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- PDB-6mvq: HCV NS5B 1b N316 bound to Compound 31 -

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Basic information

Entry
Database: PDB / ID: 6mvq
TitleHCV NS5B 1b N316 bound to Compound 31
ComponentsHCV Polymerase
KeywordsVIRAL PROTEIN / Hepatitus C / NS5B / REPLICATION
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 / : ...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 / clathrin-dependent endocytosis of virus by host cell / viral nucleocapsid / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / induction by virus of host autophagy / ribonucleoprotein complex / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / structural molecule activity / virion attachment to host cell / host cell plasma membrane / virion membrane / proteolysis / RNA binding / zinc ion binding / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
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 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. / Reverse transcriptase/Diguanylate cyclase domain / DEAD box, Flavivirus / Flavivirus DEAD domain / 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 / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Alpha-Beta Plaits / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-K4M / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus subtype 1b
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.14 Å
Model detailsHCV NS5B 1b N316 bound to Compound 31
AuthorsWilliams, S.P. / Kahler, K. / Price, D.J. / Peat, A.J.
Citation
Journal: J.Med.Chem. / Year: 2019
Title: Design of N-Benzoxaborole Benzofuran GSK8175-Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV Inhibitor.
Authors: Chong, P.Y. / Shotwell, J.B. / