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- PDB-5eqq: Crystal structure of HCV NS3/4A WT protease in complex with 5172-... -

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Basic information

Entry
Database: PDB / ID: 5eqq
TitleCrystal structure of HCV NS3/4A WT protease in complex with 5172-Linear (MK-5172 linear analogue)
ComponentsNS3 protease
KeywordsHydrolase/Hydrolase Inhibitor / macrocyclization / MK-5172 analogue / grazoprevir / HCV protease inhibitor resistance / Hydrolase-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
Thrombin, subunit H - #120 / Hepatitis C virus, NS3 protease, Peptidase S29 / Hepacivirus/Pegivirus NS3 protease domain profile. / Hepatitis C virus NS3 protease / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-5RS / NS3 protease
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.65 Å
AuthorsSoumana, D. / Yilmaz, N.K. / Ali, A. / Prachanronarong, K.L. / Aydin, C. / 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
Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor085P1000817 United States
Citation
Journal: Acs Chem.Biol. / Year: 2016
Title: Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172.
Authors: Soumana, D.I. / Kurt Yilmaz, N. / Prachanronarong, K.L. / Aydin, C. / Ali, A. / Schiffer, C.A.
#1: Journal: ACS Chem. Biol. / Year: 2013
Title: Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance.
Authors: Ali, A. / Aydin, C. / Gildemeister, R. / Romano, K.P. / Cao, H. / Ozen, A. / Soumana, D. / Newton, A. / Petropoulos, C.J. / Huang, W. / Schiffer, C.A.
History
DepositionNov 13, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2016Group: Database references
Revision 1.2Sep 27, 2017Group: Author supporting evidence / Derived calculations / Category: pdbx_audit_support / pdbx_struct_oper_list
Item: _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 6, 2024Group: 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 protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,9784
Polymers20,0721
Non-polymers9063
Water2,630146
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.713, 58.420, 59.968
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 protease


Mass: 20071.639 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Plasmid: pET28a / Cell line (production host): BL21-DE3 / Production host: Escherichia coli (E. coli) / References: UniProt: C1KIK8
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / 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-5RS / ~{tert}-butyl ~{N}-[(2~{S})-1-[(2~{S},4~{R})-2-[[(1~{R},2~{R})-1-(cyclopropylsulfonylcarbamoyl)-2-ethyl-cyclopropyl]carbamoyl]-4-(3-ethyl-7-methoxy-quinoxalin-2-yl)oxy-pyrrolidin-1-yl]-3,3-dimethyl-1-oxidanylidene-butan-2-yl]carbamate / MK-5172 linear analogue


Mass: 744.898 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H52N6O9S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 146 / 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: 48.48 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 100mM MES buffer, 4% (w/v) ammonium sulfate, 20-26% PEG 3350

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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: Jun 20, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 1.65→50 Å / Num. obs: 23941 / % possible obs: 99.9 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.098 / Χ2: 1.071 / Net I/av σ(I): 16.02 / Net I/σ(I): 9.1 / Num. measured all: 157020
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.65-1.716.60.38823541.07599.9
1.71-1.786.50.32723521.16199.9
1.78-1.866.50.25723511.09199.8
1.86-1.966.30.22323531.25599.9
1.96-2.086.30.17223601.093100
2.08-2.246.40.14723911.025100
2.24-2.466.50.12523801.00999.9
2.46-2.826.70.10824021.071100
2.82-3.556.90.08124390.914100
3.55-506.90.06125591.0499.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å33.24 Å
Translation2.5 Å33.24 Å

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHASER2.3.0phasing
PHENIXrefinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→29.9 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflectionSelection details
Rfree0.1973 1218 5.1 %Random
Rwork0.1629 ---
obs0.1647 23878 99 %-
Solvent computationVDW probe radii: 1.11 Å
Displacement parametersBiso max: 71.2 Å2 / Biso mean: 17.8155 Å2 / Biso min: 0 Å2
Refinement stepCycle: LAST / Resolution: 1.65→29.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1355 0 58 146 1559

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