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- PDB-2gvf: HCV NS3-4A protease domain complexed with a macrocyclic ketoamide... -

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Basic information

Entry
Database: PDB / ID: 2gvf
TitleHCV NS3-4A protease domain complexed with a macrocyclic ketoamide inhibitor, SCH419021
Components
  • PolyproteinProteolysis
  • polyproteinProteolysis
KeywordsHYDROLASE / hepatitis C / protease / ketoamide inhibitor
Function / homology
Function and homology information


hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / 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 / SH3 domain binding / : ...hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / 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 / SH3 domain binding / : / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / clathrin-dependent endocytosis of virus by host cell / viral nucleocapsid / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / ribonucleoprotein complex / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / structural molecule activity / virion attachment to host cell / host cell plasma membrane / virion membrane / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
Thrombin, subunit H - #120 / Hepatitis C virus core protein, chain A superfamily / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 / HCV NS5a protein C-terminal region / Hepatitis C virus, Non-structural protein NS4b / Hepatitis C virus, Core protein, N-terminal ...Thrombin, subunit H - #120 / Hepatitis C virus core protein, chain A superfamily / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 / HCV NS5a protein C-terminal region / Hepatitis C virus, Non-structural protein NS4b / Hepatitis C virus, Core protein, N-terminal / Hepatitis C virus non-structural protein NS4b / Hepatitis C virus capsid protein / Hepatitis C virus, Non-structural protein NS2 / Hepatitis C virus, Non-structural 5a protein / Hepatitis C virus, Non-structural 5a protein, domain 1a / Hepatitis C virus non-structural 5a, 1B domain / NS5A domain 1a superfamily / Hepatitis C virus non-structural 5a protein membrane anchor / Hepatitis C virus non-structural 5a zinc finger domain / Hepatitis C virus non-structural 5a domain 1b / Hepacivirus nonstructural protein 2 (NS2) protease domain profile. / Hepatitis C virus, Non-structural protein NS4a / Hepatitis C virus non-structural protein NS4a / Hepatitis C virus, Core protein, C-terminal / Hepatitis C virus core protein / Hepatitis C virus, Non-structural protein E2/NS1 / Hepatitis C virus non-structural protein E2/NS1 / Hepatitis C virus, Envelope glycoprotein E1 / Hepatitis C virus envelope glycoprotein E1 / RNA dependent RNA polymerase, hepatitis C virus / Viral RNA dependent RNA polymerase / Hepatitis C virus, NS3 protease, Peptidase S29 / Hepatitis C virus NS3 protease / Hepacivirus/Pegivirus NS3 protease domain profile. / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal domain / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Trypsin-like serine proteases / Thrombin, subunit H / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Peptidase S1, PA clan, chymotrypsin-like fold / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / Beta Barrel / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Chem-NHN / : / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.5 Å
AuthorsArasappan, A. / Njoroge, F.G. / Chen, K.X. / Venkatraman, S. / Parekh, T.N. / Gu, H. / Pichardo, J. / Butkiewicz, N. / Prongay, A. / Madison, V. / Girijavallabhan, V.
Citation
#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. / Landro, J.A. / Chambers, S.P. / Markland, W. / Lepre, C. / O'Malley, E.
#2: Journal: J.Biol.Chem. / Year: 2006
Title: Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. Reduced RNA replication fitness and partial rescue by second-site mutations
Authors: Yi, M. / Tong, X. / Skelton, A. / Chase, R. / Chen, T. / Prongay, A. / Bogen, S.L. / Saksena, A.K. / Njoroge, F.G. / Veselenak, R.L. / Pyles, R.B. / Bourne, N. / Malcolm, B.A. / Lemon, S.M.
#3: Journal: ARCH.BIOCHEM.BIOPHYS. / Year: 2004
Title: Hepatitis C NS3 protease inhibition by peptidyl-alpha-ketoamide inhibitors: kinetic mechanism and structure
Authors: Liu, Y. / Stoll, V.S. / Richardson, P.L. / Saldivar, A. / Klaus, J.L. / Molla, A. / Kohlbrenner, W. / Kati, W.M.
#4: Journal: BIOORG.MED.CHEM.LETT. / Year: 2005
Title: Hepatitis C Virus NS3-4A serine protease inhibitors: SAR of P'2 moiety with improved potency
Authors: Arasappan, A. / Njoroge, F.G. / Chan, T.-Y. / Bennett, F. / Bogen, S.L. / Chen, K. / Gu, H. / Hong, L. / Jao, E. / Liu, Y.-T. / Lovey, R.G. / Parekh, T. / Pike, R.E. / Pinto, P. / Santhanam, ...Authors: Arasappan, A. / Njoroge, F.G. / Chan, T.-Y. / Bennett, F. / Bogen, S.L. / Chen, K. / Gu, H. / Hong, L. / Jao, E. / Liu, Y.-T. / Lovey, R.G. / Parekh, T. / Pike, R.E. / Pinto, P. / Santhanam, B. / Venkatraman, S. / Vaccaro, H. / Wang, H. / Yang, X. / Zhu, Z. / McKittrick, B. / Saksena, A.K. / Girijavallabhan, V. / Pichardo, J. / Butkiewicz, N. / Ingram, R. / Malcolm, B. / Prongay, A.J. / Yao, N. / Marten, B. / Madison, V. / Kemp, S. / Levy, O. / Lim-Wilby, M. / Tamura, S. / Ganguly, A.K.
History
DepositionMay 2, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 23, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: polyprotein
B: Polyprotein
C: polyprotein
D: Polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,9127
Polymers46,9924
Non-polymers9203
Water2,306128
1
A: polyprotein
B: Polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,3504
Polymers23,4962
Non-polymers8542
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3760 Å2
ΔGint-57 kcal/mol
Surface area9940 Å2
MethodPISA
2
C: polyprotein
D: Polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,5613
Polymers23,4962
Non-polymers651
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1700 Å2
ΔGint-45 kcal/mol
Surface area7960 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7780 Å2
ΔGint-125 kcal/mol
Surface area15590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)224.615, 224.615, 75.321
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32
DetailsThe asymmetric unit contains a dimer of the NS3 protease domain, with each monomer complexed with a molecule of the NS4a peptide. Both monomers of the NS3-4a complex have a structurally bound zinc atom. The Chain A monomer of the NS3-4a complex has a covalently bound ketoamide, with a linkage between Ser139 OG and C38 of the ketoamide. The NS3 protease domain is part of the larger NS3 protease-helicase protein that is catalytically active when complexed with the NS4a protein. The NS3 protease domain-NS4a peptide complex is catalytically active, but this is not the biologically active form.

