 338833 OO LLEEUU AA 116622 3.784 29.279 23.870 1.00 25.46 O

ATOM 384 CB LEU A 162 5.751 30.132 21.999 1.00 23.77 C

ATOM 385 CG LEU A 162 7.083 30.158 21.261 1.00 24.78 C

ATOM 386 CD1 LEU A 162 7.772 31.517 21.579 1.00 24.05 C

ATOM 387 CD2 LEU A 162 8.035 29.027 21.780 1.00 25.38 C

AATTOOMM 338888 NN TTHHRR AA 116633 2.648 28.102 22.281 1.00 33.72 N

ATOM 389 CA THR A 163 1.426 27.933 23.021 1.00 34.30 C

ATOM 390 C THR A 163 1.605 27.355 24.405 1.00 32.24 C

ATOM 391 O THR A 163 1.038 27.846 25.352 1.00 37.92 O

ATOM 392 CB THR A 163 0.304 27.257 22.238 1.00 50.44 C

AATTOOMM 339933 OOGG11 TTHHRR AA 116633 0.579 25.851 22.212 1.00 41.17 O ATOM 394 CG2 THR A 163 0.359 27.673 20.762 1.00 37.36 C

ATOM 395 N ALA A 164 2.575 26.400 24.460 1.00 32.95 N

ATOM 396 CA ALA A 164 2.860 25.919 25.797 1.00 33.55 C

ATOM 397 C ALA A 164 3.585 26.806 26.718 1.00 35.24 C ATOM 398 O ALA A 164 3.697 26.461 27.906 1.00 32.41 O

ATOM 399 CB ALA A 164 3.315 24.481 25.766 1.00 39.49 C

ATOM 400 N LEU A 165 4.091 27.987 26.277 1.00 33.05 N

ATOM 401 CA LEU A 165 4.713 28.934 27.170 1.00 31.37 C

ATOM 402 C LEU A 165 3.847 30.044 27.639 1.00 28.59 C ATOM 403 O LEU A 165 4.160 30.749 28.603 1.00 31.69 O

ATOM 404 CB LEU A 165 5.792 29.699 26.290 1.00 28.17 C

ATOM 405 CG LEU A 165 7.222 29.534 26.511 1.00 27.01 C

ATOM 406 CD1 LEU A 165 8.004 30.520 25.746 1.00 23.83 C

ATOM 407 CD2 LEU A 165 7.826 28.591 27.467 1.00 27.70 C ATOM 408 N THR A 166 2.561 30.087 27.075 1.00 31.94 N

ATOM 409 CA THR A 166 1.689 31.171 27.588 1.00 40.87 C

ATOM 410 C THR A 166 1.516 31.275 29.073 1.00 42.39 C

ATOM 411 O THR A 166 1.563 32.362 29.701 1.00 38.40 O

ATOM 412 CB THR A 166 0.448 31.306 26.680 1.00 36.13 C ATOM 413 OG1 THR A 166 0.804 31.293 25.311 1.00 36.62 O

ATOM 414 CG2 THR A 166 -0.435 32.499 26.978 1.00 44.79 C

ATOM 415 N THR A 167 1.399 30.168 29.837 1.00 42.15 N

ATOM 416 CA THR A 167 1.302 30.193 31.270 1.00 40.32 C

ATOM 417 C THR A 167 2.376 30.942 32.017 1.00 36.81 C ATOM 418 0 THR A 167 2.358 31.776 32.931 1.00 37.99 O

ATOM 419 CB THR A 167 1.201 28.762 31.883 1.00 61.23 C

ATOM 420 OG1 THR A 167 0.557 27.876 30.964 1.00 67.37 O

ATOM 421 CG2 THR A 167 0.376 28.868 33.146 1.00 53.56 C

ATOM 422 N SER A 168 3.590 30.607 31.494 1.00 35.37 N ATOM 423 CA SER A 168 4.825 31.188 31.902 1.00 31.87 C

ATOM 424 C SER A 168 4.873 32.668 31.486 1.00 30.23 C

ATOM 425 O SER A 168 5.226 33.518 32.274 1.00 34.03 O

ATOM 426 CB SER A 168 5.911 30.387 31.166 1.00 40.72 C

ATOM 427 OG SER A 168 7.074 30.623 31.911 1.00 41.48 O ATOM 428 N VAL A 169 4.409 32.950 30.280 1.00 36.11 N

ATOM 429 CA VAL A 169 4.454 34.354 29.866 1.00 26.69 C

ATOM 430 C VAL A 169 3.607 35.222 30.816 1.00 32.76 C

ATOM 431 O VAL A 169 3.926 36.296 31.349 1.00 36.23 O

ATOM 432 CB VAL A 169 4.106 34.440 28.374 1.00 30.41 C ATOM 433 CG1 VAL A 169 4.076 35.927 27.930 1.00 25.68 C ATOM 434 CG2 VAL A 169 5.156 33.698 27.574 1.00 33.52 C

ATOM 435 N LEU A 170 2.443 34.712 31.170 1.00 35.41 N

ATOM 436 CA LEU A 170 1.519 35.415 32.068 1.00 40.24 C

ATOM 437 C LEU A 170 2.089 35.585 33.450 1.00 36.07 C

ATOM 438 O LEU A 170 2.021 36.646 34.047 1.00 37.93 O

ATOM 439 CB LEU A 170 0.287 34.558 32.121 1.00 34.96 C

ATOM 440 CG LEU A 170 -0.755 34.811 31.021 1.00 38.88 C

ATOM 441 CD1 LEU A 170 -2.050 34.225 31.647 1.00 42.60 C

ATOM 442 CD2 LEU A 170 -1.038 36.249 30.722 1.00 45.47 C

AATTOOMM 444433 NN LLYYSS AA 117711 2.675 34.477 33.945 1.00 40.34 N

ATOM 444 CA LYS A 171 3.223 34.540 35.317 1.00 45.51 C

ATOM 445 C LYS A 171 4.338 35.539 35.439 1.00 44.28 C

ATOM 446 O LYS A 171 4.525 36.108 36.536 1.00 41.55 O

ATOM 447 CB LYS A 171 3.821 33.166 35.694 1.00 69.69 C

AATTOOMM 444488 CCGG LLYYSS AA 117711 4.311 33.137 37.140 1.00 79.83 C

ATOM 449 CD LYS A 171 3.175 32.835 38.111 1.00 95.86 C

ATOM 450 CE LYS A 171 3.497 33.257 39.535 1.00 94.11 C

ATOM 451 NZ LYS A 171 2.737 32.464 40.542 1.00 99.00 N

ATOM 452 N ASN A 172 5.103 35.691 34.317 1.00 33.49 N ATOM 453 CA ASN A 172 6.157 36.717 34.392 1.00 32.00 C

ATOM 454 C ASN A 172 5.665 38.134 34.144 1.00 32.19 C

ATOM 455 O ASN A 172 6.466 39.064 33.993 1.00 34.93 O

ATOM 456 CB ASN A 172 7.198 36.377 33.271 1.00 38.64 C ATOM 457 CG ASN A 172 8.169 35.294 33.642 1.00 47.08 C ATOM 458 OD1 ASN A 172 9.214 35.622 34.197 1.00 50.53 O

ATOM 459 ND2 ASN A 172 7.916 34.038 33.334 1.00 37.12 N

ATOM 460 N ASN A 173 4.355 38.407 34.211 1.00 31.88 N

ATOM 461 CA ASN A 173 3.768 39.741 34.092 1.00 28.39 C

ATOM 462 C ASN A 173 4.219 40.419 32.746 1.00 29.05 C ATOM 463 0 ASN A 173 4.317 41.667 32.724 1.00 32.53 O

ATOM 464 CB ASN A 173 4.000 40.649 35.250 1.00 36.22 C ATOM 465 CG ASN A 173 3.422 39.922 36.518 1.00 34.79 C

ATOM 466 OD1 ASN A 173 2.550 39.072 36.379 1.00 40.09 O

ATOM 467 ND2 ASN A 173 4.051 40.320 37.608 1.00 54.78 N ATOM 468 N LEU A 174 4.263 39.558 31.711 1.00 31.35 N

ATOM 469 CA LEU A 174 4.666 40.153 30.400 1.00 26.80 C

ATOM 470 C LEU A 174 3.456 40.549 29.567 1.00 30.61 C

ATOM 471 0 LEU A 174 3.735 41.127 28.467 1.00 26.30 O

ATOM 472 CB LEU A 174 5.493 39.102 29.554 1.00 27.25 C ATOM 473 CG LEU A 174 6.789 38.710 30.323 1.00 29.12 C ATOM 474 CD1 LEU A 174 7.407 37.492 29.580 1.00 28.38 C

ATOM 475 CD2 LEU A 174 7.781 39.902 30.305 1.00 30.60 C

ATOM 476 N CYS A 175 2.239 40.256 30.018 1.00 30.48 N

ATOM 477 CA CYS A 175 1.099 40.710 29.225 1.00 30.38 C

ATOM 478 C CYS A 175 0.355 41.866 29.885 1.00 31.31 C

ATOM 479 O CYS A 175 0.399 41.963 31.124 1.00 28.50 O

ATOM 480 CB CYS A 175 0.199 39.520 28.920 1.00 33.34 C

ATOM 481 SG CYS A 175 1.156 38.385 27.801 1.00 34.59 S

ATOM 482 N PRO A 176 -0.204 42.749 29.139 1.00 26.97 N

AATTOOMM 448833 CCAA PPRROO AA 117766 -1.053 43.853 29.594 1.00 29.17 C

ATOM 484 C PRO A 176 -2.084 43.390 30.647 1.00 27.85 C

ATOM 485 O PRO A 176 -2.604 42.299 30.578 1.00 29.34 O

ATOM 486 CB PRO A 176 -1.827 44.329 28.344 1.00 31.13 C

ATOM 487 CG PRO A 176 -0.663 44.246 27.400 1.00 30.18 C

AATTOOMM 448888 CCDD PPRROO AA 117766 -0.193 42.805 27.620 1.00 27.08 C

ATOM 489 N SER A 177 -2.235 44.409 31.562 1.00 30.71 N

ATOM 490 CA SER A 177 -3.167 44.149 32.688 1.00 34.85 C

ATOM 491 C SER A 177 -4.474 43.650 32.148 1.00 38.23 C

ATOM 492 O SER A 177 -4.906 44.246 31.131 1.00 44.22 O

AATTOOMM 449933 CCBB SSEERR AA 117777 -3.430 45.468 33.436 1.00 36.64 C

ATOM 494 OG SER A 177 -2.230 46.130 33.766 1.00 47.00 O

ATOM 495 N GLY A 178 -5.092 42.630 32.719 1.00 42.86 N

ATOM 496 CA GLY A 178 -6.328 42.131 32.167 1.00 43.31 C

ATOM 497 C GLY A 178 -6.163 40.767 31.552 1.00 49.40 C

AATTOOMM 449988 O0 GGLLYY AA 117788 -7.083 39.958 31.631 1.00 50.03 O

ATOM 499 N SER A 179 -5.002 40.522 30.904 1.00 40.11 N

ATOM 500 CA SER A 179 -4.740 39.228 30.344 1.00 38.50 C

ATOM 501 C SER A 179 -4.702 38.131 31.408 1.00 42.66 C

ATOM 502 O SER A 179 ■4.184 38.293 32.525 1.00 38.05 O

AATTOOMM 550033 CCBB SSEERR AA 117799 -3.244 39.353 29.832 1.00 34.49 C

ATOM 504 OG SER A 179 -3.426 40.086 28.568 1.00 45.66 O

ATOM 505 N ASN A 180 -5.255 36.994 31.049 1.00 36.63 N

ATOM 506 CA ASN A 180 -5.357 35.816 31.870 1.00 38.62 C

ATOM 507 C ASN A 180 -5.683 34.707 30.858 1.00 39.82 C

AATTOOMM 550088 OO AASSNN AA 118800 -5.910 35.039 29.670 1.00 42.39 O

ATOM 509 CB ASN A 180 -6.475 35.962 32.911 1.00 44.98 C

ATOM 510 CG ASN A 180 -7.734 36.498 32.242 1.00 54.54 C

ATOM 511 OD1 ASN A 180 -7.928 37.720 32.228 1.00 48.38 O

ATOM 512 ND2 ASN A 180 -8.540 35.625 31.660 1.00 40.36 N

AATTOOMM 551133 NN IILLEE AA 118811 -5.536 33.473 31.246 1.00 40.38 N ATOM 514 CA ILE A 181 -5.619 32.322 30.350 1.00 33.89 C

ATOM 515 C ILE A 181 -6.927 32.320 29.578 1.00 39.65 C

ATOM 516 O ILE A 181 -6.906 32.314 28.339 1.00 40.11 O

ATOM 517 CB ILE A 181 -5.290 31.027 31.097 1.00 42.70 C

ATOM 518 CG1 ILE A 181 -5.682 29.801 30.268 1.00 36.84 C

ATOM 519 CG2 ILE A 181 -5.990 30.883 32.438 1.00 55.03 C

ATOM 520 CD1 ILE A 181 -5.037 28.508 30.724 1.00 68.03 C

ATOM 521 N ILE A 182 -8.052 32.516 30.283 1.00 30.27 N

ATOM 522 CA ILE A 182 -9.314 32.528 29.550 1.00 33.50 C

AATTOOMM 552233 CC IILLEE AA 118822 -9.455 33.647 28.558 1.00 32.77 C

ATOM 524 O ILE A 182 -9.685 33.380 27.358 1.00 32.51 O

ATOM 525 CB ILE A 182 -10.567 32.386 30.435 1.00 34.82 C

ATOM 526 CG1 ILE A 182 -10.600 30.970 31.022 1.00 33.43 C

ATOM 527 CG2 ILE A 182 -11.790 32.405 29.474 1.00 38.83 C

AATTOOMM 552288 CCDD11 IILLEE AA 118822 -11.987 30.860 31.646 1.00 40.57 C

ATOM 529 N SER A 183 -9.278 34.894 28.997 1.00 32.05 N

ATOM 530 CA SER A 183 -9.493 35.999 28.043 1.00 29.75 C

ATOM 531 C SER A 183 -8.547 35.850 26.870 1.00 29.63 C

ATOM 532 O SER A 183 -8.841 36.216 25.711 1.00 30.58 O

AATTOOMM 553333 CCBB SSEERR AA 118833 -9.198 37.356 28.688 1.00 40.54 C

ATOM 534 OG SER A 183 -7.868 37.360 29.219 1.00 51.48 O

ATOM 535 N ASN A 184 -7.323 35.333 27.167 1.00 29.71 N

ATOM 536 CA ASN A 184 -6.380 35.237 26.066 1.00 29.17 C

ATOM 537 C ASN A 184 -6.778 34.178 25.058 1.00 30.40 C

AATTOOMM 553388 O0 AASSNN AA 118844 -6.425 34.318 23.902 1.00 30.51 O

ATOM 539 CB ASN A 184 -4.964 35.149 26.618 1.00 33.28 C

ATOM 540 CG ASN A 184 -3.919 35.618 25.611 1.00 40.11 C

ATOM 541 OD1 ASN A 184 -3.908 36.769 25.141 1.00 39.35 O

ATOM 542 ND2 ASN A 184 -3.047 34.682 25.259 1.00 37.40 N

AATTOOMM 554433 NN LLEEUU AA 118855 -7.599 33.181 25.411 1.00 28.40 N

ATOM 544 CA LEU A 185 -8.001 32.193 24.408 1.00 28.04 C

ATOM 545 C LEU A 185 -8.978 32.805 23.402 1.00 25.68 C

ATOM 546 O LEU A 185 -9.124 32.206 22.298 1.00 29.24 O

ATOM 547 CB LEU A 185 -8.796 31.070 25.161 1.00 32.33 C

AATTOOMM 554488 CCGG LLEEUU AA 118855 -7.869 30.239 26.084 1.00 37.66 C

ATOM 549 CD1 LEU A 185 -8.768 29.246 26.840 1.00 38.27 C

ATOM 550 CD2 LEU A 185 -6.856 29.476 25.205 1.00 30.37 C

ATOM 551 N PHE A 186 -9.573 33.938 23.697 1.00 24.99 N

ATOM 552 CA PHE A 186 -10.529 34.513 22.702 1.00 29.36 C

AATTOOMM 555533 CC PPHHEE AA 118866 -9.895 35.675 21.914 1.00 28.13 C ATOM 554 O PHE A 186 -10.571 36.481 21.285 1.00 31.04 O

