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- PDB-4wf8: Crystal structure of NS3/4A protease in complex with Asunaprevir -

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Basic information

Entry
Database: PDB / ID: 4wf8
TitleCrystal structure of NS3/4A protease in complex with Asunaprevir
ComponentsNS3 protein
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HCV protease inhibitor complex / Resistance / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


virion component => GO:0044423 / transformation of host cell by virus / serine-type peptidase activity / ATP binding / metal ion binding
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, chymotrypsin-like fold / Peptidase S1, PA clan / 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
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 Å
AuthorsSchiffer, C.A. / Soumana, D.I. / Ali, A.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)F31-GM103259 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)RO1-AI085051 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 13, 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
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: NS3 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,1054
Polymers20,2561
Non-polymers8493
Water4,378243
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.350, 60.893, 80.875
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 NS3 protein


Mass: 20255.904 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) / References: UniProt: X2G809
#2: Chemical ChemComp-ZN / ZINC ION


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


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#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 / Asunaprevir


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


Mass: 18.015 Da / Num. of mol.: 243 / 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: 2.39 Å3/Da / Density % sol: 48.57 % / Mosaicity: 0.44 °
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20 to 26% PEG-3350, 0.1 M sodium MES buffer at pH 6.5, and 4% ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97857 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Apr 9, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 1.66→50 Å / Num. obs: 22158 / % possible obs: 92.7 % / Redundancy: 7.7 % / Rmerge(I) obs: 0.068 / Χ2: 1.062 / Net I/av σ(I): 24.783 / Net I/σ(I): 11.6 / Num. measured all: 170394
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.6-1.77.80.31522711.03896.8
1.72-1.797.90.22322631.08897
1.79-1.877.90.17122861.14797.7
1.87-1.976.70.1741735173.2
1.97-2.0980.10523121.04598.1
2.09-2.257.70.08820861.10288.2
2.25-2.487.80.07621021.01488.3
2.48-2.848.10.06823661.09198.8
2.84-3.587.80.05524031.01798.9
3.58-506.90.04123341.04990.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1.65 Å30.59 Å
Translation1.65 Å30.59 Å

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Processing

Software
NameVersionClassification
HKL-2000data reduction
PHENIX(phenix.refine: 1.8.2_1309)refinement
PDB_EXTRACT3.15data extraction
HKL-2000data scaling
PHASERphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→30.594 Å / FOM work R set: 0.8538 / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2179 1123 5.1 %
Rwork0.1924 20882 -
obs0.1937 22005 91.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 85.14 Å2 / Biso mean: 18.52 Å2 / Biso min: 4.36 Å2
Refinement stepCycle: final / Resolution: 1.7→30.594 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1358 0 99 243 1700
Biso mean--20.14 31.52 -
Num. residues----192
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.081454
X-RAY DIFFRACTIONf_angle_d1.6922006
X-RAY DIFFRACTIONf_chiral_restr0.119241
X-RAY DIFFRACTIONf_plane_restr0.008252
X-RAY DIFFRACTIONf_dihedral_angle_d20.643537
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6531-1.72830.25481330.21372620275393
1.7283-1.81940.23481490.19692689283897
1.8194-1.93340.28561200.25052113223376
1.9334-2.08270.2271510.1892750290197
2.0827-2.29220.21981230.19292278240181
2.2922-2.62370.2241520.18452800295299
2.6237-3.3050.24771610.19132836299799
3.305-30.59910.16911340.18122796293093
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)
10.2397-0.03660.14130.1861-0.22370.3047-0.0497-0.0446-0.1007-0.05120.0675-0.05330.0789-0.06730.00040.1225-0.0241-0.00520.076-0.00140.082542.4296-2.77221.9112
20.24330.07280.08420.7638-0.42460.29540.1391-0.123-0.02980.1949-0.1314-0.08290.0147-0.0938-0.00030.18190.02-0.0390.14860.00570.158348.37020.789530.6341
30.45550.26160.1480.6523-0.23350.6076-0.0476-0.05540.03210.1135-0.0072-0.0787-0.0150.0476-0.08230.05390.0057-0.00680.0643-0.00950.067147.92358.131521.8447
40.4106-0.1301-0.22521.00660.15711.0987-0.02260.10690.0397-0.1168-0.0002-0.1170.11590.0667-0.05260.0955-0.00160.00160.0701-0.00340.075446.43295.904210.2584
50.5608-0.17590.26530.46420.27120.42640.01150.1245-0.0163-0.17740.06390.1165-0.0279-0.14560.0030.1108-0.0313-0.01320.13920.01670.118530.6446.05839.9752
60.35870.04160.36160.9189-0.00071.2268-0.0620.06810.069-0.17710.10920.0022-0.00310.03160.03230.0759-0.01670.00340.077-0.01150.085539.37089.22198.8069
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 989 through 1009 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 1010 through 1032 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 1033 through 1074 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 1075 through 1107 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 1108 through 1135 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 1136 through 1180 )A0

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