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- PDB-6p6v: HCV NS3/4A protease domain of genotype 5a in complex with glecaprevir -

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Basic information

Entry
Database: PDB / ID: 6p6v
TitleHCV NS3/4A protease domain of genotype 5a in complex with glecaprevir
ComponentsNon-structural protein 4A,Serine protease NS3
KeywordsVIRAL PROTEIN / Hydrolase / HCV NS3/4A protease HCV protease domain Glecaprevir / GLE 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 ...: / 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 / 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 / apoptotic process / 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
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 / 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 / Helicase superfamily 1/2, ATP-binding domain / 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-O31 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus genotype 5a
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 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
Revision 1.2Jan 29, 2025Group: Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_entity_nonpoly / pdbx_entry_details
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3725
Polymers21,3701
Non-polymers1,0024
Water4,053225
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.551, 60.147, 83.788
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 21370.412 Da / Num. of mol.: 1 / Mutation: V1040E, L1041E, I1044Q, I1045E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus genotype 5a (isolate SA13)
Strain: isolate SA13 / Production host: Escherichia coli (E. coli)
References: UniProt: O91936, hepacivirin, nucleoside-triphosphate phosphatase, RNA helicase

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Non-polymers , 5 types, 229 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-O31 / Glecaprevir / (3aR,7S,10S,12R,21E,24aR)-7-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-20,20-difluoro-5,8-dioxo-2,3,3a,5,6,7,8,11,12,20,23,24a-dodecahydro-1H,10H-9,12-methanocyclopenta[18,19][1,10,17,3,6]trioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide


Mass: 838.865 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H46F4N6O9S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 225 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationN

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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: 2.33 Å3/Da / Density % sol: 47.25 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.2 M TMAO 0.1 M Tris pH 8.5 16% PEG 2000 MME 3 mM glecaprevir

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Jul 3, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→22.814 Å / Num. obs: 13535 / % possible obs: 96.05 % / Redundancy: 7.2 % / Rmerge(I) obs: 0.045 / Net I/σ(I): 44.17
Reflection shellResolution: 2→2.072 Å / Rmerge(I) obs: 0.14 / Num. unique obs: 1289

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Processing

Software
NameVersionClassification
PHENIX(1.14_3211: ???)refinement
HKL-3000data reduction
Aimlessdata scaling
MrBUMPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5voj

5voj


Resolution: 2→22.814 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.2
RfactorNum. reflection% reflection
Rfree0.2131 677 5.01 %
Rwork0.1654 --
obs0.1678 13515 96.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2→22.814 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1414 0 64 225 1703
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061584
X-RAY DIFFRACTIONf_angle_d0.7992184
X-RAY DIFFRACTIONf_dihedral_angle_d12.606930
X-RAY DIFFRACTIONf_chiral_restr0.051249
X-RAY DIFFRACTIONf_plane_restr0.005284
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.1540.21791280.17452435X-RAY DIFFRACTION94
2.154-2.37060.19851320.17512502X-RAY DIFFRACTION95
2.3706-2.71310.24451340.18392540X-RAY DIFFRACTION96
2.7131-3.41640.22381370.16752606X-RAY DIFFRACTION97
3.4164-22.81590.19521460.15192755X-RAY DIFFRACTION98

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