ATOM 555 CB PHE A 186 -11.728 35.132 23.493 1.00 29.08 C

ATOM 556 CG PHE A 186 -12.625 34.081 24.099 1.00 32.29 C

ATOM 557 CD1 PHE A 186 -12.436 33.599 25.337 1.00 30.56 C

ATOM 558 CD2 PHE A 186 -13.703 33.693 23.334 1.00 29.12 C

ATOM 559 CE1 PHE A 186 -13.292 32.589 25.881 1.00 34.73 C

ATOM 560 CE2 PHE A 186 -14.592 32.742 23.884 1.00 27.34 C

ATOM 561 CZ PHE A 186 -14.365 32.198 25.091 1.00 30.52 C

ATOM 562 N LYS A 187 -8.559 35.758 21.958 1.00 29.75 N

AATTOOMM 556633 CCAA LLYYSS AA 118877 -7.850 36.828 21.190 1.00 30.16 C

ATOM 564 C LYS A 187 -6.870 36.196 20.212 1.00 27.54 C

ATOM 565 O LYS A 187 -6.369 35.096 20.451 1.00 29.14 O

ATOM 566 CB LYS A 187 -6.950 37.552 22.237 1.00 31.45 C

ATOM 567 CG LYS A 187 -7.789 38.660 22.850 1.00 44.24 C

AATTOOMM 556688 CCDD LLYYSS AA 118877 -7.042 39.413 23.917 1.00 50.91 C

ATOM 569 CE LYS A 187 -6.068 40.421 23.290 1.00 41.03 C

ATOM 570 NZ LYS A 187 -5.788 41.434 24.348 1.00 42.16 N

ATOM 571 N GLU A 188 -6.613 36.918 19.077 1.00 26.33 N

ATOM 572 CA GLU A 188 -5.605 36.497 18.138 1.00 25.15 C

AATTOOMM 557733 CC GGLLUU AA 118888 -4.173 36.621 18.820 1.00 20.95 C

ATOM 574 O GLU A 188 -4.023 37.452 19.696 1.00 25.60 O

ATOM 575 CB GLU A 188 -5.534 37.536 17.003 1.00 30.19 C

ATOM 576 CG GLU A 188 -6.917 37.630 16.345 1.00 39.33 C

ATOM 577 CD GLU A 188 -6.924 38.451 15.077 1.00 62.86 C

AATTOOMM 557788 OOEE11 GGLLUU AA 118888 -6.644 39.671 15.116 1.00 57.85 O

ATOM 579 OE2 GLU A 188 -7.234 37.823 14.039 1.00 69.92 O

ATOM 580 N ASP A 189 -3.388 35.694 18.396 1.00 25.72 N

ATOM 581 CA ASP A 189 -2.034 35.624 18.977 1.00 22.36 C

ATOM 582 C ASP A 189 -1.163 36.692 18.313 1.00 22.67 C

AATTOOMM 558833 OO AASSPP AA 118899 -1.535 37.333 17.268 1.00 23.90 O

ATOM 584 CB ASP A 189 -1.384 34.229 18.800 1.00 28.19 C

ATOM 585 CG ASP A 189 -0.828 34.102 17.432 1.00 23.97 C

ATOM 586 OD1 ASP A 189 0.444 33.906 17.301 1.00 27.23 O

ATOM 587 OD2 ASP A 189 -1.280 34.345 16.311 1.00 35.18 O

AATTOOMM 558888 NN CCYYSS AA 119900 0.069 36.801 18.812 1.00 22.63 N

ATOM 589 CA CYS A 190 0.962 37.863 18.218 1.00 21.85 C

ATOM 590 C CYS A 190 1.355 37.538 16.787 1.00 21.58 C

ATOM 591 O CYS A 190 1.567 38.595 16.082 1.00 24.53 O

ATOM 592 CB CYS A 190 2.127 38.130 19.098 1.00 23.37 C

AATTOOMM 559933 SSGG CCYYSS AA 119900 1.734 38.715 20.750 1.00 27.18 S ATOM 594 N HIS A 191 1.500 36.320 16.296 1.00 22.69 N

ATOM 595 CA HIS A 191 1.879 36.206 14.899 1.00 21.61 C

ATOM 596 C HIS A 191 0.835 36.792 14.024 1.00 21.85 C

ATOM 597 O HIS A 191 1.141 37.323 12.894 1.00 24.99 O

ATOM 598 CB HIS A 191 2.238 34.743 14.596 1.00 26.50 C

ATOM 599 CG HIS A 191 3.562 34.373 15.239 1.00 27.06 C

ATOM 600 ND1 HIS A 191 4.111 33.174 14.859 1.00 29.05 N

ATOM 601 CD2 HIS A 191 4.375 34.972 16.080 1.00 27.99 C

ATOM 602 CE1 HIS A 191 5.281 33.116 15.522 1.00 25.16 C

AATTOOMM 660033 NNEE22 HHIISS AA 119911 5.435 34.101 16.356 1.00 26.21 N

ATOM 604 N GLN A 192 -0.438 36.467 14.384 1.00 26.34 N

ATOM 605 CA GLN A 192 -1.522 36.979 13.515 1.00 26.48 C

ATOM 606 C GLN A 192 -1.503 38.492 13.540 1.00 26.16 C

ATOM 607 O GLN A 192 -1.716 39.137 12.488 1.00 25.33 O

AATTOOMM 660088 CCBB GGLLNN AA 119922 -2.876 36.550 14.173 1.00 25.24 C

ATOM 609 CG GLN A 192 -3.942 37.057 13.181 1.00 36.75 C

ATOM 610 CD GLN A 192 -3.936 36.521 11.790 1.00 44.62 C

ATOM 611 OE1 GLN A 192 ■4.135 35.362 11.492 1.00 47.15 O

ATOM 612 NE2 GLN A 192 -3.751 37.335 10.736 1.00 34.56 N

AATTOOMM 661133 NN LLYYSS AA 119933 -1.329 39.160 14.690 1.00 23.16 N

ATOM 614 CA LYS A 193 -1.206 40.598 14.776 1.00 21.55 C

ATOM 615 C LYS A 193 -0.027 41.129 13.979 1.00 24.18 C

ATOM 616 O LYS A 193 -0.184 42.211 13.368 1.00 25.04 O

ATOM 617 CB LYS A 193 -1.175 41.147 16.231 1.00 21.00 C

AATTOOMM 661188 CCGG LLYYSS AA 119933 -2.470 40.784 16.893 1.00 22.09 C

ATOM 619 CD LYS A 193 -3.691 41.485 16.251 1.00 28.55 C

ATOM 620 CE LYS A 193 -4.974 41.632 17.082 1.00 41.86 C

ATOM 621 NZ LYS A 193 -4.886 42.624 18.158 1.00 43.09 N

ATOM 622 N ILE A 194 1.102 40.447 13.928 1.00 20.51 N

AATTOOMM 662233 CCAA IILLEE AA 119944 2.216 40.881 13.064 1.00 22.80 C

ATOM 624 C ILE A 194 1.766 40.844 11.636 1.00 22.89 C

ATOM 625 O ILE A 194 1.949 41.793 10.875 1.00 23.90 O

ATOM 626 CB ILE A 194 3.443 39.973 13.316 1.00 22.37 C

ATOM 627 CG1 ILE A 194 3.906 40.423 14.719 1.00 20.93 C

AATTOOMM 662288 CCGG22 IILLEE AA 119944 4.504 40.098 12.156 1.00 23.35 C

ATOM 629 CD1 ILE A 194 4.909 39.440 15.373 1.00 24.02 C

ATOM 630 N ASP A 195 1.084 39.718 11.301 1.00 25.74 N

ATOM 631 CA ASP A 195 0.668 39.648 9.871 1.00 28.30 C

ATOM 632 C ASP A 195 -0.329 40.794 9.595 1.00 25.05 C

AATTOOMM 663333 OO AASSPP AA 119955 -0.251 41.449 8.523 1.00 28.16 O ATOM 634 CB ASP A 195 -0.152 38.352 9.678 1.00 31.28 C

ATOM 635 CG ASP A 195 0.718 37.210 9.174 1.00 46.09 C

ATOM 636 OD1 ASP A 195 0.316 36.027 9.312 1.00 41.35 O

ATOM 637 OD2 ASP A 195 1.760 37.572 8.669 1.00 40.30 O

ATOM 638 N ASP A 196 -1.217 41.115 10.484 1.00 25.73 N

ATOM 639 CA ASP A 196 -2.232 42.179 10.283 1.00 27.60 C

ATOM 640 C ASP A 196 -1.509 43.501 10.052 1.00 30.61 C

ATOM 641 O ASP A 196 -1.968 44.397 9.310 1.00 28.90 O

ATOM 642 CB ASP A 196 -3.208 42.318 11.472 1.00 26.94 C

AATTOOMM 664433 CCGG AASSPP AA 119966 -4.136 41.119 11.526 1.00 35.93 C

ATOM 644 OD1 ASP A 196 ■4.177 40.397 10.506 1.00 37.15 O

ATOM 645 OD2 ASP A 196 -4.846 40.880 12.529 1.00 39.81 O

ATOM 646 N LEU A 197 -0.453 43.756 10.837 1.00 26.22 N

ATOM 647 CA LEU A 197 0.333 44.981 10.641 1.00 24.82 C

AATTOOMM 664488 CC LLEEUU AA 119977 0.863 45.122 9.183 1.00 22.79 C

ATOM 649 O LEU A 197 0.751 46.207 8.598 1.00 25.32 O

ATOM 650 CB LEU A 197 1.463 45.077 11.611 1.00 23.28 C

ATOM 651 CG LEU A 197 2.383 46.265 11.536 1.00 24.62 C

ATOM 652 CD1 LEU A 197 1.777 47.633 11.859 1.00 28.09 C

AATTOOMM 665533 CCDD22 LLEEUU AA 119977 3.571 45.954 12.461 1.00 27.71 C

ATOM 654 N PHE A 198 1.461 44.123 8.667 1.00 22.04 N

ATOM 655 CA PHE A 198 2.079 44.191 7.292 1.00 26.13 C

ATOM 656 C PHE A 198 1.059 44.049 6.211 1.00 28.05 C

ATOM 657 O PHE A 198 1.400 44.535 5.131 1.00 29.34 O

AATTOOMM 665588 CCBB PPHHEE AA 119988 3.185 43.173 7.240 1.00 25.38 C

ATOM 659 CG PHE A 198 4.410 43.555 8.033 1.00 24.43 C

ATOM 660 CD1 PHE A 198 4.580 43.022 9.308 1.00 28.24 C

ATOM 661 CD2 PHE A 198 5.301 44.487 7.607 1.00 25.92 C

ATOM 662 CE1 PHE A 198 5.663 43.425 10.067 1.00 26.65 C

AATTOOMM 666633 CCEE22 PPHHEE AA 119988 6.381 44.911 8.320 1.00 26.61 C

ATOM 664 CZ PHE A 198 6.589 44.372 9.590 1.00 24.33 C

ATOM 665 N SER A 199 -0.174 43.659 6.579 1.00 29.98 N

ATOM 666 CA SER A 199 -1.185 43.616 5.508 1.00 32.71 C

ATOM 667 C SER A 199 -2.109 44.784 5.575 1.00 32.16 C

AATTOOMM 666688 O0 SSEERR AA 119999 -3.095 44.885 4.812 1.00 37.24 O

ATOM 669 CB SER A 199 -1.922 42.255 5.637 1.00 35.46 C

ATOM 670 OG SER A 199 -2.765 42.483 6.739 1.00 44.29 O

ATOM 671 N GLY A 200 -1.941 45.713 6.499 1.00 26.22 N

ATOM 672 CA GLY A 200 -2.716 46.906 6.625 1.00 29.91 C

AATTOOMM 667733 CC GGLLYY AA 220000 -4.091 46.674 7.198 1.00 38.21 C ATOM 674 O GLY A 200 -5.052 47.375 6.885 1.00 43.66 O

ATOM 675 N LYS A 201 -4.190 45.788 8.172 1.00 35.17 N

ATOM 676 CA LYS A 201 -5.461 45.573 8.888 1.00 39.35 C

ATOM 677 C LYS A 201 -5.348 46.318 10.202 1.00 44.71 C

ATOM 678 O LYS A 201 -5.971 47.376 10.413 1.00 49.67 O

ATOM 679 CB LYS A 201 -5.747 44.086 9.136 1.00 40.21 C

ATOM 680 CG LYS A 201 -5.604 43.404 7.780 1.00 43.04 C

ATOM 681 CD LYS A 201 -6.339 42.071 7.665 1.00 54.53 C

ATOM 682 CE LYS A 201 -6.446 41.874 6.136 1.00 55.98 C

AATTOOMM 668833 NNZZ LLYYSS AA 220011 -6.339 43.249 5.533 1.00 52.57 N

ATOM 684 N HIS A 202 -4.651 45.701 11.114 1.00 41.23 N

ATOM 685 CA HIS A 202 -4.434 46.283 12.438 1.00 47.90 C

ATOM 686 C HIS A 202 -4.979 47.679 12.559 1.00 53.34 C

ATOM 687 O HIS A 202 -6.090 47.898 13.099 1.00 53.27 O

AATTOOMM 668888 CCBB HHIISS AA 220022 -2.885 46.285 12.654 1.00 38.96 C

ATOM 689 CG HIS A 202 -2.577 45.518 13.899 1.00 56.54 C

ATOM 690 ND1 HIS A 202 -3.210 45.799 15.094 1.00 65.67 N

ATOM 691 CD2 HIS A 202 -1.741 44.480 14.102 1.00 31.29 C

ATOM 692 CE1 HIS A 202 -2.753 44.973 16.037 1.00 60.49 C

AATTOOMM 669933 NNEE22 HHIISS AA 220022 -1.871 44.167 15.449 1.00 75.99 N TER 694 HIS A 202

ATOM 695 N PHE B 213 20.058 33.920 13.960 0.00 39.06 N ATOM 696 CA PHE B 213 18.978 34.566 14.749 1.00 38.41 C

ATOM 697 C PHE B 213 18.659 35.842 13.948 1.00 40.74 C ATOM 698 0 PHE B 213 19.499 36.370 13.188 1.00 42.23 O ATOM 699 CB PHE B 213 19.717 35.136 16.091 0.00 34.83 C

ATOM 700 CG PHE B 213 20.197 34.465 17.321 0.00 44.80 C

ATOM 701 CD1 PHE B 213 21.533 34.182 17.521 0.00 58.13 C

ATOM 702 CD2 PHE B 213 19.319 34.146 18.350 0.00 62.44 C ATOM 703 CE1 PHE B 213 21.983 33.580 18.677 0.00 56.87 C

ATOM 704 CE2 PHE B 213 19.751 33.535 19.518 0.00 69.83 C

ATOM 705 CZ PHE B 213 21.091 33.243 19.683 0.00 53.63 C

ATOM 706 N VAL B 214 17.443 36.311 14.054 1.00 28.80 N ATOM 707 CA VAL B 214 17.119 37.603 13.402 1.00 28.19 C ATOM 708 C VAL B 214 17.743 38.629 14.254 1.00 28.65 C

ATOM 709 O VAL B 214 17.539 38.806 15.455 1.00 28.65 O ATOM 710 CB VAL B 214 15.592 37.799 13.483 1.00 22.91 C

ATOM 711 CG1 VAL B 214 15.158 39.177 12.869 1.00 26.83 C

ATOM 712 CG2 VAL B 214 14.962 36.737 12.578 1.00 28.94 C ATOM 713 N ASN B 215 18.422 39.630 13.608 1.00 29.43 N ATOM 714 CA ASN B 215 19.111 40.632 14.417 1.00 28.01 C

ATOM 715 C ASN B 215 18.250 41.899 14.531 1.00 26.65 C

ATOM 716 O ASN B 215 17.721 42.319 13.493 1.00 27.96 O

ATOM 717 CB ASN B 215 20.425 40.910 13.648 1.00 33.11 C

ATOM 718 CG ASN B 215 21.123 42.071 14.253 1.00 39.12 C

ATOM 719 OD1 ASN B 215 21.817 41.841 15.248 1.00 56.16 O

ATOM 720 ND2 ASN B 215 20.892 43.271 13.756 1.00 37.49 N

ATOM 721 N LYS B 216 18.227 42.531 15.676 1.00 29.82 N

ATOM 722 CA LYS B 216 17.431 43.700 15.908 1.00 29.12 C

AATTOOMM 772233 CC LLYYSS BB 221166 17.562 44.847 14.904 1.00 34.06 C

ATOM 724 O LYS B 216 16.653 45.383 14.266 1.00 33.52 O

ATOM 725 CB LYS B 216 17.580 44.261 17.335 1.00 36.94 C

ATOM 726 CG LYS B 216 17.289 45.709 17.513 1.00 54.25 C

ATOM 727 CD LYS B 216 18.239 46.428 18.458 1.00 64.48 C

AATTOOMM 772288 CCEE LLYYSS BB 221166 17.962 47.933 18.361 1.00 38.71 C

ATOM 729 NZ LYS B 216 18.156 48.577 19.701 1.00 58.40 N

ATOM 730 N ASP B 217 18.816 45.213 14.659 1.00 30.48 N

ATOM 731 CA ASP B 217 19.064 46.400 13.757 1.00 27.61 C

ATOM 732 C ASP B 217 18.715 46.051 12.331 1.00 28.01 C

AATTOOMM 773333 O0 AASSPP BB 221177 18.213 46.925 11.581 1.00 30.15 O

ATOM 734 CB ASP B 217 20.621 46.565 13.847 1.00 36.86 C

ATOM 735 CG ASP B 217 20.988 47.040 15.245 1.00 51.98 C

ATOM 736 OD1 ASP B 217 20.330 47.972 15.757 1.00 52.18 O

ATOM 737 OD2 ASP B 217 21.885 46.396 15.841 1.00 47.67 O

AATTOOMM 773388 NN GGLLNN BB 221188 18.952 44.837 11.886 1.00 27.01 N

ATOM 739 CA GLN B 218 18.651 44.360 10.561 1.00 26.84 C

ATOM 740 C GLN B 218 17.114 44.418 10.338 1.00 27.29 C

ATOM 741 O GLN B 218 16.690 44.973 9.344 1.00 23.91 O

ATOM 742 CB GLN B 218 19.185 43.019 10.100 1.00 28.38 C

AATTOOMM 774433 CCGG GGLLNN BB 221188 18.864 42.617 8.674 1.00 28.89 C

ATOM 744 CD GLN B 218 19.524 43.615 7.718 1.00 39.42 C

ATOM 745 OE1 GLN B 218 20.719 43.874 7.908 1.00 51.78 O

ATOM 746 NE2 GLN B 218 18.883 44.178 6.720 1.00 38.09 N

ATOM 747 N ILE B 219 16.363 43.802 11.271 1.00 23.35 N

AATTOOMM 774488 CCAA IILLEE BB 221199 14.913 43.779 11.028 1.00 22.53 C

ATOM 749 C ILE B 219 14.358 45.188 11.119 1.00 23.20 C

ATOM 750 O ILE B 219 13.419 45.540 10.380 1.00 24.75 O

ATOM 751 CB ILE B 219 14.214 42.799 11.995 1.00 24.05 C

ATOM 752 CG1 ILE B 219 12.719 42.604 11.632 1.00 28.34 C

AATTOOMM 775533 CCGG22 IILLEE BB 221199 14.324 43.075 13.482 1.00 23.51 C ATOM 754 CD1 ILE B 219 12.584 42.167 10.195 1.00 28.70 C

ATOM 755 N ALA B 220 14.867 46.026 11.971 1.00 21.26 N

ATOM 756 CA ALA B 220 14.394 47.398 12.036 1.00 23.23 C

ATOM 757 C ALA B 220 14.562 48.139 10.721 1.00 24.18 C

ATOM 758 O ALA B 220 13.693 48.843 10.260 1.00 23.88 O

ATOM 759 CB ALA B 220 14.924 48.143 13.203 1.00 28.83 C

ATOM 760 N LYS B 221 15.777 47.919 10.174 1.00 26.11 N

ATOM 761 CA LYS B 221 16.087 48.583 8.865 1.00 26.06 C

ATOM 762 C LYS B 221 15.114 48.094 7.776 1.00 26.41 C

AATTOOMM 776633 O0 LLYYSS BB 222211 14.587 48.888 6.957 1.00 25.25 O

ATOM 764 CB LYS B 221 17.522 48.113 8.524 1.00 23.76 C

ATOM 765 CG LYS B 221 17.847 48.631 7.093 1.00 32.95 C

ATOM 766 CD LYS B 221 19.345 48.559 6.864 1.00 54.82 C

ATOM 767 CE LYS B 221 19.731 48.843 5.400 1.00 52.81 C

AATTOOMM 776688 NNZZ LLYYSS BB 222211 18.551 48.626 4.505 1.00 64.66 N

ATOM 769 N ASP B 222 14.909 46.751 7.728 1.00 24.33 N

ATOM 770 CA ASP B 222 13.993 46.174 6.769 1.00 22.83 C

ATOM 771 C ASP B 222 12.591 46.755 6.856 1.00 24.06 C

ATOM 772 O ASP B 222 11.822 46.980 5.901 1.00 25.49 O

AATTOOMM 777733 CCBB AASSPP BB 222222 13.988 44.694 6.974 1.00 26.43 C

ATOM 774 CG ASP B 222 15.290 43.940 6.667 1.00 38.66 C

ATOM 775 OD1 ASP B 222 16.186 44.549 6.004 1.00 35.31 O

ATOM 776 OD2 ASP B 222 15.440 42.767 7.105 1.00 31.82 O

ATOM 777 N VAL B 223 12.132 46.913 8.186 1.00 22.14 N

AATTOOMM 777788 CCAA VVAALL BB 222233 10.762 47.428 8.371 1.00 20.33 C

ATOM 779 C VAL B 223 10.663 48.907 8.026 1.00 22.02 C

ATOM 780 O VAL B 223 9.645 49.303 7.488 1.00 24.09 O

ATOM 781 CB VAL B 223 10.359 47.221 9.914 1.00 20.11 C

ATOM 782 CG 1 VAL B 223 8.923 47.827 10.101 1.00 20.89 C

AATTOOMM 778833 CCGG22 VVAALL BB 222233 10.266 45.704 10.015 1.00 22.50 C

ATOM 784 N LYS B 224 11.692 49.718 8.317 1.00 24.63 N

ATOM 785 CA LYS B 224 11.648 51.112 7.867 1.00 22.39 C

ATOM 786 C LYS B 224 11.742 51.101 6.333 1.00 22.61 C

ATOM 787 O LYS B 224 11.018 51.997 5.790 1.00 25.15 O

AATTOOMM 778888 CCBB LLYYSS BB 222244 12.866 51.847 8.429 1.00 23.88 C

ATOM 789 CG LYS B 224 12.803 51.930 9.957 1.00 27.07 C

ATOM 790 CD LYS B 224 14.039 52.838 10.291 1.00 30.44 C

ATOM 791 CE LYS B 224 14.473 52.595 11.710 1.00 37.24 C

ATOM 792 NZ LYS B 224 15.959 52.861 11.954 1.00 36.84 N

AATTOOMM 779933 NN GGLLNN BB 222255 12.399 50.170 5.716 1.00 23.11 N ATOM 794 CA GLN B 225 12.361 50.229 4.231 1.00 25.47 C

ATOM 795 C GLN B 225 11.027 49.943 3.641 1.00 26.73 C

ATOM 796 O GLN B 225 10.493 50.497 2.664 1.00 27.89 O

ATOM 797 CB GLN B 225 13.411 49.249 3.687 1.00 31.78 C

ATOM 798 CG GLN B 225 13.591 49.218 2.169 1.00 38.01 C

ATOM 799 CD GLN B 225 14.593 48.122 1.787 1.00 52.24 C

ATOM 800 OE1 GLN B 225 14.887 47.110 2.466 1.00 39.10 O

ATOM 801 NE2 GLN B 225 15.161 48.357 0.596 1.00 52.36 N

ATOM 802 N PHE B 226 10.293 48.963 4.237 1.00 26.05 N

AATTOOMM 880033 CCAA PPHHEE BB 222266 8.973 48.532 3.931 1.00 19.95 C

ATOM 804 C PHE B 226 8.061 49.723 4.114 1.00 25.34 C

ATOM 805 O PHE B 226 7.137 49.995 3.322 1.00 25.01 O

ATOM 806 CB PHE B 226 8.520 47.335 4.808 1.00 23.99 C

ATOM 807 CG PHE B 226 7.078 47.018 4.704 1.00 23.19 C

AATTOOMM 880088 CCDD11 PPHHEE BB 222266 6.614 46.106 3.757 1.00 32.26 C

ATOM 809 CD2 PHE B 226 6.114 47.611 5.520 1.00 24.45 C

ATOM 810 CE1 PHE B 226 5.294 45.767 3.622 1.00 31.82 C

ATOM 811 CE2 PHE B 226 4.767 47.297 5.398 1.00 27.22 C

ATOM 812 CZ PHE B 226 4.345 46.351 4.485 1.00 31.10 C

AATTOOMM 881133 NN TTYYRR BB 222277 8.136 50.361 5.335 1.00 24.23 N

ATOM 814 CA TYR B 227 7.277 51.568 5.520 1.00 23.29 C

ATOM 815 C TYR B 227 7.515 52.651 4.467 1.00 21.71 C

ATOM 816 O TYR B 227 6.536 53.214 3.929 1.00 27.93 O

ATOM 817 CB TYR B 227 7.521 52.038 6.991 1.00 24.74 C

AATTOOMM 881188 CCGG TTYYRR BB 222277 6.901 53.409 7.209 1.00 23.08 C

ATOM 819 CD1 TYR B 227 5.522 53.556 7.483 1.00 23.12 C

ATOM 820 CD2 TYR B 227 7.590 54.577 7.181 1.00 23.26 C

ATOM 821 CE1 TYR B 227 4.877 54.744 7.637 1.00 21.74 C

ATOM 822 CE2 TYR B 227 6.971 55.810 7.347 1.00 26.24 C

AATTOOMM 882233 CCZZ TTYYRR BB 222277 5.622 55.906 7.534 1.00 23.27 C

ATOM 824 OH TYR B 227 5.113 57.204 7.736 1.00 28.41 O

ATOM 825 N ASP B 228 8.771 52.947 4.225 1.00 24.07 N

ATOM 826 CA ASP B 228 9.112 54.010 3.219 1.00 26.13 C

ATOM 827 C ASP B 228 8.530 53.681 1.848 1.00 25.40 C

AATTOOMM 882288 O0 AASSPP BB 222288 7.948 54.619 1.256 1.00 28.30 O

ATOM 829 CB ASP B 228 10.598 54.183 3.098 1.00 26.65 C

ATOM 830 CG ASP B 228 11.283 54.732 4.341 1.00 27.40 C

ATOM 831 OD1 ASP B 228 10.503 55.158 5.247 1.00 28.45 O

ATOM 832 OD2 ASP B 228 12.550 54.757 4.381 1.00 31.87 O

AATTOOMM 883333 NN GGLLNN BB 222299 8.547 52.455 1.467 1.00 27.81 N ATOM 834 CA GLN B 229 7.973 52.053 0.189 1.00 31.66 C

ATOM 835 C GLN B 229 6.486 52.170 0.149 1.00 30.19 C

ATOM 836 O GLN B 229 5.831 52.682 -0.747 1.00 30.67 O

ATOM 837 CB GLN B 229 8.476 50.634 -0.146 1.00 31.73 C

ATOM 838 CG GLN B 229 7.591 50.067 -1.270 1.00 40.23 C

ATOM 839 CD GLN B 229 8.057 48.688 -1.756 1.00 35.25 C

ATOM 840 OE1 GLN B 229 7.384 47.710 -1.522 1.00 55.87 O

ATOM 841 NE2 GLN B 229 9.225 48.775 -2.390 1.00 50.23 N

ATOM 842 N ALA B 230 5.754 51.854 1.279 1.00 28.10 N

AATTOOMM 884433 CCAA AALLAA BB 223300 4.290 52.029 1.307 1.00 24.10 C

ATOM 844 C ALA B 230 3.931 53.498 1.278 1.00 27.94 C

ATOM 845 O ALA B 230 2.888 53.958 0.745 1.00 31.55 O

ATOM 846 CB ALA B 230 3.795 51.431 2.642 1.00 29.30 C

ATOM 847 N LEU B 231 4.740 54.354 1.931 1.00 23.97 N

AATTOOMM 884488 CCAA LLEEUU BB 223311 4.442 55.785 1.967 1.00 26.83 C

ATOM 849 C LEU B 231 4.529 56.323 0.503 1.00 28.89 C

ATOM 850 O LEU B 231 3.647 57.118 0.180 1.00 32.83 O

ATOM 851 CB LEU B 231 5.448 56.501 2.793 1.00 33.06 C

ATOM 852 CG LEU B 231 5.286 57.827 3.481 1.00 34.95 C

AATTOOMM 885533 CCDD11 LLEEUU BB 223311 4.017 57.819 4.373 1.00 37.01 C

ATOM 854 CD2 LEU B 231 6.460 57.952 4.470 1.00 30.54 C

ATOM 855 N GLN B 232 5.592 55.891 -0.152 1.00 28.34 N

ATOM 856 CA GLN B 232 5.808 56.306 -1.543 1.00 25.85 C

ATOM 857 C GLN B 232 4.606 55.803 -2.297 1.00 32.51 C

AATTOOMM 885588 O0 GGLLNN BB 223322 3.984 56.532 -3.068 1.00 35.03 O

ATOM 859 CB GLN B 232 7.146 55.923 -2.148 1.00 27.31 C

ATOM 860 CG GLN B 232 7.040 56.328 -3.665 1.00 39.26 C

ATOM 861 CD GLN B 232 7.200 57.837 -3.811 1.00 48.48 C

ATOM 862 OE1 GLN B 232 8.230 58.427 -3.464 1.00 48.35 O

AATTOOMM 886633 NNEE22 GGLLNN BB 223322 6.175 58.514 -4.347 1.00 63.54 N

ATOM 864 N GLN B 233 4.282 54.521 -2.251 1.00 30.22 N

ATOM 865 CA GLN B 233 3.123 53.964 -2.883 1.00 31.30 C

ATOM 866 C GLN B 233 1.804 54.580 -2.597 1.00 37.96 C

ATOM 867 O GLN B 233 1.001 54.779 -3.493 1.00 32.91 O

AATTOOMM 886688 CCBB GGLLNN BB 223333 3.062 52.438 -2.817 1.00 35.74 C

ATOM 869 CG GLN B 233 4.280 51.738 -3.376 1.00 48.14 C

ATOM 870 CD GLN B 233 4.237 50.226 -3.100 1.00 60.95 C

ATOM 871 OE1 GLN B 233 3.335 49.679 -2.460 1.00 55.12 O

ATOM 872 NE2 GLN B 233 5.249 49.503 -3.591 1.00 53.03 N

AATTOOMM 887733 NN AALLAA BB 223344 1.478 54.933 -1.343 1.00 33.85 N ATOM 874 CA ALA B 234 0.212 55.540 -0.966 1.00 30.65 C

ATOM 875 C ALA B 234 -0.035 56.911 -1.609 1.00 37.42 C

ATOM 876 O ALA B 234 -1.164 57.383 -1.543 1.00 40.95 O

ATOM 877 CB ALA B 234 0.227 55.871 0.528 1.00 37.79 C

ATOM 878 N VAL B 235 1.009 57.576 -1.999 1.00 34.25 N

ATOM 879 CA VAL B 235 0.879 58.954 -2.490 1.00 46.72 C

ATOM 880 C VAL B 235 0.344 58.994 -3.902 1.00 47.75 C

ATOM 881 O VAL B 235 -0.480 59.829 -4.219 1.00 42.71 O

ATOM 882 CB VAL B 235 2.243 59.671 -2.437 1.00 46.39 C

AATTOOMM 888833 CCGG 11 VVAALL BB 223355 2.400 60.622 -3.584 1.00 55.69 C

ATOM 884 CG2 VAL B 235 2.511 60.147 -1.040 1.00 52.76 C

ATOM 885 N VAL B 236 0.661 57.984 -4.673 1.00 55.00 N

ATOM 886 CA VAL B 236 0.241 57.833 -6.051 1.00 63.72 C

ATOM 887 C VAL B 236 -1.111 57.157 -6.210 1.00 65.71 C

AATTOOMM 888888 O0 VVAALL BB 223366 -1.763 56.686 -5.285 1.00 67.29 O

ATOM 889 CB VAL B 236 1.284 56.949 -6.776 1.00 64.32 C

ATOM 890 CG 1 VAL B 236 2.592 56.862 -6.003 1.00 58.65 C

ATOM 891 CG2 VAL B 236 0.676 55.569 -6.973 1.00 55.88 C

ATOM 892 N ASP B 237 -1.574 57.092 -7.452 1.00 69.34 N

AATTOOMM 889933 CCAA AASSPP BB 223377 -2.819 56.471 -7.841 1.00 70.85 C

ATOM 894 C ASP B 237 -3.935 56.519 -6.817 1.00 70.40 C

ATOM 895 O ASP B 237 -3.875 57.426 -5.951 1.00 72.42 O

ATOM 896 CB ASP B 237 -2.566 55.033 -8.302 1.00 74.85 C

ATOM 897 CG ASP B 237 -2.566 54.902 -9.815 1.00 77.81 C

AATTOOMM 889988 OODD11 AASSPP BB 223377 -2.807 55.913 -10.514 1.00 73.42 O

ATOM 899 OD2 ASP B 237 -2.333 53.766 -10.290 1.00 73.26 O

ATOM 900 N ASN B 242 -3.210 48.670 -1.883 1.00 39.18 N

ATOM 901 CA ASN B 242 -3.055 48.493 -0.438 1.00 44.04 C

ATOM 902 C ASN B 242 -2.190 49.418 0.378 1.00 40.11 C

AATTOOMM 990033 OO AASSNN BB 224422 -2.350 49.368 1.631 1.00 39.92 O

ATOM 904 CB ASN B 242 -2.785 47.028 -0.089 1.00 53.02 C

ATOM 905 CG ASN B 242 -3.593 46.705 1.154 1.00 52.89 C

ATOM 906 OD1 ASN B 242 -4.816 46.659 1.117 1.00 74.32 O

ATOM 907 ND2 ASN B 242 -2.903 46.505 2.255 1.00 60.76 N

AATTOOMM 990088 NN AALLAA BB 224433 -1.374 50.266 -0.256 1.00 36.30 N

ATOM 909 CA ALA B 243 -0.477 51.139 0.437 1.00 33.91 C

ATOM 910 C ALA B 243 -1.149 52.151 1.352 1.00 37.82 C

ATOM 911 O ALA B 243 -0.611 52.347 2.465 1.00 33.56 O

ATOM 912 CB ALA B 243 0.520 51.837 -0.521 1.00 32.40 C

AATTOOMM 991133 NN LLYYSS BB 224444 -2.321 52.706 0.984 1.00 31.44 N ATOM 914 CA LYS B 244 -2.917 53.649 1.905 1.00 35.82 C

ATOM 915 C LYS B 244 -3.226 52.940 3.220 1.00 30.55 C

ATOM 916 O LYS B 244 -3.050 53.525 4.305 1.00 38.19 O

ATOM 917 CB LYS B 244 -4.095 54.431 1.321 1.00 39.68 C

ATOM 918 CG LYS B 244 -3.645 55.272 0.105 1.00 48.03 C

ATOM 919 CD LYS B 244 -4.610 56.417 -0.160 1.00 61.93 C

ATOM 920 CE LYS B 244 -4.235 57.325 -1.338 1.00 44.53 C

ATOM 921 NZ LYS B 244 -3.769 56.503 -2.497 1.00 47.52 N

ATOM 922 N ALA B 245 -3.860 51.781 3.154 1.00 36.14 N

AATTOOMM 992233 CCAA AALLAA BB 224455 -4.192 51.049 4.369 1.00 35.51 C

ATOM 924 C ALA B 245 -2.969 50.595 5.178 1.00 32.87 C

ATOM 925 O ALA B 245 -3.057 50.755 6.423 1.00 30.07 O

ATOM 926 CB ALA B 245 -5.204 49.939 4.220 1.00 37.71 C

ATOM 927 N VAL B 246 -1.895 50.248 4.473 1.00 34.22 N

AATTOOMM 992288 CCAA VVAALL BB 224466 -0.706 49.853 5.279 1.00 29.25 C

ATOM 929 C VAL B 246 -0.168 51.056 5.995 1.00 30.43 C

ATOM 930 O VAL B 246 0.202 51.090 7.187 1.00 29.85 O

ATOM 931 CB VAL B 246 0.365 49.273 4.377 1.00 29.35 C

ATOM 932 CG 1 VAL B 246 1.786 49.347 4.933 1.00 29.84 C

AATTOOMM 993333 CCGG22 VVAALL BB 224466 0.092 47.930 3.736 1.00 34.46 C

ATOM 934 N VAL B 247 -0.089 52.213 5.275 1.00 28.21 N

ATOM 935 CA VAL B 247 0.358 53.458 5.918 1.00 26.35 C

ATOM 936 C VAL B 247 -0.534 53.835 7.097 1.00 28.87 C

ATOM 937 O VAL B 247 -0.042 54.180 8.176 1.00 26.97 O

AATTOOMM 993388 CCBB VVAALL BB 224477 0.296 54.642 4.861 1.00 32.02 C

ATOM 939 CG 1 VAL B 247 0.476 55.967 5.598 1.00 28.64 C

ATOM 940 CG2 VAL B 247 1.542 54.413 3.985 1.00 38.44 C

ATOM 941 N LYS B 248 -1.855 53.790 6.924 1.00 25.72 N

ATOM 942 CA LYS B 248 -2.712 54.159 8.046 1.00 28.85 C

AATTOOMM 994433 CC LLYYSS BB 224488 -2.550 53.215 9.244 1.00 27.54 C

ATOM 944 O LYS B 248 -2.550 53.735 10.357 1.00 27.13 O

ATOM 945 CB LYS B 248 -4.194 54.134 7.636 1.00 42.84 C

ATOM 946 CG LYS B 248 -5.069 54.520 8.847 1.00 58.35 C

ATOM 947 CD LYS B 248 -6.463 53.918 8.740 1.00 54.75 C

AATTOOMM 994488 CCEE LLYYSS BB 224488 -7.516 54.714 9.498 1.00 59.22 C

ATOM 949 NZ LYS B 248 -7.758 56.018 8.804 1.00 69.89 N

ATOM 950 N THR B 249 -2.355 51.944 8.971 1.00 28.19 N

ATOM 951 CA THR B 249 -2.139 50.941 10.018 1.00 25.54 C

ATOM 952 C THR B 249 -0.864 51.232 10.713 1.00 22.00 C

AATTOOMM 995533 OO TTHHRR BB 224499 -0.862 51.158 11.961 1.00 26.72 O ATOM 954 CB THR B 249 -2.072 49.561 9.309 1.00 32.90 C

ATOM 955 OG1 THR B 249 -3.456 49.249 8.998 1.00 34.27 O

ATOM 956 CG2 THR B 249 -1.701 48.502 10.386 1.00 28.18 C

ATOM 957 N PHE B 250 0.223 51.503 10.050 1.00 24.03 N

ATOM 958 CA PHE B 250 1.442 51.890 10.752 1.00 22.07 C

ATOM 959 C PHE B 250 1.256 53.105 11.616 1.00 24.13 C

ATOM 960 O PHE B 250 1.722 53.169 12.779 1.00 23.95 O

ATOM 961 CB PHE B 250 2.632 51.983 9.774 1.00 24.35 C

ATOM 962 CG PHE B 250 3.359 50.718 9.517 1.00 20.35 C

AATTOOMM 996633 CCDD11 PPHHEE BB 225500 2.734 49.631 8.939 1.00 27.04 C

ATOM 964 CD2 PHE B 250 4.711 50.655 9.879 1.00 24.67 C

ATOM 965 CE1 PHE B 250 3.463 48.450 8.759 1.00 26.35 C

ATOM 966 CE2 PHE B 250 5.401 49.452 9.717 1.00 27.07 C

ATOM 967 CZ PHE B 250 4.813 48.395 9.092 1.00 25.85 C

AATTOOMM 996688 NN HHIISS BB 225511 0.645 54.147 11.025 1.00 23.26 N

ATOM 969 CA HIS B 251 0.507 55.413 11.786 1.00 24.35 C

ATOM 970 C HIS B 251 -0.302 55.195 13.025 1.00 20.70 C

ATOM 971 O HIS B 251 0.069 55.679 14.076 1.00 27.98 O

ATOM 972 CB HIS B 251 -0.106 56.471 10.897 1.00 28.47 C

AATTOOMM 997733 CCGG HHIISS BB 225511 0.845 56.859 9.809 1.00 22.44 C

ATOM 974 ND1 HIS B 251 0.466 57.612 8.744 1.00 27.96 N

ATOM 975 CD2 HIS B 251 2.173 56.588 9.692 1.00 20.58 C

ATOM 976 CE1 HIS B 251 1.546 57.769 7.996 1.00 24.43 C

ATOM 977 NE2 HIS B 251 2.607 57.164 8.463 1.00 22.99 N

AATTOOMM 997788 NN GGLLUU BB 225522 -1.408 54.485 12.899 1.00 25.24 N

ATOM 979 CA GLU B 252 -2.283 54.273 14.078 1.00 28.83 C

ATOM 980 C GLU B 252 -1.656 53.316 15.065 1.00 24.84 C

ATOM 981 O GLU B 252 -1.715 53.637 16.291 1.00 28.08 O

ATOM 982 CB GLU B 252 -3.520 53.530 13.531 1.00 33.80 C

AATTOOMM 998833 CCGG GGLLUU BB 225522 -4.529 54.586 13.053 1.00 51.18 C

ATOM 984 CD GLU B 252 -5.195 55.154 14.298 1.00 62.22 C

ATOM 985 OE1 GLU B 252 -5.078 54.441 15.318 1.00 75.33 O

ATOM 986 OE2 GLU B 252 -5.789 56.246 14.231 1.00 81.41 O

ATOM 987 N THR B 253 -0.940 52.278 14.602 1.00 24.38 N

AATTOOMM 998888 CCAA TTHHRR BB 225533 -0.335 51.348 15.543 1.00 25.28 C

ATOM 989 C THR B 253 0.815 51.947 16.284 1.00 26.73 C

ATOM 990 O THR B 253 0.983 51.668 17.495 1.00 26.95 O

ATOM 991 CB THR B 253 0.142 50.092 14.754 1.00 30.77 C

ATOM 992 OG1 THR B 253 -1.082 49.514 14.253 1.00 30.13 O

AATTOOMM 999933 CCGG22 TTHHRR BB 225533 0.636 49.050 15.765 1.00 29.29 C ATOM 994 N LEU B 254 1.653 52.721 15.598 1.00 25.61 N

