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- PDB-4wh6: Crystal structure of HCV NS3/4A protease variant R155K in complex... -

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Basic information

Entry
Database: PDB / ID: 4wh6
TitleCrystal structure of HCV NS3/4A protease variant R155K in complex with Asunaprevir
ComponentsGenome polyprotein
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HCV Drug resistant / protease-inhibitor complex / Asunaprevir / HYDROLASE-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 / protein complex oligomerization ...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 endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / 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 / serine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / structural molecule activity / virion membrane / proteolysis / RNA binding / zinc ion binding / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
Thrombin, subunit H - #120 / : / 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 ...Thrombin, subunit H - #120 / : / 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 / 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-2R9 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus subtype 1a
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.99 Å
AuthorsSoumana, D.I. / Ali, A. / Schiffer, C.A.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)RO1-AI085051 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)F31-GM103259 United States
CitationJournal: Acs Chem.Biol. / Year: 2014
Title: Structural Analysis of Asunaprevir Resistance in HCV NS3/4A Protease.
Authors: Soumana, D.I. / Ali, A. / Schiffer, C.A.
History
DepositionSep 20, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 8, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 3, 2014Group: Database references
Revision 1.2Sep 9, 2015Group: Data collection
Revision 1.3Nov 25, 2015Group: Non-polymer description
Revision 1.4Sep 6, 2017Group: Author supporting evidence / Derived calculations / Refinement description
Category: pdbx_audit_support / pdbx_struct_oper_list / software
Item: _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation / _software.name
Revision 1.5Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.6Dec 27, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2405
Polymers21,2341
Non-polymers1,0064
Water2,864159
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)54.924, 58.415, 60.090
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Genome polyprotein


Mass: 21234.068 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus subtype 1a / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / References: UniProt: A8DG50
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-2R9 / N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-L-prolinamide / Asunaprevir


Mass: 748.286 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H46ClN5O9S / Comment: inhibitor*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 159 / 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: 2.27 Å3/Da / Density % sol: 45.81 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20 to 26% PEG-3350, 0.1 M sodium MES buffer, and 4% ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Aug 11, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5 Å / Relative weight: 1
ReflectionResolution: 1.9→40.5 Å / Num. all: 61851 / Num. obs: 61851 / % possible obs: 91.2 % / Redundancy: 4.9 % / Rsym value: 0.1 / Net I/σ(I): 9.2

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 35.2 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å20.27 Å
Translation2.5 Å20.27 Å

