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

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Basic information

Entry
Database: PDB / ID: 5etx
TitleCrystal structure of HCV NS3/4A protease A156T variant 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


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-5RS / NS3 protease
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.35 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-Corrido085P1000817 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.
#2: Journal: PLoS Pathog. / Year: 2012
Title: The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors.
Authors: Romano, K.P. / Ali, A. / Aydin, C. / Soumana, D. / Ozen, A. / Deveau, L.M. / Silver, C. / Cao, H. / Newton, A. / Petropoulos, C.J. / Huang, W. / Schiffer, C.A.
History
DepositionNov 18, 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: Advisory / Author supporting evidence / Derived calculations
Category: pdbx_audit_support / pdbx_struct_oper_list / pdbx_unobs_or_zero_occ_atoms
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: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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
B: NS3 protease
C: NS3 protease
D: NS3 protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,86213
Polymers82,5854
Non-polymers3,2779
Water3,621201
1
A: NS3 protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,4573
Polymers20,6461
Non-polymers8102
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: NS3 protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,4924
Polymers20,6461
Non-polymers8463
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: NS3 protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,4573
Polymers20,6461
Non-polymers8102
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: NS3 protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,4573
Polymers20,6461
Non-polymers8102
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.441, 63.232, 92.304
Angle α, β, γ (deg.)90.000, 91.650, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A and segid
21chain B and segid
31chain C and segid
41chain D and segid

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111chain A and segidA0
211chain B and segidB0
311chain C and segidC0
411chain D and segidD0

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Components

#1: Protein
NS3 protease


Mass: 20646.334 Da / Num. of mol.: 4 / Mutation: A156T, S139C
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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#3: 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.: 4 / Source method: obtained synthetically / Formula: C36H52N6O9S
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 201 / 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: 2.33 Å3/Da / Density % sol: 47.13 %
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-F / Wavelength: 0.97857 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 18, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
Reflection twinOperator: -k,-h,-l / Fraction: 0.08
ReflectionResolution: 2.35→30 Å / Num. obs: 31801 / % possible obs: 99.1 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.072 / Χ2: 1.389 / Net I/av σ(I): 17.763 / Net I/σ(I): 18.4 / Num. measured all: 129154
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.35-2.4340.11831711.44599.8
2.43-2.534.10.10331631.4599.8
2.53-2.654.10.09731781.44599.9
2.65-2.794.10.08631641.45499.7
2.79-2.964.20.07932031.42399.6
2.96-3.194.20.07231781.34899.2
3.19-3.514.10.06831791.34799.3
3.51-4.0240.06631641.2998.6
4.02-5.063.80.06431441.2796.9
5.06-304.10.0732571.39898.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation7.37 Å27.66 Å
Translation7.37 Å27.66 Å

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHASER2.5.1phasing
PHENIXrefinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3M5M

3m5m


Resolution: 2.35→27.528 Å / FOM work R set: 0.8071 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflectionSelection details
Rfree0.254 2167 6.82 %random
Rwork0.2004 30116 --
obs0.2047 31763 98.3 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 127.28 Å2 / Biso mean: 24.78 Å2 / Biso min: 3.84 Å2
Refinement stepCycle: final / Resolution: 2.35→27.528 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5428 0 213 201 5842
Biso mean--20.36 24.14 -
Num. residues----760
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0155836
X-RAY DIFFRACTIONf_angle_d1.6758030
X-RAY DIFFRACTIONf_chiral_restr0.084957
X-RAY DIFFRACTIONf_plane_restr0.0081009
X-RAY DIFFRACTIONf_dihedral_angle_d22.422198
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A3208X-RAY DIFFRACTION10.993TORSIONAL
12B3208X-RAY DIFFRACTION10.993TORSIONAL
13C3208X-RAY DIFFRACTION10.993TORSIONAL
14D3208X-RAY DIFFRACTION10.993TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Highest resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.35-2.40370.34581550.2883228588
2.4037-2.48120.321320.272252495
2.4812-2.56970.3441230.2755253795
2.5697-2.67240.28291300.2579255595
2.6724-2.79380.31711380.2477251894
2.7938-2.94070.24881600.2251248894
2.9407-3.12440.26281220.2161254795
3.1244-3.36480.2271330.1885251994
3.3648-3.70190.23361330.1698251694
3.7019-4.23390.19811300.1539251393
4.2339-5.32070.2321130.146252493
5.32070.2611480.1997259094

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