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Yorodumi- PDB-2f9v: HCV NS3 protease domain with NS4a peptide and a ketoamide inhibit... -
+Open data
-Basic information
Entry | Database: PDB / ID: 2f9v | ||||||
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Title | HCV NS3 protease domain with NS4a peptide and a ketoamide inhibitor with P1 and P2 cyclopropylalannines | ||||||
Components |
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Keywords | VIRAL PROTEIN / HCV / Hepatitis C protease / NS3 protease / ketoamide inhibitor | ||||||
Function / homology | Function and homology information positive regulation of hexokinase activity / modulation by virus of host cellular process / translocation of peptides or proteins into host cell cytoplasm / Toll-like receptor 2 binding / viral capsid assembly / adhesion receptor-mediated virion attachment to host cell / TBC/RABGAPs / hepacivirin / host cell mitochondrial membrane / host cell lipid droplet ...positive regulation of hexokinase activity / modulation by virus of host cellular process / translocation of peptides or proteins into host cell cytoplasm / Toll-like receptor 2 binding / viral capsid assembly / adhesion receptor-mediated virion attachment to host cell / TBC/RABGAPs / hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / positive regulation of cytokinesis / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / negative regulation of protein secretion / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / endoplasmic reticulum-Golgi intermediate compartment membrane / kinase binding / SH3 domain binding / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / viral nucleocapsid / clathrin-dependent endocytosis of virus by host cell / entry receptor-mediated virion attachment to host cell / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA helicase / ribonucleoprotein complex / induction by virus of host autophagy / serine-type endopeptidase activity / cysteine-type endopeptidase activity / RNA-directed RNA polymerase / viral RNA genome replication / virus-mediated perturbation of host defense response / RNA-dependent RNA polymerase activity / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / apoptotic process / host cell plasma membrane / structural molecule activity / virion membrane / negative regulation of transcription by RNA polymerase II / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding Similarity search - Function | ||||||
Biological species | Hepatitis C virus | ||||||
Method | X-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.6 Å | ||||||
Authors | Bogen, S.L. / Ruan, S. / Liu, R. / Agrawal, S. / Pichardo, J. / Prongay, A. / Baroudy, B. / Saksena, A. / Girijavallabhan, V. / Njoroge, F.G. | ||||||
Citation | Journal: Bioorg.Med.Chem.Lett. / Year: 2006 Title: Depeptidization efforts on P3-P2 a-ketoamide inhibitors of HCV NS3-4A serine protease: Effect on HCV replicon activity. Authors: Bogen, S.L. / Ruan, S. / Liu, R. / Agrawal, S. / Pichardo, J. / Prongay, A. / Baroudy, B. / Saksena, A. / Girijavallabhan, V. / Njoroge, F.G. #1: Journal: Cell(Cambridge,Mass.) / Year: 1996 Title: Crystal Structure of the Hepatitis C Virus NS3 Protease Domain Complexed with a Synthetic NS4a Cofactor Peptide Authors: Kim, J.L. / Morgenstern, K.A. / Lin, C. / Fox, T. / Dwyer, M.D. / Landro, J.A. / Chambers, S.P. / Markland, W. / Lepre, C.A. / O'Malley, E.T. / Harbeson, S.L. / Rice, C.M. / Murcko, M.A. / ...Authors: Kim, J.L. / Morgenstern, K.A. / Lin, C. / Fox, T. / Dwyer, M.D. / Landro, J.A. / Chambers, S.P. / Markland, W. / Lepre, C.A. / O'Malley, E.T. / Harbeson, S.L. / Rice, C.M. / Murcko, M.A. / Caron, P.R. / Thomson, J.A. #2: Journal: Bioorg.Med.Chem.Lett. / Year: 2005 Title: Hepatitis C virus NS3-4A serine protease inhibitors: Use of a P2-P1 cyclopropyl alanine combination to improve potency. Authors: Bogen, S. / Saksena, A.K. / Arasappan, A. / Gu, N. / Njoroge, F.G. / Girijavallabhan, V. / Pichardo, J. / Butkiewicz, N. / Prongay, A. / Madison, A. #3: Journal: J.Med.Chem. / Year: 2005 Title: Design and Synthesis of Depeptidized Macrocyclic Inhibitors of Hepatitis C NS3-4A Protease Using Structure-Based Drug Design Authors: Venkatraman, S. / Njoroge, F.G. / Girijavallabhan, V.M. / Madison, V.S. / Yao, N.H. / Prongay, A.J. / Butkiewicz, N. / Pichardo, J. #4: Journal: Angew.Chem.Int.Ed.Engl. / Year: 2005 Title: Proline-Based Macrocyclic Inhibitors of the Hepatitis C Virus: Stereoselective Synthesis and Biological Activity. Authors: Chen, K.X. / Njoroge, F.G. / Vibulbhan, B. / Prongay, A. / Pichardo, J. / Madison, V. / Buevich, A. / Chan, T.M. #5: Journal: Bioorg.Med.Chem.Lett. / Year: 2004 Title: Novel 2-oxoimidazolidine-4-carboxylic acid derivatives as Hepatitis C virus NS3-4A serine protease inhibitors: synthesis, activity and X-ray crystal structure of an enzyme inhibitor complex Authors: Arasappan, A. / Njoroge, F.G. / Parekh, T.N. / Yang, X. / Pichardo, J. / Butkiewicz, N. / Prongay, A. / Yao, N. / Girijavallabhan, V. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 2f9v.cif.gz | 90.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb2f9v.ent.gz | 67.1 KB | Display | PDB format |
