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- PDB-6cvw: Crystal structure of HCV NS3/4A WT protease in complex with AJ-52... -

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Basic information

Entry
Database: PDB / ID: 6cvw
TitleCrystal structure of HCV NS3/4A WT protease in complex with AJ-52 (MK-5172 linear analogue)
ComponentsNS3 protease
KeywordsHYDROLASE/HYDROLASE Inhibitor / NS3/4a Protease / Hepatitis C virus / Drug Resistance / protease inhibitor / HYDROLASE-HYDROLASE Inhibitor complex
Function / homology
Function and homology information


symbiont-mediated transformation of host cell / host cell membrane / serine-type peptidase activity / host cell / symbiont entry into host cell / virion attachment to host cell / virion membrane / proteolysis / metal ion binding / membrane
Similarity search - Function
Thrombin, subunit H - #120 / Hepatitis C virus, NS3 protease, Peptidase S29 / Hepatitis C virus NS3 protease / Hepacivirus/Pegivirus NS3 protease domain profile. / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-FH1 / NS3 protease
Similarity search - Component
Biological speciesHepacivirus C
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.78 Å
AuthorsMatthew, A.N. / Schiffer, C.A.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 AI085051 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)F31 GM119345 United States
CitationJournal: ACS Med Chem Lett / Year: 2018
Title: Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants.
Authors: Rusere, L.N. / Matthew, A.N. / Lockbaum, G.J. / Jahangir, M. / Newton, A. / Petropoulos, C.J. / Huang, W. / Kurt Yilmaz, N. / Schiffer, C.A. / Ali, A.
History
DepositionMar 29, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 8, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
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: NS3 protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,5407
Polymers21,3351
Non-polymers1,2056
Water4,612256
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area410 Å2
ΔGint-26 kcal/mol
Surface area10030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.186, 58.516, 59.852
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 NS3 protease


Mass: 21335.201 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepacivirus C / Plasmid: pET-28a / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: A0A0B4WYC6
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-FH1 / N-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-N-[(1R,2S)-2-ethenyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-4-[(7-methoxy-3-methylquinoxalin-2-yl)oxy]-L-prolinamide


Mass: 754.893 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H50N6O9S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 256 / 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: 46.24 %
Crystal growTemperature: 293 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: Aug 1, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.78→26.307 Å / Num. obs: 18870 / % possible obs: 98.3 % / Redundancy: 3.8 % / Net I/σ(I): 18.5
Reflection shellResolution: 1.78→1.874 Å

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Processing

Software
NameVersionClassification
HKL-3000703xdata scaling
PHASERphasing
PHENIX1.12-2829refinement
Coot0.8.8model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5EQQ

5eqq


Resolution: 1.78→26.307 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 17.65
RfactorNum. reflection% reflection
Rfree0.1854 935 4.96 %
Rwork0.1487 --
obs0.1506 18836 98.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.78→26.307 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1450 0 74 256 1780
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0141568
X-RAY DIFFRACTIONf_angle_d1.432147
X-RAY DIFFRACTIONf_dihedral_angle_d17.349914
X-RAY DIFFRACTIONf_chiral_restr0.075246
X-RAY DIFFRACTIONf_plane_restr0.009269
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.78-1.87380.26171280.17092409X-RAY DIFFRACTION95
1.8738-1.99120.19651310.14652493X-RAY DIFFRACTION98
1.9912-2.14490.20121340.14212512X-RAY DIFFRACTION98
2.1449-2.36060.18521280.13662565X-RAY DIFFRACTION99
2.3606-2.70190.20881360.15132588X-RAY DIFFRACTION100
2.7019-3.40290.18231390.1482608X-RAY DIFFRACTION100
3.4029-26.30980.15231390.15122726X-RAY DIFFRACTION99

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