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- PDB-4i31: Crystal structure of HCV NS3/NS4A protease complexed with compound 4 -

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Basic information

Entry
Database: PDB / ID: 4i31
TitleCrystal structure of HCV NS3/NS4A protease complexed with compound 4
Components
  • Genome polyprotein
  • HCV non-structural protein 4A
KeywordsHydrolase/Hydrolase inhibitor / Hepatitis C Virus / NS3 / NS4A / protein-inhibitor complex compound 4 / serine protease / Hydrolase-Hydrolase inhibitor complex
Function / homology
Function and homology information


RNA stabilization / RNA folding chaperone / DNA/DNA annealing activity / RNA strand annealing activity / 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 ...RNA stabilization / RNA folding chaperone / DNA/DNA annealing activity / RNA strand annealing activity / 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 / protein-DNA complex / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport / viral nucleocapsid / clathrin-dependent endocytosis of virus by host cell / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / ribonucleoprotein complex / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / serine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / virion attachment to host cell / apoptotic process / host cell plasma membrane / structural molecule activity / virion membrane / ATP hydrolysis activity / proteolysis / DNA binding / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
Thrombin, subunit H - #120 / 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 core protein, chain A superfamily ...Thrombin, subunit H - #120 / 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 core protein, chain A superfamily / : / 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 / NS3 RNA helicase, C-terminal helical domain / 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 / Trypsin-like serine proteases / 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 / Thrombin, subunit H / Helicase superfamily 1/2, ATP-binding domain / 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 / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / Beta Barrel / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Chem-1BV / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9301 Å
AuthorsLemke, C.T.
CitationJournal: J.Biol.Chem. / Year: 2013
Title: Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance.
Authors: O'Meara, J.A. / Lemke, C.T. / Godbout, C. / Kukolj, G. / Lagace, L. / Moreau, B. / Thibeault, D. / White, P.W. / Llinas-Brunet, M.
History
DepositionNov 23, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 2, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 9, 2013Group: Database references
Revision 1.2Mar 13, 2013Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Genome polyprotein
B: Genome polyprotein
C: HCV non-structural protein 4A
D: HCV non-structural protein 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,9028
Polymers43,2204
Non-polymers1,6824
Water1,964109
1
A: Genome polyprotein
C: HCV non-structural protein 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,4514
Polymers21,6102
Non-polymers8412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2520 Å2
ΔGint-21 kcal/mol
Surface area8980 Å2
MethodPISA
2
B: Genome polyprotein
D: HCV non-structural protein 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,4514
Polymers21,6102
Non-polymers8412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2500 Å2
ΔGint-21 kcal/mol
Surface area8990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.243, 94.243, 82.075
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

#1: Protein Genome polyprotein / Core protein p21 / Capsid protein C / p21 / Core protein p19 / Envelope glycoprotein E1 / gp32 / ...Core protein p21 / Capsid protein C / p21 / Core protein p19 / Envelope glycoprotein E1 / gp32 / gp35 / Envelope glycoprotein E2 / NS1 / gp68 / gp70 / p7 / Protease NS2-3 / p23 / Serine protease NS3 / Hepacivirin / NS3P / p70 / Non-structural protein 4A / NS4A / p8 / Non-structural protein 4B / NS4B / p27 / Non-structural protein 5A / NS5A / p56 / RNA-directed RNA polymerase / NS5B / p68


Mass: 19794.834 Da / Num. of mol.: 2 / Fragment: NS3 protease domain (UNP Residues 1027-1206)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Strain: Isolate Japanese / Gene: POLG_HCVJA / Production host: Escherichia coli (E. coli)
References: UniProt: P26662, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases, hepacivirin, nucleoside-triphosphate phosphatase, RNA helicase, RNA-directed RNA polymerase
#2: Protein/peptide HCV non-structural protein 4A


Mass: 1815.277 Da / Num. of mol.: 2 / Fragment: NS3 interacting peptide (UNP Residues 1678-1691) / Source method: obtained synthetically / Details: Chemically synthesized / Source: (synth.) Hepatitis C virus / References: UniProt: P26662
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-1BV / (2R,6S,7E,10E,13aR,14aR,16aS)-2-{[7-methoxy-8-methyl-2-(propan-2-yloxy)quinolin-4-yl]oxy}-N-[(1-methylcyclopropyl)sulfonyl]-6-{[(1-methyl-1H-pyrazol-3-yl)carbonyl]amino}-5,16-dioxo-1,2,3,6,9,12,13,13a,14,15,16,16a-dodecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide


Mass: 817.950 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C41H51N7O9S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 109 / 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: 2.43 Å3/Da / Density % sol: 49.48 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 3M NaCl, 0.1M Na Citrate pH6, 2.5% t-butanol, 20mM OBG, 5mM DTT, 3mM sodium azide, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RAYONIX SX-165mm / Detector: CCD / Details: VariMax-HF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.93→57.9 Å / Num. all: 31178 / Num. obs: 31114 / % possible obs: 99.8 % / Redundancy: 4.56 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 14.6
Reflection shellResolution: 1.93→2 Å / Redundancy: 3.86 % / Rmerge(I) obs: 0.317 / Mean I/σ(I) obs: 3.9 / Num. unique all: 3068 / % possible all: 99.8

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
PHENIXmodel building
PHENIX(phenix.refine: 1.7_650)refinement
d*TREKdata reduction
d*TREKdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9301→36.541 Å / SU ML: 0.34 / σ(F): 0 / Phase error: 25.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.247 1557 5.06 %
Rwork0.2159 --
obs0.2175 30772 98.69 %
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 55.828 Å2 / ksol: 0.411 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--2.5977 Å2-0 Å20 Å2
2---2.5977 Å20 Å2
3---5.1953 Å2
Refinement stepCycle: LAST / Resolution: 1.9301→36.541 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2834 0 118 109 3061
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083030
X-RAY DIFFRACTIONf_angle_d1.3744145
X-RAY DIFFRACTIONf_dihedral_angle_d15.1751095
X-RAY DIFFRACTIONf_chiral_restr0.087483
X-RAY DIFFRACTIONf_plane_restr0.006522
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9301-1.99240.43391370.37252540X-RAY DIFFRACTION95
1.9924-2.06360.32241450.32872586X-RAY DIFFRACTION97
2.0636-2.14620.31571520.29132614X-RAY DIFFRACTION98
2.1462-2.24390.28991340.25822661X-RAY DIFFRACTION99
2.2439-2.36220.27611320.24012669X-RAY DIFFRACTION99
2.3622-2.51010.29361330.24612655X-RAY DIFFRACTION99
2.5101-2.70390.2851400.23952686X-RAY DIFFRACTION100
2.7039-2.97590.22731490.2192681X-RAY DIFFRACTION100
2.9759-3.40620.2711620.20252683X-RAY DIFFRACTION100
3.4062-4.29040.2291390.19162713X-RAY DIFFRACTION100
4.2904-36.54740.20281340.19792727X-RAY DIFFRACTION99

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