ATOM 995 CA LEU B 254 2.892 53.219 16.200 1.00 26.00 C

ATOM 996 C LEU B 254 2.783 54.632 16.714 1.00 22.88 C

ATOM 997 O LEU B 254 3.697 55.128 17.327 1.00 30.40 O

ATOM 998 CB LEU B 254 4.118 53.101 15.235 1.00 26.38 C

ATOM 999 CG LEU B 254 4.366 51.789 14.516 1.00 28.75 C

ATOM 1000 CD1 LEU B 254 5.329 51.864 13.337 1.00 26.49 C

ATOM 1001 CD2 LEU B 254 4.772 50.720 15.562 1.00 31.20 C

ATOM 1002 N ASP B 255 1.662 55.314 16.415 1.00 26.40 N ATOM 1003 CA ASP B 255 1.352 56.656 16.876 1.00 29.10 C

ATOM 1004 C ASP B 255 2.396 57.628 16.358 1.00 26.00 C

ATOM 1005 O ASP B 255 3.199 58.345 16.968 1.00 30.49 O

ATOM 1006 CB ASP B 255 1.586 56.728 18.458 1.00 27.91 C

ATOM 1007 CG ASP B 255 0.716 57.837 18.996 1.00 39.98 C ATOM 1008 OD1 ASP B 255 -0.400 57.996 18.450 1.00 40.21 O

ATOM 1009 OD2 ASP B 255 1.140 58.490 19.981 1.00 52.19 O

ATOM 1010 N CYS B 256 2.402 57.595 14.962 1.00 23.36 N

ATOM 1011 CA CYS B 256 3.291 58.553 14.232 1.00 23.75 C

ATOM 1012 C CYS B 256 2.652 58.844 12.864 1.00 23.79 C ATOM 1013 O CYS B 256 1.512 58.452 12.503 1.00 25.84 O

ATOM 1014 CB CYS B 256 4.633 57.847 13.915 1.00 27.39 C

ATOM 1015 SG CYS B 256 4.516 56.306 12.977 1.00 25.46 S

ATOM 1016 N CYS B 257 3.398 59.728 12.150 1.00 23.91 N

ATOM 1017 CA CYS B 257 2.877 60.183 10.857 1.00 23.10 C ATOM 1018 C CYS B 257 4.132 60.537 10.008 1.00 24.58 C

ATOM 1019 O CYS B 257 4.858 61.478 10.306 1.00 35.32 O

ATOM 1020 CB CYS B 257 1.990 61.433 11.086 1.00 24.93 C

ATOM 1021 SG CYS B 257 1.462 62.126 9.522 1.00 38.86 S

ATOM 1022 N GLY B 258 4.499 59.751 9.003 1.00 28.29 N ATOM 1023 CA GLY B 258 5.582 60.043 8.168 1.00 29.82 C

ATOM 1024 C GLY B 258 6.985 59.918 8.772 1.00 28.11 C

ATOM 1025 O GLY B 258 7.323 59.282 9.774 1.00 27.13 O

ATOM 1026 N SER B 259 7.902 60.536 7.973 1.00 23.81 N

ATOM 1027 CA SER B 259 9.313 60.368 8.266 1.00 24.67 C ATOM 1028 C SER B 259 10.025 61.698 8.103 1.00 23.57 C

ATOM 1029 O SER B 259 9.876 62.252 6.979 1.00 25.69 O

ATOM 1030 CB SER B 259 9.928 59.300 7.326 1.00 25.07 C

ATOM 1031 OG SER B 259 11.349 59.212 7.646 1.00 25.11 O

ATOM 1032 N SER B 260 10.983 62.038 8.915 1.00 23.52 N ATOM 1033 CA SER B 260 11.844 63.194 8.671 1.00 26.60 C ATOM 1034 C SER B 260 12.687 63.035 7.368 1.00 30.13 C

ATOM 1035 O SER B 260 13.078 64.065 6.854 1.00 31.35 O

ATOM 1036 CB SER B 260 12.899 63.255 9.763 1.00 27.65 C

ATOM 1037 OG SER B 260 12.181 63.575 10.970 1.00 28.41 O ATOM 1038 N THR B 261 12.891 61.835 6.872 1.00 26.25 N

ATOM 1039 CA THR B 261 13.701 61.600 5.664 1.00 26.86 C

ATOM 1040 C THR B 261 12.862 61.805 4.427 1.00 28.21 C

ATOM 1041 O THR B 261 13.431 61.761 3.286 1.00 31.07 O

ATOM 1042 CB THR B 261 14.262 60.145 5.670 1.00 34.63 C ATOM 1043 OG1 THR B 261 13.250 59.130 5.650 1.00 27.58 O

ATOM 1044 CG2 THR B 261 15.182 59.966 6.845 1.00 32.42 C

ATOM 1045 N LEU B 262 11.547 61.905 4.538 1.00 24.65 N

ATOM 1046 CA LEU B 262 10.632 61.948 3.435 1.00 26.11 C

ATOM 1047 C LEU B 262 9.613 63.054 3.649 1.00 23.05 C ATOM 1048 O LEU B 262 8.451 62.765 3.797 1.00 26.64 O

ATOM 1049 CB LEU B 262 9.876 60.609 3.119 1.00 28.16 C

ATOM 1050 CG LEU B 262 10.880 59.522 2.727 1.00 26.71 C

ATOM 1051 CD1 LEU B 262 10.363 58.132 2.880 1.00 30.36 C

ATOM 1052 CD2 LEU B 262 11.273 59.679 1.213 1.00 28.82 C ATOM 1053 N THR B 263 10.110 64.271 3.759 1.00 26.37 N

ATOM 1054 CA THR B 263 9.166 65.383 4.052 1.00 28.15 C

ATOM 1055 C THR B 263 8.031 65.640 3.112 1.00 26.08 C

ATOM 1056 O THR B 263 6.867 65.841 3.488 1.00 29.18 O

ATOM 1057 CB THR B 263 9.882 66.710 4.411 1.00 26.13 C ATOM 1058 OG1 THR B 263 10.725 66.983 3.289 1.00 30.06 O

ATOM 1059 CG2 THR B 263 10.828 66.428 5.583 1.00 27.31 C

ATOM 1060 N ALA B 264 8.320 65.541 1.756 1.00 26.65 N

ATOM 1061 CA ALA B 264 7.200 65.689 0.854 1.00 28.62 C

ATOM 1062 C ALA B 264 6.122 64.622 0.960 1.00 30.46 C ATOM 1063 O ALA B 264 4.913 64.883 0.824 1.00 27.48 O

ATOM 1064 CB ALA B 264 7.792 65.648 -0.580 1.00 37.44 C

ATOM 1065 N LEU B 265 6.572 63.328 1.103 1.00 26.43 N

ATOM 1066 CA LEU B 265 5.525 62.299 1.258 1.00 24.79 C

ATOM 1067 C LEU B 265 4.747 62.415 2.561 1.00 22.99 C ATOM 1068 O LEU B 265 3.551 62.173 2.557 1.00 27.18 O

ATOM 1069 CB LEU B 265 6.174 60.876 1.277 1.00 28.63 C

ATOM 1070 CG LEU B 265 6.906 60.624 -0.059 1.00 30.02 C

ATOM 1071 CD1 LEU B 265 7.551 59.278 0.106 1.00 33.74 C

ATOM 1072 CD2 LEU B 265 5.826 60.540 -1.141 1.00 29.11 C ATOM 1073 N THR B 266 5.455 63.026 3.541 1.00 25.60 N ATOM 1074 CA THR B 266 4.714 63.275 4.809 1.00 21.94 C

ATOM 1075 C THR B 266 3.646 64.393 4.568 1.00 22.37 C

ATOM 1076 O THR B 266 2.563 64.267 5.086 1.00 28.65 O

ATOM 1077 CB THR B 266 5.727 63.736 5.883 1.00 23.32 C ATOM 1078 OG1 THR B 266 6.653 62.623 6.058 1.00 25.53 O

ATOM 1079 CG2 THR B 266 5.065 63.999 7.261 1.00 23.80 C

ATOM 1080 N THR B 267 4.055 65.401 3.791 1.00 25.88 N

ATOM 1081 CA THR B 267 3.009 66.434 3.520 1.00 25.86 C

ATOM 1082 C THR B 267 1.809 65.737 2.864 1.00 28.07 C ATOM 1083 O THR B 267 0.684 65.971 3.201 1.00 29.20 O

ATOM 1084 CB THR B 267 3.640 67.463 2.606 1.00 28.82 C

ATOM 1085 OG1 THR B 267 4.741 68.114 3.207 1.00 28.97 O

ATOM 1086 CG2 THR B 267 2.567 68.483 2.131 1.00 28.36 C

ATOM 1087 N SER B 268 2.100 64.819 1.910 1.00 27.77 N ATOM 1088 CA SER B 268 0.980 64.132 1.240 1.00 25.14 C

ATOM 1089 C SER B 268 0.085 63.350 2.124 1.00 30.63 C

ATOM 1090 O SER B 268 -1.170 63.416 2.200 1.00 33.42 O

ATOM 1091 CB SER B 268 1.584 63.597 -0.086 1.00 32.82 C

ATOM 1092 OG SER B 268 0.590 62.714 -0.614 1.00 44.95 O ATOM 1093 N VAL B 269 0.740 62.576 3.063 1.00 27.41 N

ATOM 1094 CA VAL B 269 -0.109 61.858 4.007 1.00 35.06 C

ATOM 1095 C VAL B 269 -0.916 62.801 4.886 1.00 30.74 C

ATOM 1096 O VAL B 269 -2.059 62.350 5.136 1.00 33.39 O

ATOM 1097 CB VAL B 269 0.609 60.683 4.632 1.00 38.56 C ATOM 1098 CG 1 VAL B 269 0.874 59.618 3.566 1.00 46.61 C

ATOM 1099 CG2 VAL B 269 1.839 61.044 5.415 1.00 45.95 C

ATOM 1100 N LEU B 270 -0.405 63.984 5.270 1.00 28.46 N

ATOM 1101 CA LEU B 270 -1.300 64.824 6.093 1.00 30.42 C

ATOM 1102 C LEU B 270 -2.391 65.379 5.191 1.00 33.09 C ATOM 1103 O LEU B 270 -3.505 65.541 5.686 1.00 49.14 O

ATOM 1104 CB LEU B 270 -0.497 66.080 6.565 1.00 36.39 C

ATOM 1105 CG LEU B 270 0.523 65.639 7.630 1.00 33.94 C

ATOM 1106 CD1 LEU B 270 1.528 66.779 7.853 1.00 42.38 C

ATOM 1107 CD2 LEU B 270 -0.242 65.417 8.913 1.00 35.66 C ATOM 1108 N LYS B 271 -2.124 65.639 3.953 1.00 33.63 N

ATOM 1109 CA LYS B 271 -3.148 66.240 3.071 1.00 41.91 C

ATOM 1110 C LYS B 271 -4.212 65.210 2.700 1.00 48.60 C

ATOM 1111 O LYS B 271 -5.248 65.555 2.127 1.00 48.91 O

ATOM 1112 CB LYS B 271 -2.480 66.753 1.809 1.00 32.24 C ATOM 1113 CG LYS B 271 -2.054 68.186 1.686 1.00 44.33 C ATOM 1114 CD LYS B 271 -0.929 68.387 0.709 1.00 55.54 C

ATOM 1115 CE LYS B 271 -1.200 69.070 -0.604 1.00 57.61 C

ATOM 1116 NZ LYS B 271 0.002 69.089 -1.513 1.00 56.79 N

ATOM 1117 N ASN B 272 -3.886 63.940 2.833 1.00 45.66 N ATOM 1118 CA ASN B 272 -4.790 62.838 2.477 1.00 41.76 C

ATOM 1119 C ASN B 272 -5.354 62.111 3.684 1.00 42.61 C

ATOM 1120 O ASN B 272 -5.852 60.978 3.608 1.00 42.97 O

ATOM 1121 CB ASN B 272 -4.101 61.820 1.574 1.00 50.22 C

ATOM 1122 CG ASN B 272 -3.727 62.434 0.234 1.00 49.65 C ATOM 1123 OD1 ASN B 272 -2.921 61.846 -0.482 1.00 60.21 O

ATOM 1124 ND2 ASN B 272 -4.315 63.591 -0.035 1.00 51.81 N

ATOM 1125 N ASN B 273 -5.360 62.721 4.869 1.00 41.71 N

ATOM 1126 CA ASN B 273 -5.944 62.081 6.051 1.00 45.37 C

ATOM 1127 C ASN B 273 -5.448 60.660 6.255 1.00 46.94 C ATOM 1128 0 ASN B 273 -6.212 59.731 6.572 1.00 42.59 O

ATOM 1129 CB ASN B 273 -7.440 62.261 6.197 1.00 55.99 C

ATOM 1130 CG ASN B 273 -8.146 61.973 7.499 1.00 72.23 C

ATOM 1131 OD1 ASN B 273 -9.295 61.480 7.449 1.00 60.94 O

ATOM 1132 ND2 ASN B 273 -7.609 62.219 8.694 1.00 49.92 N ATOM 1133 N LEU B 274 -4.110 60.522 6.192 1.00 32.57 N

ATOM 1134 CA LEU B 274 -3.513 59.186 6.422 1.00 37.62 C

ATOM 1135 C LEU B 274 -2.797 59.240 7.778 1.00 34.70 C

ATOM 1136 0 LEU B 274 -2.223 58.226 8.190 1.00 40.32 O

ATOM 1137 CB LEU B 274 -2.537 58.790 5.304 1.00 32.87 C ATOM 1138 CG LEU B 274 -3.131 58.533 3.903 1.00 36.48 C

ATOM 1139 CD1 LEU B 274 -2.191 58.031 2.850 1.00 36.11 C

ATOM 1140 CD2 LEU B 274 -4.255 57.495 3.999 1.00 44.60 C

ATOM 1141 N CYS B 275 -3.000 60.318 8.517 1.00 34.07 N

ATOM 1142 CA CYS B 275 -2.507 60.328 9.903 1.00 35.97 C ATOM 1143 C CYS B 275 -3.582 60.423 10.977 1.00 41.71 C

ATOM 1144 0 CYS B 275 -4.477 61.280 10.878 1.00 43.31 O

ATOM 1145 CB CYS B 275 -1.450 61.425 10.009 1.00 37.23 C

ATOM 1146 SG CYS B 275 0.034 60.839 8.984 1.00 40.12 S

ATOM 1147 N PRO B 276 -3.355 59.744 12.093 1.00 42.17 N ATOM 1148 CA PRO B 276 -4.203 59.752 13.252 1.00 45.49 C

ATOM 1149 C PRO B 276 -4.546 61.112 13.832 1.00 44.88 C

ATOM 1150 O PRO B 276 -3.726 62.022 13.871 1.00 39.71 O

ATOM 1151 CB PRO B 276 -3.414 58.959 14.292 1.00 41.06 C

ATOM 1152 CG PRO B 276 -2.174 58.448 13.720 1.00 43.43 C ATOM 1153 CD PRO B 276 -2.217 58.798 12.266 1.00 47.75 C ATOM 1154 N SER B 277 -5.782 61.285 14.330 1.00 49.29 N

