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- PDB-7mm2: Crystal structure of HCV NS3/4A protease in complex with NR02-61 -

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Basic information

Entry
Database: PDB / ID: 7mm2
TitleCrystal structure of HCV NS3/4A protease in complex with NR02-61
ComponentsNS3/4a protease
KeywordsHYDROLASE/INHIBITOR / NS3/4a Protease / Hepatitis C virus / Drug Resistance / Protease inhibitor / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


transformation of host cell by virus / host cell membrane / serine-type peptidase activity / virion component / symbiont entry into host cell / virion attachment to host cell / proteolysis / membrane / metal ion binding
Similarity search - Function
Hepatitis C virus, NS3 protease, Peptidase S29 / Hepatitis C virus NS3 protease / Hepacivirus/Pegivirus NS3 protease domain profile. / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-OMS / NS3 protease
Similarity search - Component
Biological speciesHepacivirus C
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.891 Å
AuthorsZephyr, J. / 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 GM131635 United States
CitationJournal: J.Mol.Biol. / Year: 2022
Title: Deciphering the Molecular Mechanism of HCV Protease Inhibitor Fluorination as a General Approach to Avoid Drug Resistance.
Authors: Zephyr, J. / Nageswara Rao, D. / Vo, S.V. / Henes, M. / Kosovrasti, K. / Matthew, A.N. / Hedger, A.K. / Timm, J. / Chan, E.T. / Ali, A. / Kurt Yilmaz, N. / Schiffer, C.A.
History
DepositionApr 29, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 30, 2022Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: NS3/4a protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,62511
Polymers21,2621
Non-polymers1,36310
Water2,918162
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1240 Å2
ΔGint9 kcal/mol
Surface area9530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.478, 58.718, 59.509
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein NS3/4a protease


Mass: 21262.084 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepacivirus C / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: A0A0B4WYC6

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Non-polymers , 5 types, 172 molecules

#2: Chemical ChemComp-OMS / 1-methylcyclobutyl [(2R,6S,12Z,13aS,14aR,16aS)-2-[(7-methoxy-3-methylquinoxalin-2-yl)oxy]-14a-{[(1-methylcyclopropyl)sulfonyl]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 / P4-2 (NR02-61)


Mass: 766.903 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H50N6O9S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 162 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.24 Å3/Da / Density % sol: 45.05 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 100 mM MES, pH 6.5, 4% w/v ammonium sulfate, 20-26% PEG3350, cryoprotectant = same + 15% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Jul 17, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.891→20.09 Å / Num. obs: 15792 / % possible obs: 99.78 % / Redundancy: 5.7 % / Biso Wilson estimate: 15.86 Å2 / CC1/2: 0.998 / Net I/σ(I): 12.86
Reflection shellResolution: 1.891→1.958 Å / Num. unique obs: 1550 / CC1/2: 0.891

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PHASERphasing
HKL-3000703xdata scaling
Coot0.8.8model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5VOJ

5voj


Resolution: 1.891→20.09 Å / SU ML: 0.1613 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 18.1167
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2006 783 4.96 %
Rwork0.16 15008 -
obs0.162 15791 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 18.84 Å2
Refinement stepCycle: LAST / Resolution: 1.891→20.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1428 0 88 162 1678
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00541544
X-RAY DIFFRACTIONf_angle_d1.06132100
X-RAY DIFFRACTIONf_chiral_restr0.0507243
X-RAY DIFFRACTIONf_plane_restr0.0065265
X-RAY DIFFRACTIONf_dihedral_angle_d16.386237
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.89-2.010.21461270.18042435X-RAY DIFFRACTION99.3
2.01-2.160.2021290.1572466X-RAY DIFFRACTION100
2.16-2.380.21731290.15712486X-RAY DIFFRACTION100
2.38-2.730.22161340.15772468X-RAY DIFFRACTION100
2.73-3.430.18561300.15292523X-RAY DIFFRACTION100
3.43-22.820.19191340.16242630X-RAY DIFFRACTION99.96

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