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- PDB-5epy: Crystal structure of HCV NS3/4A protease A156T variant in complex... -

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Basic information

Entry
Database: PDB / ID: 5epy
TitleCrystal structure of HCV NS3/4A protease A156T variant in complex with 5172-mcP1P3 (MK-5172 P1-P3 macrocyclic analogue)
ComponentsNS3 protease
KeywordsHYDROLASE / grazoprevir analogue / macrocycle / drug resistance / HCV protease inhibitor / MK-5172
Function / homology
Function and homology information


symbiont-mediated transformation of host cell / host cell membrane / serine-type peptidase activity / host cell / symbiont entry into host cell / virion attachment to host cell / virion membrane / proteolysis / metal ion binding / membrane
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 / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-5R2 / NS3 protease
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsSoumana, D.I. / 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 12, 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 1.4Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)21,9484
Polymers21,0321
Non-polymers9163
Water1,40578
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.994, 58.440, 60.089
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: 21031.838 Da / Num. of mol.: 1 / Mutation: A156T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Plasmid: pET28-a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-DE3 / References: UniProt: C1KIK8
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-5R2 / 2-Methyl-2-propanyl {(2R,6S,12Z,13aS,14aR,16aS)-14a-[(cyclopropylsulfonyl)carbamoyl]-2-[(3-ethyl-7-methoxy-2-quinoxalinyl)oxy]-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclop ropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl}carbamate / MK-5172 P1-P3 macrocyclic analogue


Mass: 754.893 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H50N6O9S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 78 / 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: 2.3 Å3/Da / Density % sol: 46.42 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 100mM MES buffer pH 6.5, 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-G / Wavelength: 0.97857 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 14, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.3→35 Å / Num. obs: 9070 / % possible obs: 100 % / Redundancy: 4.4 % / Rmerge(I) obs: 0.068 / Χ2: 1.075 / Net I/av σ(I): 22.401 / Net I/σ(I): 9.1 / Num. measured all: 39511
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.3-2.384.40.28801.041100
2.38-2.484.40.188761.069100
2.48-2.594.40.1639001.056100
2.59-2.734.40.1388861.035100
2.73-2.94.40.1068941.085100
2.9-3.124.40.0848971.098100
3.12-3.434.40.0629011.084100
3.43-3.934.40.0499161.09299.9
3.93-4.954.30.0399261.091100
4.95-3540.0439941.099100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3m5m

3m5m


Resolution: 2.3→35 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflectionSelection details
Rfree0.2167 431 4.7 %Random
Rwork0.1735 ---
obs0.1756 9034 100 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 71.59 Å2 / Biso mean: 20.3824 Å2 / Biso min: 7.63 Å2
Refinement stepCycle: LAST / Resolution: 2.3→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1395 0 59 78 1532

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