ATOM 1155 CA SER B 277 -6.089 62.561 14.975 1.00 54.22 C

ATOM 1156 C SER B 277 -5.580 62.399 16.427 1.00 58.72 C

ATOM 1157 O SER B 277 -4.853 63.241 16.939 1.00 60.37 O ATOM 1158 CB SER B 277 -7.584 62.855 14.999 1.00 64.24 C

ATOM 1159 OG SER B 277 -7.855 63.410 16.288 1.00 58.29 O

ATOM 1160 N GLY B 278 -4.040 62.942 16.826 0.00 72.91 N

ATOM 1161 CA GLY B 278 -3.441 63.319 18.073 0.00 72.16 C

ATOM 1162 C GLY B 278 -2.623 64.614 17.863 0.00 71.11 C ATOM 1163 0 GLY B 278 -1.745 64.671 17.014 0.00 72.04 O

ATOM 1164 N SER B 279 -2.952 65.657 18.662 0.00 67.96 N

ATOM 1165 CA SER B 279 -2.265 66.962 18.645 0.00 66.01 C

ATOM 1166 C SER B 279 -0.889 66.699 19.187 0.00 61.41 C

ATOM 1167 0 SER B 279 0.045 67.486 19.082 0.00 60.21 O ATOM 1168 N ASN B 280 -0.831 65.502 19.816 0.00 43.63 N

ATOM 1169 CA ASN B 280 0.516 64.893 20.332 1.00 41.52 C

ATOM 1170 C ASN B 280 1.095 64.425 18.979 1.00 39.21 C

ATOM 1171 O ASN B 280 2.335 64.401 18.895 1.00 45.78 O

ATOM 1172 CB ASN B 280 0.346 63.670 21.244 1.00 50.54 C ATOM 1173 CG ASN B 280 1.546 62.856 21.624 1.00 68.21 C

ATOM 1174 OD1 ASN B 280 2.207 63.064 22.646 1.00 65.20 O

ATOM 1175 ND2 ASN B 280 1.904 61.830 20.842 1.00 75.37 N

ATOM 1176 N ILE B 281 0.249 64.007 18.025 1.00 36.82 N

ATOM 1177 CA ILE B 281 0.892 63.548 16.792 1.00 40.92 C ATOM 1178 C ILE B 281 1.634 64.712 16.156 1.00 38.73 C

ATOM 1179 0 ILE B 281 2.803 64.571 15.783 1.00 38.63 O

ATOM 1180 CB ILE B 281 -0.001 62.914 15.718 1.00 35.85 C

ATOM 1181 CG1 ILE B 281 -0.643 61.609 16.206 1.00 33.19 C

ATOM 1182 CG2 ILE B 281 0.956 62.467 14.587 1.00 50.96 C ATOM 1183 CD1 ILE B 281 0.365 60.492 16.128 1.00 39.56 C

ATOM 1184 N ILE B 282 0.919 65.849 16.022 1.00 29.27 N

ATOM 1185 CA ILE B 282 1.457 66.992 15.332 1.00 29.07 C

ATOM 1186 C ILE B 282 2.624 67.557 16.088 1.00 27.73 C

ATOM 1187 O ILE B 282 3.614 67.974 15.466 1.00 27.37 O ATOM 1188 CB ILE B 282 0.322 68.011 15.054 1.00 29.28 C

ATOM 1189 CG1 ILE B 282 -0.876 67.390 14.361 1.00 37.40 C

ATOM 1190 CG2 ILE B 282 0.830 69.268 14.380 1.00 32.57 C

ATOM 1191 CD1 ILE B 282 -0.464 66.633 13.121 1.00 40.21 C

ATOM 1192 N SER B 283 2.544 67.673 17.447 1.00 31.59 N ATOM 1193 CA SER B 283 3.643 68.243 18.178 1.00 27.76 C ATOM 1194 C SER B 283 4.901 67.386 18.070 1.00 30.37 C

ATOM 1195 O SER B 283 6.010 67.933 18.272 1.00 30.76 O

ATOM 1196 CB SER B 283 3.232 68.496 19.653 1.00 36.68 C

ATOM 1197 OG SER B 283 3.256 67.364 20.451 1.00 56.57 O ATOM 1198 N ASN B 284 4.770 66.101 17.790 1.00 26.37 N

ATOM 1199 CA ASN B 284 5.992 65.274 17.629 1.00 27.78 C

ATOM 1200 C ASN B 284 6.070 64.706 16.199 1.00 21.84 C

ATOM 1201 O ASN B 284 6.748 63.711 15.987 1.00 27.17 O

ATOM 1202 CB ASN B 284 5.744 64.004 18.525 1.00 29.03 C ATOM 1203 CG ASN B 284 5.951 64.593 19.959 1.00 37.00 C

ATOM 1204 OD1 ASN B 284 7.016 65.184 20.168 1.00 33.60 O

ATOM 1205 ND2 ASN B 284 4.924 64.444 20.727 1.00 40.16 N

ATOM 1206 N LEU B 285 5.431 65.412 15.244 1.00 25.64 N

ATOM 1207 CA LEU B 285 5.470 64.927 13.838 1.00 23.96 C ATOM 1208 C LEU B 285 6.819 64.397 13.395 1.00 29.62 C

ATOM 1209 O LEU B 285 6.908 63.266 12.842 1.00 26.40 O

ATOM 1210 CB LEU B 285 5.002 66.067 12.904 1.00 28.34 C

ATOM 1211 CG LEU B 285 5.069 65.740 11.397 1.00 26.79 C

ATOM 1212 CD1 LEU B 285 4.109 64.561 11.188 1.00 27.83 C ATOM 1213 CD2 LEU B 285 4.493 67.010 10.671 1.00 24.57 C

ATOM 1214 N PHE B 286 7.897 65.203 13.548 1.00 25.76 N

ATOM 1215 CA PHE B 286 9.219 64.787 13.175 1.00 22.99 C

ATOM 1216 C PHE B 286 10.090 64.505 14.425 1.00 24.06 C

ATOM 1217 O PHE B 286 11.150 63.937 14.218 1.00 28.06 O ATOM 1218 CB PHE B 286 9.895 65.849 12.282 1.00 23.00 C

ATOM 1219 CG PHE B 286 9.193 65.968 10.935 1.00 20.76 C

ATOM 1220 CD1 PHE B 286 8.527 67.111 10.535 1.00 24.21 C

ATOM 1221 CD2 PHE B 286 9.104 64.906 10.059 1.00 24.16 C

ATOM 1222 CE1 PHE B 286 7.908 67.333 9.345 1.00 28.76 C ATOM 1223 CE2 PHE B 286 8.483 65.070 8.834 1.00 26.34 C

ATOM 1224 CZ PHE B 286 7.929 66.268 8.444 1.00 25.84 C

ATOM 1225 N LYS B 287 9.630 64.973 15.581 1.00 25.94 N

ATOM 1226 CA LYS B 287 10.497 64.672 16.748 1.00 28.87 C

ATOM 1227 C LYS B 287 10.380 63.155 17.036 1.00 27.08 C ATOM 1228 O LYS B 287 11.384 62.698 17.635 1.00 32.05 O

ATOM 1229 CB LYS B 287 9.988 65.355 18.011 1.00 30.07 C

ATOM 1230 CG LYS B 287 10.028 66.861 17.818 1.00 39.43 C

ATOM 1231 CD LYS B 287 9.570 67.558 19.107 1.00 38.49 C

ATOM 1232 CE LYS B 287 10.244 67.044 20.346 1.00 45.19 C ATOM 1233 NZ LYS B 287 9.672 67.754 21.535 1.00 54.43 N ATOM 1234 N GLU B 288 9.242 62.575 16.862 1.00 25.64 N

ATOM 1235 CA GLU B 288 9.178 61.116 17.052 1.00 26.32 C

ATOM 1236 C GLU B 288 8.413 60.476 15.877 1.00 24.61 C

ATOM 1237 0 GLU B 288 7.285 60.027 15.991 1.00 25.25 O ATOM 1238 CB GLU B 288 8.387 60.806 18.309 1.00 32.86 C

ATOM 1239 CG GLU B 288 8.902 61.607 19.503 1.00 35.25 C

ATOM 1240 CD GLU B 288 7.951 61.297 20.659 1.00 54.44 C

ATOM 1241 OE1 GLU B 288 7.664 62.114 21.548 1.00 57.99 O

ATOM 1242 OE2 GLU B 288 7.431 60.153 20.674 1.00 68.94 O ATOM 1243 N ASP B 289 9.128 60.422 14.758 1.00 27.23 N

ATOM 1244 CA ASP B 289 8.555 59.981 13.522 1.00 24.79 C

ATOM 1245 C ASP B 289 8.508 58.473 13.335 1.00 25.29 C

ATOM 1246 O ASP B 289 8.887 57.768 14.308 1.00 24.41 O

ATOM 1247 CB ASP B 289 9.360 60.708 12.422 1.00 25.83 C ATOM 1248 CG ASP B 289 10.692 60.129 12.073 1.00 27.56 C

ATOM 1249 OD1 ASP B 289 11.569 60.765 11.368 1.00 26.69 O

ATOM 1250 OD2 ASP B 289 11.066 58.996 12.481 1.00 26.79 O

ATOM 1251 N CYS B 290 7.886 58.010 12.275 1.00 22.84 N

ATOM 1252 CA CYS B 290 7.704 56.500 12.199 1.00 21.60 C ATOM 1253 C CYS B 290 9.037 55.805 12.161 1.00 23.32 C

ATOM 1254 0 CYS B 290 8.987 54.643 12.636 1.00 24.35 O

ATOM 1255 CB CYS B 290 6.852 56.139 11.005 1.00 26.57 C

ATOM 1256 SG CYS B 290 5.243 56.859 11.098 1.00 24.46 S

ATOM 1257 N HIS B 291 10.201 56.313 11.700 1.00 22.17 N ATOM 1258 CA HIS B 291 11.434 55.536 11.831 1.00 19.85 C

ATOM 1259 C HIS B 291 11.748 55.412 13.330 1.00 22.53 C

ATOM 1260 O HIS B 291 12.291 54.353 13.749 1.00 25.72 O

ATOM 1261 CB HIS B 291 12.580 56.283 11.067 1.00 25.25 C

ATOM 1262 CG HIS B 291 12.309 56.139 9.600 1.00 23.27 C ATOM 1263 ND1 HIS B 291 13.419 56.391 8.799 1.00 28.09 N

ATOM 1264 CD2 HIS B 291 11.299 55.759 8.803 1.00 26.35 C

ATOM 1265 CE1 HIS B 291 13.068 56.164 7.518 1.00 30.90 C

ATOM 1266 NE2 HIS B 291 11.827 55.756 7.487 1.00 25.80 N

ATOM 1267 N GLN B 292 11.617 56.535 14.053 1.00 20.87 N ATOM 1268 CA GLN B 292 11.899 56.378 15.528 1.00 21.35 C

ATOM 1269 C GLN B 292 10.971 55.416 16.173 1.00 22.91 C

ATOM 1270 O GLN B 292 11.438 54.601 16.992 1.00 25.94 O

ATOM 1271 CB GLN B 292 11.760 57.776 16.134 1.00 27.57 C

ATOM 1272 CG GLN B 292 11.963 57.676 17.656 1.00 28.32 C ATOM 1273 CD GLN B 292 13.452 57.457 17.835 1.00 31.90 C ATOM 1274 OE1 GLN B 292 14.419 58.099 17.349 1.00 38.69 O

ATOM 1275 NE2 GLN B 292 13.881 56.477 18.651 1.00 35.17 N

ATOM 1276 N LYS B 293 9.712 55.406 15.846 1.00 20.55 N

ATOM 1277 CA LYS B 293 8.762 54.451 16.449 1.00 24.55 C ATOM 1278 C LYS B 293 9.085 53.009 16.085 1.00 25.63 C

ATOM 1279 O LYS B 293 9.017 52.090 16.922 1.00 25.63 O

ATOM 1280 CB LYS B 293 7.318 54.705 16.127 1.00 21.56 C

ATOM 1281 CG LYS B 293 6.901 56.145 16.539 1.00 21.24 C

ATOM 1282 CD LYS B 293 7.196 56.244 18.097 1.00 26.20 C ATOM 1283 CE LYS B 293 6.384 57.524 18.409 1.00 31.10 C

ATOM 1284 NZ LYS B 293 6.423 57.726 19.903 1.00 43.02 N

ATOM 1285 N ILE B 294 9.490 52.776 14.823 1.00 23.31 N

ATOM 1286 CA ILE B 294 9.902 51.416 14.444 1.00 21.72 C

ATOM 1287 C ILE B 294 11.119 50.970 15.201 1.00 21.93 C ATOM 1288 0 ILE B 294 11.260 49.854 15.735 1.00 23.80 O

ATOM 1289 CB ILE B 294 10.141 51.380 12.882 1.00 20.77 C

ATOM 1290 CG1 ILE B 294 8.820 51.436 12.192 1.00 23.01 C

ATOM 1291 CG2 ILE B 294 10.908 50.055 12.593 1.00 22.59 C

ATOM 1292 CD1 ILE B 294 9.017 51.734 10.679 1.00 22.74 C ATOM 1293 N ASP B 295 12.090 51.915 15.439 1.00 24.00 N

ATOM 1294 CA ASP B 295 13.279 51.556 16.193 1.00 23.03 C

ATOM 1295 C ASP B 295 12.810 51.238 17.660 1.00 22.93 C

ATOM 1296 O ASP B 295 13.358 50.296 18.280 1.00 26.64 O

ATOM 1297 CB ASP B 295 14.306 52.726 16.294 1.00 28.01 C ATOM 1298 CG ASP B 295 15.087 52.932 15.022 1.00 38.27 C

ATOM 1299 OD1 ASP B 295 15.208 51.983 14.218 1.00 33.40 O

ATOM 1300 OD2 ASP B 295 15.581 54.108 14.880 1.00 42.08 O

ATOM 1301 N ASP B 296 11.920 52.041 18.191 1.00 23.66 N

ATOM 1302 CA ASP B 296 11.461 51.902 19.576 1.00 23.31 C ATOM 1303 C ASP B 296 10.754 50.568 19.719 1.00 27.34 C

ATOM 1304 O ASP B 296 10.846 49.917 20.781 1.00 29.90 O

ATOM 1305 CB ASP B 296 10.523 53.024 20.023 1.00 27.92 C

ATOM 1306 CG ASP B 296 11.243 54.375 20.115 1.00 29.10 C

ATOM 1307 OD1 ASP B 296 12.476 54.417 20.174 1.00 31.43 O ATOM 1308 OD2 ASP B 296 10.435 55.308 20.207 1.00 39.50 O

ATOM 1309 N LEU B 297 9.999 50.114 18.738 1.00 23.57 N

ATOM 1310 CA LEU B 297 9.297 48.826 18.793 1.00 27.72 C

ATOM 1311 C LEU B 297 10.306 47.716 18.989 1.00 22.65 C

ATOM 1312 0 LEU B 297 10.243 46.851 19.874 1.00 25.81 O ATOM 1313 CB LEU B 297 8.513 48.608 17.442 1.00 23.42 C ATOM 1314 CG LEU B 297 7.866 47.205 17.399 1.00 25.90 C

