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- PDB-6p6q: HCV NS3/4A protease domain of genotype 1a3a chimera in complex wi... -

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Basic information

Entry
Database: PDB / ID: 6p6q
TitleHCV NS3/4A protease domain of genotype 1a3a chimera in complex with grazoprevir
ComponentsNon-structural protein 4A,Serine protease NS3
KeywordsVIRAL PROTEIN / Hydrolase / HCV NS3/4A protease HCV protease domain Grazoprevir / GZR Genotype 1a3a chimera
Function / homology
Function and homology information


hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated transformation of host cell / symbiont-mediated suppression of host TRAF-mediated signal transduction / 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 ...hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated transformation of host cell / symbiont-mediated suppression of host TRAF-mediated signal transduction / 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 / channel activity / viral nucleocapsid / monoatomic ion transmembrane transport / 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 / ribonucleoprotein complex / viral translational frameshifting / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / serine-type endopeptidase activity / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
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 / : ...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 / 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 / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-SUE / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus genotype 1a
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsTimm, J. / Schiffer, C.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI085051 United States
CitationJournal: To Be Published
Title: Molecular mechanism of pan-genotypic HCV NS3/4A protease inhibition by glecaprevir and characterization of genotype-specific structural differences
Authors: Timm, J. / Kosovrasti, K. / Henes, M. / Leidner, F. / Hou, S. / Kurt-Yilmaz, N. / Schiffer, C.A.
History
DepositionJun 4, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Non-structural protein 4A,Serine protease NS3
B: Non-structural protein 4A,Serine protease NS3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,64815
Polymers42,9212
Non-polymers2,72813
Water93752
1
A: Non-structural protein 4A,Serine protease NS3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,9718
Polymers21,4601
Non-polymers1,5117
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Non-structural protein 4A,Serine protease NS3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,6777
Polymers21,4601
Non-polymers1,2176
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.750, 58.968, 65.891
Angle α, β, γ (deg.)90.00, 100.27, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Non-structural protein 4A,Serine protease NS3


Mass: 21460.281 Da / Num. of mol.: 2
Mutation: C991S, V9941, V995N, L1013E, L1014E, I1017Q, I1018E, L1021Q, A1040T, C1047S, C1052L, I1072T, Q1080K, P1086Q, N1174S, C1159S, I1132L, D1168Q, R1123T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus genotype 1a (isolate 1)
Strain: isolate 1 / Production host: Escherichia coli (E. coli)
References: UniProt: P26664, hepacivirin, nucleoside-triphosphate phosphatase, RNA helicase

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Non-polymers , 5 types, 65 molecules

#2: Chemical ChemComp-SUE / (1aR,5S,8S,10R,22aR)-5-tert-butyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-14-methoxy-3,6-di oxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadec ino[11,12-b]quinoxaline-8-carboxamide / Grazoprevir, MK-5172


Mass: 766.903 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C38H50N6O9S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 52 / 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: 2.22 Å3/Da / Density % sol: 44.49 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 0.1 M MES pH 6.5 5 % (NH4)2SO4 24 % PEG 3350 3 mM grazoprevir

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 24, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 3.5→48.954 Å / Num. obs: 9272 / % possible obs: 99.86 % / Redundancy: 2 % / Rmerge(I) obs: 0.0819 / Net I/σ(I): 7.18
Reflection shellResolution: 3.5→3.625 Å / Rmerge(I) obs: 0.1376 / Num. unique obs: 475

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Processing

Software
NameVersionClassification
PHENIX(1.14_3260: ???)refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5voj

5voj


Resolution: 3.5→48.954 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 26.67
RfactorNum. reflection% reflection
Rfree0.2583 467 5.04 %
Rwork0.2202 --
obs0.2222 9272 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3.5→48.954 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2723 0 169 52 2944
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022942
X-RAY DIFFRACTIONf_angle_d0.7154050
X-RAY DIFFRACTIONf_dihedral_angle_d16.4231684
X-RAY DIFFRACTIONf_chiral_restr0.047484
X-RAY DIFFRACTIONf_plane_restr0.003500
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.5001-4.00630.27631560.21162944X-RAY DIFFRACTION100
4.0063-5.04680.23631540.19122922X-RAY DIFFRACTION100
5.0468-48.95850.26941570.2642939X-RAY DIFFRACTION100

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