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Processing

Software
NameVersionClassification
HKL-2000data reduction
REFMAC5.6.0117refinement
PDB_EXTRACT3.15data extraction
HKL-2000data scaling
PHASERphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.99→40 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.923 / SU B: 6.784 / SU ML: 0.112 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.198 / ESU R Free: 0.171 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2196 638 5.1 %RANDOM
Rwork0.1686 11958 --
obs0.1711 61851 91.42 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 48.26 Å2 / Biso mean: 10.243 Å2 / Biso min: 6.1 Å2
Baniso -1Baniso -2Baniso -3
1-1.64 Å20 Å20 Å2
2---0.8 Å20 Å2
3----0.84 Å2
Refinement stepCycle: final / Resolution: 1.99→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1433 0 108 159 1700
Biso mean--21.47 28.43 -
Num. residues----200
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.021532
X-RAY DIFFRACTIONr_bond_other_d0.0040.02978
X-RAY DIFFRACTIONr_angle_refined_deg1.5122.0032103
X-RAY DIFFRACTIONr_angle_other_deg1.0313.0052401
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1575203
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.64923.46949
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.47515224
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.878159
X-RAY DIFFRACTIONr_chiral_restr0.1730.2251
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211708
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02292
LS refinement shellResolution: 1.99→2.042 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.27 43 -
Rwork0.198 802 -
all-845 -
obs--92.45 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
120.24220.008-8.316325.289620.266719.66420.37470.02320.1843-0.6509-0.2351-0.0705-0.6891-0.1931-0.13960.1952-0.01210.04860.14380.07440.08718.3469-21.3377-4.0374
23.2765-1.15-1.62284.1893-0.47261.09220.0440.0317-0.0077-0.2332-0.0741-0.1410.03670.00870.03010.07410.01110.00330.1407-0.00980.11165.267-7.442913.5114
33.65241.079-4.5510.8712-1.49137.68840.0595-0.33590.20050.22230.048-0.0639-0.05630.2129-0.10750.1290.0169-0.02250.1317-0.02020.11921.00826.348925.2288
47.0404-2.66851.954817.3052.45911.1805-0.1770.17220.1934-0.97130.08130.0541-0.23670.04210.09570.2194-0.02740.09790.1518-0.01230.09299.6407-3.77928.676
57.7598-3.2307-8.93126.0867.437313.20020.2213-0.69430.1121-0.3928-0.0352-0.0953-0.51530.556-0.18610.1329-0.0071-0.01740.0973-0.00840.216313.0041-4.41618.3452
65.5017-3.46411.35744.06681.10764.3530.0367-0.23080.2280.37770.1182-0.1961-0.25540.1928-0.15490.3273-0.08370.03720.1133-0.01350.1072.8482-1.597924.8008
712.33452.20993.45570.40190.7727.0109-0.10110.5367-0.093-0.03770.0727-0.03490.36180.11270.02840.22280.08570.04760.11580.01560.1246-0.4035-6.23769.666
81.72790.30690.4750.50510.59470.94920.0285-0.0310.03090.03680.0113-0.01690.09330.0062-0.03980.07680.00370.00810.06560.00880.0862-2.1958-10.72620.8983
914.11876.92083.316910.58741.85510.78670.21890.00450.199-0.0477-0.26410.0770.0493-0.0060.04520.0854-0.00670.02240.11430.01090.06265.8011-13.733514.4011
101.39522.8289-1.26315.8019-2.34762.4204-0.0889-0.0993-0.2785-0.2039-0.126-0.56070.02240.1290.21490.08290.00540.00620.1766-0.00570.15889.6167-15.856718.4728
110.731-0.35940.06151.01130.21631.20450.06090.0189-0.02910.0514-0.0492-0.06880.03840.0849-0.01170.08450.01040.00470.08640.01250.1003-0.3131-15.49422.4747
122.09850.7608-1.51430.7555-0.82371.26140.0173-0.17220.0990.03330.03490.0246-0.03360.0403-0.05220.0889-0.00640.0020.1113-0.03690.0735-9.5253-4.338632.3012
135.56070.9946-1.71250.2003-0.30460.52760.1361-0.01030.5481-0.01010.02510.1366-0.0410.004-0.16120.138-0.02160.00650.12160.01560.1662-13.4142.399126.3409
144.71961.22672.62711.964-2.86229.12410.015-0.0087-0.0515-0.04180.0198-0.01260.0967-0.0006-0.03470.0651-0.01890.01670.0993-0.00150.107-20.0333-10.499330.4483
153.9764-4.26531.99024.8549-3.3546.44370.0420.0803-0.26040.0064-0.02380.2827-0.1122-0.0885-0.01810.10870.00690.02840.17690.04840.1794-21.3282-1.565725.3706
1631.75627.71873.11286.4077-6.011210.4398-0.1933-0.92730.51350.11980.0135-0.005-0.2092-0.41910.17970.19360.1096-0.08730.1791-0.04740.1889-16.63383.179616.6388
171.49880.0923-1.12860.8464-0.92781.72680.1444-0.0163-0.00150.0563-0.03070.1187-0.15650.0503-0.11370.1075-0.00740.010.0965-0.01280.1165-9.319-3.533721.6961
181.526-0.24940.43470.69410.19473.30120.08110.01730.04380.03570.02990.0718-0.0075-0.1501-0.1110.0662-0.02240.0220.06870.0240.0895-15.2685-5.159524.4965
196.8765-5.82823.36912.5088-3.95178.1401-0.0424-0.2383-0.44050.38660.31720.4621-0.1201-0.2307-0.27480.0792-0.01420.0260.06420.01690.0781-12.3239-13.013728.0423
2020.9895-6.3611-8.38866.97161.76483.4734-0.5728-1.1515-1.0210.14920.1007-0.00880.22330.49980.47210.24130.02-0.03060.11310.07480.1334-5.227-19.380130.2639
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A982 - 987
2X-RAY DIFFRACTION2A988 - 997
3X-RAY DIFFRACTION3A998 - 1010
4X-RAY DIFFRACTION4A1011 - 1022
5X-RAY DIFFRACTION5A1023 - 1029
6X-RAY DIFFRACTION6A1030 - 1035
7X-RAY DIFFRACTION7A1036 - 1041
8X-RAY DIFFRACTION8A1042 - 1060
9X-RAY DIFFRACTION9A1061 - 1066
10X-RAY DIFFRACTION10A1067 - 1074
11X-RAY DIFFRACTION11A1075 - 1092
12X-RAY DIFFRACTION12A1093 - 1109
13X-RAY DIFFRACTION13A1110 - 1117
14X-RAY DIFFRACTION14A1118 - 1122
15X-RAY DIFFRACTION15A1123 - 1129
16X-RAY DIFFRACTION16A1130 - 1134
17X-RAY DIFFRACTION17A1135 - 1144
18X-RAY DIFFRACTION18A1145 - 1167
19X-RAY DIFFRACTION19A1168 - 1173
20X-RAY DIFFRACTION20A1174 - 1179

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