PDBx/mmJSON format | 2f9v.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 2f9v_validation.pdf.gz | 806.6 KB | Display | wwPDB validaton report |
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Full document | 2f9v_full_validation.pdf.gz | 813 KB | Display | |
Data in XML | 2f9v_validation.xml.gz | 18.3 KB | Display | |
Data in CIF | 2f9v_validation.cif.gz | 25.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/f9/2f9v ftp://data.pdbj.org/pub/pdb/validation_reports/f9/2f9v | HTTPS FTP |
-Related structure data
Related structure data | |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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Unit cell |
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Details | The NS3 protease domain, residues 1-181 of NS3, exists in a complex with an NS4a peptide and an inhibitor. There is a dimer of the NS3 domain-NS4a peptide complex, but only one monomer (Chains A and B) have the inhibitor bound to the active site. This dimer is the component of the asymmetric unit. In vivo, the protease domain is part of a multi enzyme protein (having both protease and helicase activities). The NS3 protease domain with the NS4A peptide is known to be catalytically active in the absence of the helicase domain, although it is not known whether it is active as a monomer or dimer. |
-Components
#1: Protein | Mass: 21290.277 Da / Num. of mol.: 2 / Fragment: protease domain (Residues : 1-181) Source method: isolated from a genetically manipulated source Source: (gene. exp.) Hepatitis C virus / Genus: Hepacivirus / Strain: H Gene: NS3 protease domain ( residues 1027-1207 of the polyprotein). Plasmid: NS3(181)His6/pET22b / Production host: Escherichia coli (E. coli) / Strain (production host): JM109(DE3) / References: GenBank: 28921568, UniProt: P27958*PLUS #2: Protein/peptide | Mass: 2394.039 Da / Num. of mol.: 2 / Fragment: Residues 21-39 / Source method: obtained synthetically Details: Solid-phase peptide synthesis of the NS4a residues 21-39 peptide with N-terminal KK and C-terminal KK extensions. References: GenBank: 51039195, UniProt: P27958*PLUS #3: Chemical | #4: Chemical | ChemComp-BN6 / ( | #5: Water | ChemComp-HOH / | |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 3.82 Å3/Da / Density % sol: 67.83 % |
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Crystal grow | Temperature: 285 K / pH: 5.7 Details: 12-15 mG/mL Protein in 15 mM MES, pH 6.5 - 1.0 M NaCl equivolume mixture with (0.85-1.05M) NaCl- 0.1M MES-0.1 M Na/KPO4, pH5.5-5.8 - 5mM BME, equilibrated with 1.35-1.55M NaCl-0.1M MES-0.1M ...Details: 12-15 mG/mL Protein in 15 mM MES, pH 6.5 - 1.0 M NaCl equivolume mixture with (0.85-1.05M) NaCl- 0.1M MES-0.1 M Na/KPO4, pH5.5-5.8 - 5mM BME, equilibrated with 1.35-1.55M NaCl-0.1M MES-0.1M Na/KPO4, pH 5.6-5.8 - 5 mM BME, VAPOR DIFFUSION, HANGING DROP, temperature 285K, pH 5.70 |
-Data collection
Diffraction | Mean temperature: 95 K |
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Diffraction source | Source: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 |
Detector | Type: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Feb 27, 2000 / Details: OSMIC GREEN |
Radiation | Monochromator: OSMIC GREEN / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.5418 Å / Relative weight: 1 |
Reflection | Resolution: 2.6→2.69 Å / Num. obs: 21990 / % possible obs: 99.7 % / Observed criterion σ(I): 1.97 / Redundancy: 3.7 % / Biso Wilson estimate: 37.31 Å2 / Rsym value: 0.088 / Net I/σ(I): 16.8 |
Reflection shell | Resolution: 2.6→2.69 Å / Rsym value: 0.551 / % possible all: 99.1 |
-Processing
Software |
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Refinement | Method to determine structure: FOURIER SYNTHESIS / Resolution: 2.6→2.69 Å / σ(F): 1 / Stereochemistry target values: Engh & Huber
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Refinement step | Cycle: LAST / Resolution: 2.6→2.69 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.6→2.71 Å / Total num. of bins used: 8
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