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- PDB-7mmg: Crystal structure of HCV NS3/4A D168A protease in complex with NR02-58 -

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Basic information

Entry
Database: PDB / ID: 7mmg
TitleCrystal structure of HCV NS3/4A D168A protease in complex with NR02-58
ComponentsNS3/4A protease
KeywordsHYDROLASE/INHIBITOR / NS3/4a Protease / Hepatitis C virus / Drug Resistance / Protease inhibitor / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / 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 / lipid droplet ...host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / 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 / lipid droplet / protein complex oligomerization / monoatomic ion channel activity / viral nucleocapsid / clathrin-dependent endocytosis of virus by host cell / RNA helicase activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / ribonucleoprotein complex / induction by virus of host autophagy / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / RNA binding / zinc ion binding / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
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 non-structural protein NS4b ...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 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 / 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
ARGININE / Chem-ZK7 / Genome polyprotein
Similarity search - Component
Biological speciesHepacivirus C
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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

Downloads & links

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Assembly

Deposited unit
A: NS3/4A protease
B: NS3/4A protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,3847
Polymers42,4362
Non-polymers1,9485
Water1,964109
1
A: NS3/4A protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2804
Polymers21,2181
Non-polymers1,0613
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: NS3/4A protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1043
Polymers21,2181
Non-polymers8862
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.854, 50.987, 77.068
Angle α, β, γ (deg.)90.000, 92.836, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein NS3/4A protease


Mass: 21218.074 Da / Num. of mol.: 2 / Mutation: D168A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepacivirus C / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: A8DG50, hepacivirin
#2: Chemical ChemComp-ARG / ARGININE / Arginine


Type: L-peptide linking / Mass: 175.209 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H15N4O2
#3: Chemical ChemComp-ZK7 / 1-(trifluoromethyl)cyclobutyl {(2R,4S,6S,12Z,13aS,14aR,16aS)-2-[(7-methoxy-3-methylquinoxalin-2-yl)oxy]-14a-[(1-methylcyclopropane-1-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


Mass: 820.875 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C38H47F3N6O9S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 109 / Source method: isolated from a natural source / Formula: H2O
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: 1.84 Å3/Da / Density % sol: 33.26 %
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: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 0.918 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 20, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918 Å / Relative weight: 1
ReflectionResolution: 1.95→42.51 Å / Num. obs: 22738 / % possible obs: 99.95 % / Redundancy: 6.4 % / Biso Wilson estimate: 14.59 Å2 / CC1/2: 0.986 / Net I/σ(I): 7.6
Reflection shellResolution: 1.95→2.02 Å / Num. unique obs: 2275 / CC1/2: 0.936

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
PHASERphasing
HKL-3000703xdata scaling
Coot0.8.8model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5VOJ

5voj


Resolution: 1.95→42.51 Å / SU ML: 0.2115 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.9377
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2484 1141 5.02 %
Rwork0.199 21594 -
obs0.2015 22735 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.55 Å2
Refinement stepCycle: LAST / Resolution: 1.95→42.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2589 0 121 109 2819
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01252796
X-RAY DIFFRACTIONf_angle_d1.39523856
X-RAY DIFFRACTIONf_chiral_restr0.0689465
X-RAY DIFFRACTIONf_plane_restr0.0109490
X-RAY DIFFRACTIONf_dihedral_angle_d9.3502436
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-2.040.27411450.19472689X-RAY DIFFRACTION99.89
2.04-2.150.25231450.19352682X-RAY DIFFRACTION99.86
2.15-2.280.2281310.19182663X-RAY DIFFRACTION100
2.28-2.460.26611460.19472692X-RAY DIFFRACTION100
2.46-2.70.26821450.20932693X-RAY DIFFRACTION100
2.7-3.10.25071370.20532702X-RAY DIFFRACTION99.96
3.1-3.90.22921470.19452694X-RAY DIFFRACTION100
3.9-42.510.24691450.20192779X-RAY DIFFRACTION99.97
Refinement TLS params.Method: refined / Origin x: 8.98492294309 Å / Origin y: 7.5828190431 Å / Origin z: 13.0787572388 Å
111213212223313233
T0.0682247692786 Å20.0137948078515 Å20.00109869036258 Å2-0.0770182505957 Å2-0.00200755759846 Å2--0.27524887605 Å2
L0.107348151864 °20.0126577992723 °20.282890305722 °2-0.0408364792825 °2-0.0613597968771 °2--2.27874693019 °2
S0.0147264877621 Å °0.0223525403669 Å °0.0102023732259 Å °-0.000973327095304 Å °-0.013178952102 Å °-0.0102042480298 Å °0.0392934353815 Å °0.0727557669193 Å °-0.000800902420886 Å °
Refinement TLS groupSelection details: all

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