ATOM 1315 CD1 LEU B 297 6.812 46.977 18.509 1.00 23.36 C

ATOM 1316 CD2 LEU B 297 7.211 47.055 16.051 1.00 30.35 C

ATOM 1317 N PHE B 298 11.366 47.725 18.188 1.00 22.40 N ATOM 1318 CA PHE B 298 12.391 46.661 18.204 1.00 22.91 C

ATOM 1319 C PHE B 298 13.335 46.770 19.381 1.00 22.01 C

ATOM 1320 O PHE B 298 13.984 45.762 19.702 1.00 26.38 O

ATOM 1321 CB PHE B 298 13.156 46.542 16.835 1.00 21.43 C

ATOM 1322 CG PHE B 298 12.207 45.937 15.757 1.00 21.93 C ATOM 1323 CD1 PHE B 298 11.605 46.773 14.838 1.00 23.82 C

ATOM 1324 CD2 PHE B 298 11.960 44.572 15.714 1.00 19.56 C

ATOM 1325 CE1 PHE B 298 10.708 46.295 13.908 1.00 23.51 C

ATOM 1326 CE2 PHE B 298 10.970 44.081 14.887 1.00 23.21 C

ATOM 1327 CZ PHE B 298 10.370 44.951 13.968 1.00 22.84 C ATOM 1328 N SER B 299 13.467 47.943 19.995 1.00 25.99 N

ATOM 1329 CA SER B 299 14.276 48.175 21.182 1.00 27.97 C

ATOM 1330 C SER B 299 13.442 47.959 22.437 1.00 27.60 C

ATOM 1331 O SER B 299 14.127 47.927 23.491 1.00 33.25 O

ATOM 1332 CB SER B 299 14.675 49.724 21.230 1.00 27.83 C ATOM 1333 OG SER B 299 15.549 49.784 20.090 1.00 48.34 O

ATOM 1334 N GLY B 300 12.122 47.850 22.391 1.00 25.83 N

ATOM 1335 CA GLY B 300 11.403 47.602 23.639 1.00 26.72 C

ATOM 1336 C GLY B 300 11.192 48.880 24.413 1.00 30.91 C

ATOM 1337 0 GLY B 300 11.025 48.835 25.657 1.00 31.51 O ATOM 1338 N LYS B 301 11.070 49.971 23.686 1.00 29.75 N

ATOM 1339 CA LYS B 301 10.888 51.281 24.368 1.00 33.01 C

ATOM 1340 C LYS B 301 9.712 52.045 23.807 1.00 34.70 C

ATOM 1341 0 LYS B 301 9.648 53.260 24.046 1.00 43.76 O

ATOM 1342 CB LYS B 301 12.064 52.152 23.774 1.00 33.50 C ATOM 1343 CG LYS B 301 13.401 51.715 24.317 1.00 45.65 C

ATOM 1344 CD LYS B 301 14.547 52.570 23.781 1.00 57.56 C

ATOM 1345 CE LYS B 301 15.836 52.170 24.485 1.00 66.05 C

ATOM 1346 NZ LYS B 301 15.703 50.863 25.187 1.00 63.08 N

ATOM 1347 N HIS B 302 8.898 51.483 22.961 1.00 35.10 N ATOM 1348 CA HIS B 302 7.798 52.142 22.301 1.00 37.49 C

ATOM 1349 C HIS B 302 6.747 52.604 23.289 1.00 40.04 C

ATOM 1350 O HIS B 302 6.231 51.751 24.034 1.00 39.71 O

ATOM 1351 CB HIS B 302 7.224 51.206 21.268 1.00 35.19 C

ATOM 1352 CG HIS B 302 6.067 51.578 20.440 1.00 49.29 C ATOM 1353 ND1 HIS B 302 5.681 50.761 19.395 1.00 47.23 N ATOM 1354 CD2 HIS B 302 5.217 52.623 20.430 1.00 63.81 C

ATOM 1355 CE1 HIS B 302 4.609 51.269 18.805 1.00 64.17 C

ATOM 1356 NE2 HIS B 302 4.315 52.414 19.413 1.00 68.77 N

ATOM 1357 OXT HIS B 302 6.454 53.826 23.197 1.00 53.33 O TER 1358 HIS B 302

HETATM 1359 O HOH 1 -4.215 33.391 34.133 1.00 53.22 O

HETATM 1360 O HOH 2 18.838 49.534 11.779 1.00 44.39 O

HETATM 1361 O HOH 3 18.287 39.678 10.876 1.00 40.67 O

HETATM 1362 O HOH 4 8.917 33.059 11.916 1.00 39.17 O HETATM 1363 O HOH 5 4.222 60.992 19.391 1.00 53.63 O

HETATM 1364 O HOH 6 14.649 53.645 5.675 1.00 47.99 O

HETATM 1365 O HOH 7 11.281 35.124 -0.410 1.00 43.81 O

HETATM 1366 O HOH 8 10.073 32.343 34.003 1.00 39.83 O

HETATM 1367 O HOH 9 15.435 57.496 13.875 1.00 47.64 O HETATM 1368 O HOH 10 1.986 52.789 20.289 1.00 58.39 O

HETATM 1369 O HOH 11 4.975 60.743 16.901 1.00 39.41 O

HETATM 1370 O HOH 12 -3.385 52.917 -1.600 1.00 51.02 O

HETATM 1371 O HOH 13 -13.243 36.380 20.476 1.00 42.17 O

HETATM 1372 O HOH 14 0.264 32.024 34.744 1.00 47.18 O HETATM 1373 O HOH 15 -6.609 45.944 14.783 1.00 70.97 O

HETATM 1374 O HOH 16 12.032 51.791 0.727 1.00 41.27 O

HETATM 1375 O HOH 17 14.999 64.979 4.406 1.00 48.65 O

HETATM 1376 O HOH 18 17.982 48.567 24.010 1.00 67.58 O

HETATM 1377 O HOH 19 18.188 40.205 24.486 1.00 48.05 O HETATM 1378 O HOH 20 1.933 28.876 14.156 1.00 45.02 O

HETATM 1379 O HOH 21 3.796 66.937 -1.003 1.00 45.54 O

HETATM 1380 O HOH 22 -3.930 63.076 7.853 1.00 45.06 O

HETATM 1381 O HOH 23 19.377 45.063 31.421 1.00 63.88 O

HETATM 1382 O HOH 24 10.030 47.404 30.475 1.00 66.92 O HETATM 1383 O HOH 25 13.644 53.484 2.115 1.00 43.24 O

HETATM 1384 O HOH 26 -5.065 60.214 -2.204 1.00 60.28 O

HETATM 1385 O HOH 27 6.822 67.425 21.500 1.00 54.16 O

HETATM 1386 O HOH 28 17.916 33.371 34.751 1.00 43.97 O

HETATM 1387 O HOH 29 17.128 43.746 3.192 1.00 82.65 O HETATM 1388 O HOH 30 -6.266 67.668 0.459 1.00 46.23 O

HETATM 1389 O HOH 31 7.405 62.268 10.357 1.00 42.73 O

HETATM 1390 O HOH 32 15.581 43.945 1.401 1.00 57.25 O

HETATM 1391 O HOH 33 -7.910 47.795 12.095 1.00 45.59 O

HETATM 1392 O HOH 34 17.024 49.940 15.276 1.00 49.07 O HETATM 1393 O HOH 35 8.499 65.007 22.461 1.00 47.51 O HETATM 1394 O HOH 36 -0.367 48.312 28.954 1.00 51.02 O

HETATM 1395 O HOH 37 -1.643 35.106 10.278 1.00 51.80 O

HETATM 1396 O HOH 38 8.875 32.312 14.589 1.00 44.92 O

HETATM 1397 O HOH 39 14.591 53.421 26.734 1.00 54.47 O HETATM 1398 O HOH 40 -11.341 62.679 8.845 1.00 65.05 O

HETATM 1399 O HOH 41 3.927 62.066 15.472 1.00 38.47 O

HETATM 1400 O HOH 42 -7.281 41.736 19.860 1.00 52.54 O

HETATM 1401 O HOH 43 -2.014 56.542 17.379 1.00 58.28 O

HETATM 1402 O HOH 44 4.173 49.699 23.881 1.00 48.81 O HETATM 1403 O HOH 45 15.763 51.418 6.274 1.00 50.89 O

HETATM 1404 O HOH 46 -5.015 40.116 20.052 1.00 38.76 O

HETATM 1405 O HOH 47 -13.876 33.442 19.654 1.00 41.56 O

HETATM 1406 O HOH 48 11.100 53.490 -1.243 1.00 51.95 O

HETATM 1407 O HOH 49 14.296 48.222 26.202 1.00 46.15 O HETATM 1408 O HOH 50 12.094 58.957 -1.935 1.00 66.19 O

HETATM 1409 O HOH 51 -0.363 33.562 11.861 1.00 47.15 O

HETATM 1410 O HOH 52 16.748 63.226 4.115 1.00 49.17 O

HETATM 1411 O HOH 53 16.029 41.422 23.111 1.00 41.73 O

HETATM 1412 O HOH 54 -15.194 36.941 22.656 1.00 28.98 O HETATM 1413 O HOH 55 13.284 40.873 6.595 1.00 29.61 O

HETATM 1414 O HOH 56 12.067 61.344 14.857 1.00 27.44 O

HETATM 1415 O HOH 57 3.230 32.037 23.779 1.00 30.77 O

HETATM 1416 O HOH 58 9.568 62.641 0.360 1.00 32.73 O

HETATM 1417 O HOH 59 6.579 69.146 1.553 1.00 39.07 O HETATM 1418 O HOH 60 5.396 68.921 -0.875 1.00 43.11 O

HETATM 1419 O HOH 61 -0.765 50.376 19.294 1.00 33.30 O

HETATM 1420 O HOH 62 17.619 40.867 26.969 1.00 32.47 O

HETATM 1421 O HOH 63 1.175 39.117 32.509 1.00 34.26 O

HETATM 1422 O HOH 64 -3.108 37.232 22.171 1.00 33.78 O HETATM 1423 O HOH 65 14.036 57.095 4.198 1.00 33.08 O

HETATM 1424 O HOH 66 15.991 40.644 9.396 1.00 31.36 O

HETATM 1425 O HOH 67 5.370 35.591 5.654 1.00 34.91 O

HETATM 1426 O HOH 68 -4.254 34.143 21.881 1.00 41.64 O

HETATM 1427 O HOH 69 -10.321 38.410 25.612 1.00 36.21 O HETATM 1428 O HOH 70 -2.807 46.890 24.208 1.00 39.64 O

HETATM 1429 O HOH 71 13.876 64.869 12.996 1.00 34.52 O

HETATM 1430 O HOH 72 4.755 27.441 30.254 1.00 46.13 O

HETATM 1431 O HOH 73 -15.942 32.065 20.573 1.00 39.55 O

HETATM 1432 O HOH 74 5.416 34.430 8.102 1.00 40.39 O HETATM 1433 O HOH 75 -0.534 32.451 14.335 1.00 34.37 O HETATM 1434 O HOH 76 2.188 32.706 11.148 1.00 37.38 0

HETATM 1435 O HOH 77 10.184 56.092 -0.224 1.00 39.79 O

HETATM 1436 O HOH 78 5.731 48.343 1.193 1.00 36.56 O

HETATM 1437 O HOH 79 -4.296 33.874 16.230 1.00 37.09 O

HETATM 1438 O HOH 80 2.789 25.851 19.884 1.00 37.03 O

HETATM 1439 O HOH 81 12.818 43.187 2.482 1.00 35.03 O

HETATM 1440 O HOH 82 -7.902 39.359 18.484 1.00 41.93 O

HETATM 1441 O HOH 83 16.109 44.634 21.227 1.00 32.29 O

HETATM 1442 O HOH 84 11.052 65.001 0.599 1.00 38.18 O

HHEETTAATTMM 11444433 OO HHOOHH 8855 12.818 45.671 3.492 1.00 33.67 O

HETATM 1444 O HOH 86 15.127 60.190 1.698 1.00 45.84 O

HETATM 1445 O HOH 87 -4.938 50.954 0.702 1.00 49.34 O

HETATM 1446 O HOH 88 9.131 42.936 32.780 1.00 44.90 O

HETATM 1447 O HOH 89 9.780 58.075 20.182 1.00 48.35 O

HHEETTAATTMM 11444488 OO HHOOHH 9900 12.526 34.159 9.787 1.00 47.64 O

HETATM 1449 O HOH 91 17.890 51.629 10.711 1.00 39.90 O

HETATM 1450 O HOH 92 -3.389 39.620 8.151 1.00 45.53 O

HETATM 1451 O HOH 93 6.934 42.923 -0.634 1.00 43.21 O

HETATM 1452 O HOH 94 7.777 55.462 21.607 1.00 51.04 O

HHEETTAATTMM 11445533 OO HHOOHH 9955 12.824 64.410 2.571 1.00 38.10 O

HETATM 1454 O HOH 96 11.080 46.801 -5.487 1.00 44.36 O

HETATM 1455 O HOH 97 13.258 59.480 9.903 1.00 36.96 O

HETATM 1456 O HOH 98 14.870 39.034 19.574 1.00 41.18 O

HETATM 1457 O HOH 99 -2.140 41.896 25.495 1.00 42.12 O HETATM 1458 O HOH 100 -3.695 31.825 24.645 1.00 41.51 O

HETATM 1459 O HOH 101 5.856 33.181 1.065 1.00 44.58 O

HETATM 1460 O HOH 102 23.450 39.517 35.251 1.00 58.45 O

HETATM 1461 O HOH 103 17.607 63.014 7.448 1.00 51.52 O

HETATM 1462 O HOH 104 19.084 43.155 28.944 1.00 41.89 O HETATM 1463 O HOH 105 19.569 41.448 18.016 1.00 45.55 O

HETATM 1464 O HOH 106 6.282 39.156 -0.594 1.00 40.95 O

HETATM 1465 O HOH 107 3.608 31.521 12.838 1.00 38.29 O

HETATM 1466 O HOH 108 5.340 58.553 23.325 1.00 56.09 O

HETATM 1467 O HOH 109 -0.098 26.492 16.742 1.00 51.50 O HETATM 1468 O HOH 110 17.107 48.579 -9.575 1.00 48.19 O

HETATM 1469 O HOH 111 1.112 44.707 2.608 1.00 40.43 O

HETATM 1470 O HOH 112 16.036 35.486 8.319 1.00 51.54 O

HETATM 1471 O HOH 113 12.626 35.166 33.691 1.00 39.95 O

HETATM 1472 O HOH 114 3.330 49.012 -0.102 1.00 54.48 O HETATM 1473 O HOH 115 20.022 39.070 22.895 1.00 55.71 O HETATM 1474 O HOH 116 10.117 47.515 34.607 1.00 55.47 O

