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- PDB-5vp9: Crystal structure of HCV NS3/4A protease in complex with AM-07, a... -

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Basic information

Entry
Database: PDB / ID: 5vp9
TitleCrystal structure of HCV NS3/4A protease in complex with AM-07, an analogue of 5172-mcP1P3
ComponentsNS4A cofactor -- NS3 protein chimera
KeywordsHYDROLASE/HYDROLASE INHIBITOR / NS3/4a Protease / Hepatitis C virus / Drug Resistance / protease inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
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 / ribonucleoside triphosphate phosphatase 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 / ribonucleoside triphosphate phosphatase 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
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 / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Trypsin-like serine proteases / 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-9H7 / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus subtype 1a
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.859 Å
AuthorsMatthew, A.N. / Schiffer, C.A.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants.
Authors: Matthew, A.N. / Zephyr, J. / Hill, C.J. / Jahangir, M. / Newton, A. / Petropoulos, C.J. / Huang, W. / Kurt-Yilmaz, N. / Schiffer, C.A. / Ali, A.
History
DepositionMay 4, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 21, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: NS4A cofactor -- NS3 protein chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,4444
Polymers21,5031
Non-polymers9403
Water2,828157
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area120 Å2
ΔGint-8 kcal/mol
Surface area9930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.792, 58.355, 60.421
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein NS4A cofactor -- NS3 protein chimera


Mass: 21503.330 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus subtype 1a / Plasmid: pET-28a / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) magic / References: UniProt: A8DG50, UniProt: P26664*PLUS
#2: Chemical ChemComp-9H7 / tert-butyl [(2R,6S,12Z,13aS,14aR,16aS)-14a-[(cyclopropylsulfonyl)carbamoyl]-5,16-dioxo-2-{[3-(thiophen-2-yl)quinoxalin-2-yl]oxy}-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: 778.937 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H46N6O8S2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 157 / 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: 2.3 Å3/Da / Density % sol: 46.42 %
Crystal growTemperature: 288 K / Method: vapor diffusion, hanging drop
Details: 100 mM MES BUFFER pH 6.5, 4% (W/V) AMMONIUM SULFATE, 20-26% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Mar 12, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.859→50 Å / Num. obs: 16852 / % possible obs: 99.9 % / Redundancy: 6.6 % / Rsym value: 0.06 / Net I/σ(I): 15.7

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5EPN

5epn


Resolution: 1.859→20.987 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 20.35
RfactorNum. reflection% reflection
Rfree0.2081 844 5.03 %
Rwork0.1679 --
obs0.1699 16794 99.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.859→20.987 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1458 0 60 157 1675
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0051553
X-RAY DIFFRACTIONf_angle_d0.8852118
X-RAY DIFFRACTIONf_dihedral_angle_d12.726918
X-RAY DIFFRACTIONf_chiral_restr0.054243
X-RAY DIFFRACTIONf_plane_restr0.005269
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8592-1.97560.24751420.19522569X-RAY DIFFRACTION99
1.9756-2.1280.19531390.16092616X-RAY DIFFRACTION100
2.128-2.34180.18171370.15492651X-RAY DIFFRACTION100
2.3418-2.68010.2061320.16682644X-RAY DIFFRACTION100
2.6801-3.37440.20771450.17472676X-RAY DIFFRACTION100
3.3744-20.98860.21421490.16542794X-RAY DIFFRACTION100

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