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- PDB-4wh8: Crystal Structure of HCV NS3/4A protease in complex with an Asuna... -

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Basic information

Entry
Database: PDB / ID: 4wh8
TitleCrystal Structure of HCV NS3/4A protease in complex with an Asunaprevir P1-P3 macrocyclic analog.
ComponentsGenome polyprotein
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HCV Drug resistance / protease-inhibitor complex / Asunaprevir / macrocycle / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


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 / ribonucleoside triphosphate phosphatase activity / lipid droplet / : ...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 / ribonucleoside triphosphate phosphatase activity / lipid droplet / : / protein complex oligomerization / monoatomic ion channel activity / clathrin-dependent endocytosis of virus by host cell / viral nucleocapsid / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / induction by virus of host autophagy / 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 / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / RNA binding / zinc ion binding / ATP binding / plasma membrane / cytoplasm
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 / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / Beta Barrel / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Chem-3M7 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus subtype 1a
MethodX-RAY DIFFRACTION / Resolution: 2.703 Å
AuthorsSoumana, D.I. / Ali, A. / Schiffer, C.A.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)RO1-AI085051 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)F31-GM103259 United States
CitationJournal: Acs Chem.Biol. / Year: 2014
Title: Structural Analysis of Asunaprevir Resistance in HCV NS3/4A Protease.
Authors: Soumana, D.I. / Ali, A. / Schiffer, C.A.
History
DepositionSep 20, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 15, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 3, 2014Group: Database references
Revision 2.0Sep 6, 2017Group: Atomic model / Author supporting evidence ...Atomic model / Author supporting evidence / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: atom_site / entity_src_gen ...atom_site / entity_src_gen / pdbx_audit_support / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_oper_list / software / struct_keywords
Item: _atom_site.Cartn_x / _atom_site.Cartn_y ..._atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _struct_keywords.text
Revision 2.1Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 3.0Oct 26, 2022Group: Database references / Derived calculations ...Database references / Derived calculations / Non-polymer description / Refinement description / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / entity / pdbx_entity_nonpoly / refine_hist
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.formula_weight / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Genome polyprotein
B: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8798
Polymers42,0362
Non-polymers1,8446
Water1,08160
1
A: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0365
Polymers21,0181
Non-polymers1,0184
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,8443
Polymers21,0181
Non-polymers8262
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.412, 54.975, 59.859
Angle α, β, γ (deg.)90.000, 90.090, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Genome polyprotein


Mass: 21017.877 Da / Num. of mol.: 2 / Fragment: UNP residues 1030-1205
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus subtype 1a / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / References: UniProt: A8DG50
#2: Chemical ChemComp-3M7 / tert-butyl {(2R,4S,6S,12Z,13aS,14aR,16aS)-2-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-14a-[(cyclopropanesulfonyl)carbamoyl]-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl}carbamate


Mass: 760.297 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C36H46ClN5O9S
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 60 / 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: 2.29 Å3/Da / Density % sol: 46.2 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20 to 26% PEG-3350, 0.1 M sodium MES buffer at pH 6.5, and 4% ammonium sulfate
PH range: 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Aug 1, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.7→40 Å / Num. all: 26199 / Num. obs: 6134 / % possible obs: 90 % / Redundancy: 4.3 % / Rsym value: 0.068 / Net I/σ(I): 10.5

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Processing

Software
NameVersionClassification
HKL-3000data reduction
PDB_EXTRACT3.15data extraction
HKL-3000data scaling
PHENIX(phenix.refine: 1.8.1_1168)refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementResolution: 2.703→24.871 Å / SU ML: 0.36 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 25.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2387 488 4.74 %
Rwork0.1712 --
obs0.1744 6134 97.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 159.45 Å2 / Biso mean: 16.0907 Å2 / Biso min: 0 Å2
Refinement stepCycle: final / Resolution: 2.703→24.871 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2784 0 208 60 3052
Biso mean--21.63 14.29 -
Num. residues----396

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