HETATM 1475 O HOH 117 10.802 41.433 -3.200 1.00 41.94 O

HETATM 1476 O HOH 118 12.699 36.753 35.595 1.00 54.83 O

HETATM 1477 O HOH 119 -0.799 31.347 21.947 1.00 46.24 O HETATM 1478 O HOH 120 3.962 25.054 22.563 1.00 45.46 O

HETATM 1479 O HOH 121 13.790 59.142 13.294 1.00 41.19 O

HETATM 1480 O HOH 122 4.266 55.549 20.922 1.00 47.14 O

HETATM 1481 O HOH 123 -7.352 30.602 20.888 1.00 45.74 O

HETATM 1482 O HOH 124 15.898 45.939 -5.495 1.00 49.10 O HETATM 1483 O HOH 125 -3.050 47.320 18.265 1.00 42.75 O

HETATM 1484 O HOH 126 10.403 31.668 10.731 1.00 50.32 O

HETATM 1485 O HOH 127 17.448 40.984 20.774 1.00 55.89 O

HETATM 1486 O HOH 128 -6.202 32.811 19.196 1.00 61.25 O

HETATM 1487 O HOH 129 16.550 45.787 -1.303 1.00 60.67 O HETATM 1488 0 HOH 130 2.461 51.469 22.030 1.00 47.89 O

HETATM 1489 O HOH 131 11.519 67.677 23.175 1.00 55.94 O

HETATM 1490 O HOH 132 5.350 61.193 13.514 1.00 30.11 O

HETATM 1491 O HOH 133 13.495 40.851 3.965 1.00 37.96 O

HETATM 1492 0 HOH 134 6.125 48.964 24.558 1.00 99.00 O HETATM 1493 O HOH 135 12.692 45.086 31.102 1.00 46.72 O

HETATM 1494 O HOH 136 8.372 40.368 -2.803 1.00 47.67 O

HETATM 1495 0 HOH 137 -8.788 32.927 33.336 1.00 50.16 O

HETATM 1496 0 HOH 138 15.804 49.105 17.346 1.00 55.58 O

HETATM 1497 0 HOH 139 -15.741 39.473 21.927 1.00 60.70 O HETATM 1498 0 HOH 140 -5.089 45.153 17.414 1.00 44.88 O

HETATM 1499 0 HOH 141 -13.400 30.643 20.791 1.00 50.50 O

HETATM 1500 O HOH 142 -13.246 60.819 8.552 1.00 51.52 O

HETATM 1501 O HOH 143 23.320 40.711 16.836 1.00 47.25 O

HETATM 1502 O HOH 144 13.575 60.846 17.292 1.00 44.01 O HETATM 1503 O HOH 145 12.004 47.323 -3.094 1.00 48.02 O

HETATM 1504 O HOH 146 10.599 61.322 -1.495 1.00 48.28 O

HETATM 1505 O HOH 147 8.019 61.170 -4.066 1.00 53.49 O

HETATM 1506 O HOH 148 -6.253 49.514 11.028 1.00 56.76 O

HETATM 1507 O HOH 149 -9.451 40.692 26.921 1.00 44.83 O HETATM 1508 O HOH 150 19.204 50.228 21.178 1.00 59.13 O

HETATM 1509 O HOH 151 2.582 26.513 15.245 1.00 51.39 O

HETATM 1510 O HOH 152 4.026 46.486 -3.013 1.00 57.34 O

HETATM 1511 O HOH 153 16.267 55.892 11.019 1.00 48.44 O

HETATM 1512 O HOH 154 1.210 67.411 -1.165 1.00 48.04 O HETATM 1513 O HOH 155 2.360 46.499 0.941 1.00 66.58 O HETATM 1514 O HOH 156 11.053 55.907 23.988 1.00 54.62 O

HETATM 1515 O HOH 157 -4.436 30.868 22.082 1.00 60.65 O

HETATM 1516 O HOH 158 -3.896 44.317 24.858 1.00 42.03 O

HETATM 1517 O HOH 159 14.528 53.202 20.544 1.00 49.82 O HETATM 1518 O HOH 160 -3.587 31.389 19.616 1.00 66.25 O

HETATM 1519 O HOH 161 6.792 25.487 17.573 1.00 50.39 O

HETATM 1520 O HOH 162 10.764 30.263 35.419 1.00 36.82 O

HETATM 1521 O HOH 163 21.353 50.293 9.049 1.00 55.17 O

HETATM 1522 O HOH 164 -6.155 45.722 4.030 1.00 58.56 O HETATM 1523 O HOH 165 -1.643 33.968 22.162 1.00 32.78 O

HETATM 1524 O HOH 166 20.572 39.489 9.475 1.00 54.99 O

HETATM 1525 O HOH 167 16.138 59.711 9.718 1.00 50.63 O

HETATM 1526 O HOH 168 7.237 50.386 25.663 1.00 46.62 O

HETATM 1527 O HOH 169 23.376 32.725 15.317 1.00 57.83 O HETATM 1528 0 HOH 170 -6.893 46.336 20.725 1.00 51.05 O

HETATM 1529 O HOH 171 -8.757 52.883 -3.912 1.00 55.02 O

HETATM 1530 O HOH 172 -2.827 48.125 26.461 1.00 67.86 O

HETATM 1531 O HOH 173 -10.391 32.607 19.235 1.00 53.07 O

HETATM 1532 0 HOH 174 12.604 56.386 22.103 1.00 58.51 O HETATM 1533 O HOH 175 22.798 50.951 6.720 1.00 54.25 O

HETATM 1534 O HOH 176 9.471 60.615 -6.502 1.00 60.38 O

HETATM 1535 0 HOH 177 15.724 60.671 14.619 1.00 61.18 O

HETATM 1536 0 HOH 178 22.143 45.991 8.636 1.00 64.81 O

HETATM 1537 0 HOH 179 14.368 57.230 1.558 1.00 52.29 O HETATM 1538 0 HOH 180 6.260 72.265 1.689 1.00 58.15 O

HETATM 1539 0 HOH 181 -5.293 56.914 16.553 1.00 62.84 O

HETATM 1540 0 HOH 182 20.371 47.749 25.744 1.00 62.07 O

HETATM 1541 0 HOH 183 -0.726 65.989 -1.991 1.00 57.90 O

HETATM 1542 0 HOH 184 8.049 52.633 -3.838 1.00 56.88 O HETATM 1543 0 HOH 185 22.895 31.309 13.193 1.00 61.69 O

HETATM 1544 0 HOH 186 21.848 46.891 18.577 1.00 64.50 O

HETATM 1545 0 HOH 187 12.606 56.305 -0.147 1.00 62.06 O

HETATM 1546 0 HOH 188 0.808 33.921 8.196 1.00 52.41 O

HETATM 1547 0 HOH 189 -4.938 46.394 29.675 1.00 61.58 O HETATM 1548 0 HOH 190 -1.908 31.725 34.223 1.00 52.77 O

HETATM 1549 0 HOH 191 -1.212 41.160 2.846 1.00 55.54 O

HETATM 1550 0 HOH 192 22.586 44.657 11.116 1.00 62.81 O

HETATM 1551 0 HOH 193 -5.191 44.209 13.767 1.00 61.83 O

HETATM 1552 0 HOH 194 5.483 49.662 -0.942 1.00 53.72 O CONECT 350 593 CONECT 356 481 CONECT 481 356 CONECT 593 350 CONECT 1015 1256 CONECT 1021 1146 CONECT 1146 1021 CONECT 1256 1015

MASTER 286 0 0 11 0 0 0 6 1550 2 8 14 END

Claims

What is claimed is:

1. A method of treating or preventing a condition associated with CD81 binding in a subject in need of such treatment, the method comprising administering to the subject a compound capable of binding to a binding site in a CD81 protein, said binding site comprising one or more amino acids of CD81 selected from Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Asp 189 of CD81, under conditions such that the condition associated with CD81 binding is treated or prevented.

2. The method of claim 1, wherein the condition associated with CD81 binding is selected from HCV infection, multiple sclerosis, and malaria.

3. The method of claim 1, wherein the condition associated with CD81 binding is HCV infection.

4. The method of claim 1, wherein the compound is a compound selected from the compounds of Tables 1 and 2.

5. A method of treating HCV infection in a subject in need of such treatment, the method comprising administering to the subject a compound of Table 1, Table 2 or Table 3 under conditions such that HCV infection is treated.

6. A method of inhibiting HCV helicase in a cell, the method comprising contacting the cell with a compound capable of inhibiting HCV helicase.

7. A method of inhibiting HCV polymerase in a cell, the method comprising contacting the cell with a compound of Table 3.

8. A method of inhibiting HCV infection in a cell, the method comprising contacting the cell with a compound of Table 1, Table 2 or Table 3.

9. An oral dosage form comprising a compound of Table 1, Table 2 or Table 3, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable vehicle.

10. A method for treating a subject diagnosed as having HCV infection, the method comprising administering to the subject a pharmaceutically effective amount of a compound of Table 1, Table 2 or Table 3, or a pharmaceutically acceptable salt thereof.

11. A kit for the treatment of HCV infection, the kit comprising an effective amount of the amount of a compound of Table 1, Table 2 or Table 3 or a pharmaceutically acceptable salt thereof; and instructions for administering the compound of Table 1, Table 2 or Table 3 or a pharmaceutically acceptable salt thereof to a subject to treat HCV infection.

12. A computer for producing a three-dimensional representation of a) a molecule or molecular complex, wherein said molecule or molecular complex comprises a binding site defined by structure coordinates of amino acid residues of the NS5B protein; or b) a three-dimensional representation of a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than about 2.0 (more preferably not more than 1.5) angstroms, wherein said computer comprises:

(i) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises the structure coordinates of structure coordinates of amino acid residues of the NS5B protein;

(ii) a working memory for storing instructions for processing said machine- readable data;

(iii) a central-processing unit coupled to said working memory and to said machine-readable data storage medium for processing said machine readable data into said three-dimensional representation; and (iv) a display coupled to said central-processing unit for displaying said three- dimensional representation.

13. A method for evaluating the potential of a chemical entity to associate with a) a molecule or molecular complex comprising a binding pocket defined by structure coordinates of amino acid residues of the NS5B protein, or b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 2.0 (more preferably 1.5) angstroms, the method comprising the steps of: i) employing computational means to perform a fitting operation between the chemical entity and a binding pocket of the molecule or molecular complex; and ii) analyzing the results of the fitting operation to quantify the association between the chemical entity and the binding pocket.

14. A method of preserving liver function in a subject suffering from HCV infection, the method comprising administering to the subject a compound of Table 1 or Table 2 or a pharmaceutically acceptable salt thereof, under conditions such that liver function in the subject is preserved.

15. A packaged pharmaceutical formulation for the treatment or prevention of liver damage in a subject suffering from HCV infection, the packaged pharmaceutical formulation comprising: an effective amount of the amount of a compound of Table 1, Table 2 or Table 3 or a pharmaceutically acceptable salt thereof; and instructions for administering the compound of Table 1, Table 2 or Table 3 or a pharmaceutically acceptable salt thereof to a subject suffering from HCV infection for the treatment or prevention of liver damage in the subject.

16. A computer for producing a three-dimensional representation of a) a molecule or molecular complex, wherein said molecule or molecular complex comprises a binding site in the CD81 protein which binds to HCV E2 protein; or b) a three-dimensional representation of a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of one or more amino acids Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Aspl89 of CD81 of not more than about 2.0 (more preferably not more than 1.5) angstroms, wherein said computer comprises: (i) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises the structure coordinates of structure coordinates of one or more amino acid residues selected from Cysl57, Serl59, SerlόO, Thrl63, Alal64, Thrl66, Thrl67, Ilel81, Asnl84, Leul85 and Aspl89 of the human CD81 protein; (ii) a working memory for storing instructions for processing said machine-readable data; (iii) a central-processing unit coupled to said working memory and to said machine- readable data storage medium for processing said machine readable data into said three-dimensional representation; and (iv) a display coupled to said central-processing unit for displaying said three-dimensional representation.

17. A method for evaluating the potential of a chemical entity to bind with a) a molecule or molecular complex comprising a binding pocket defined by structure coordinates of one or more of amino acid residues Serl60,Thrl63, Alal64, Thrl67, Ilel81, Leul85 and Aspl89 of the CD81 protein, or b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 2.0 (more preferably 1.5) angstroms, the method comprising the steps of: i) employing computational means to perform a fitting operation between the chemical entity and a binding pocket of the molecule or molecular complex; and ii) analyzing the results of the fitting operation to quantify the association between the chemical entity and the binding pocket.

18. A method for preventing HCV infection in a subject, the method comprising administering to the subject an effective amount of a compound capable of disrupting binding of HCV E2 protein with CD81 protein, such that HCV infection is prevented in the subject.

19. The method of claim 18, wherein the compound is a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

20. A method for treating or preventing a condition associated with CD81 binding in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound capable of disrupting binding of a protein with CD81 protein, such that a condition associated with CD81 binding is treated or prevented in the subject.

21. The method of claim 20, wherein the compound is a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.