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Components

#1: Protein polyprotein / Proteolysis


Mass: 21102.027 Da / Num. of mol.: 2 / Fragment: NS3 protease domain, residues 1027-1207
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Genus: Hepacivirus / Production host: Escherichia coli (E. coli) / References: GenBank: 22129793, UniProt: P26664*PLUS
#2: Protein/peptide Polyprotein / Proteolysis


Mass: 2394.039 Da / Num. of mol.: 2 / Fragment: NS4a peptide, residues 1680-1696 / Source method: obtained synthetically
Details: This sequence occurs naturally in Hepatitis C virus
References: GenBank: 22129793, UniProt: P26664*PLUS
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-NHN / (6R,8S,11S)-11-CYCLOHEXYL-N-(1-{[(2-{[(1S)-2-(DIMETHYLAMINO)-2-OXO-1-PHENYLETHYL]AMINO}-2-OXOETHYL)AMINO](OXO)ACETYL}BUTYL)-10,13-DIOXO-2,5-DIOXA-9,12-DIAZATRICYCLO[14.3.1.1~6,9~]HENICOSA-1(20),16,18-TRIENE-8-CARBOXAMIDE


Mass: 788.929 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H56N6O9
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 128 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.89 Å3/Da / Density % sol: 68.37 %
Crystal growTemperature: 298 K
Details: protein solution mixed with equal volume of a solution containing 0.75-1.00 M NaCl, 0.1 M MES, 0.1 M Na/K PO4, pH 5.6-6.2. The trays were set at 277K for 5-7 days to control nucleation, ...Details: protein solution mixed with equal volume of a solution containing 0.75-1.00 M NaCl, 0.1 M MES, 0.1 M Na/K PO4, pH 5.6-6.2. The trays were set at 277K for 5-7 days to control nucleation, followed by incubation for 3 weeks at 285 K to maximize crystal growth, pH 5.6-5.8, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: ADSC QUANTUM 210 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→100 Å / Num. obs: 25194 / % possible obs: 99.9 % / Observed criterion σ(I): 2.56 / Redundancy: 5 % / Biso Wilson estimate: 43.24 Å2 / Rsym value: 0.073 / Net I/σ(I): 22.2
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 5 % / Mean I/σ(I) obs: 2.6 / Rsym value: 0.547 / % possible all: 99.9

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Processing

Software
NameVersionClassification
ADSCdata collection
DENZOdata reduction
X-PLORmodel building
X-PLOR98.1refinement
SCALEPACKdata scaling
X-PLORphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.5→8 Å / Cross valid method: THROUGHOUT / σ(F): 1 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.276 2252 RANDOM
Rwork0.204 --
obs0.204 22899 -
all-24995 -
Refinement stepCycle: LAST / Resolution: 2.5→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2748 0 59 128 2935
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.008
X-RAY DIFFRACTIONx_bond_d_na
X-RAY DIFFRACTIONx_bond_d_prot
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_d_na
X-RAY DIFFRACTIONx_angle_d_prot
X-RAY DIFFRACTIONx_angle_deg1.82
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d1.36
X-RAY DIFFRACTIONx_improper_angle_d_na
X-RAY DIFFRACTIONx_improper_angle_d_prot
X-RAY DIFFRACTIONx_mcbond_it
X-RAY DIFFRACTIONx_mcangle_it
X-RAY DIFFRACTIONx_scbond_it
X-RAY DIFFRACTIONx_scangle_it
LS refinement shellResolution: 2.5→2.61 Å
RfactorNum. reflection% reflection
Rfree0.3523 254 -
Rwork0.348 2249 -
obs--90 %

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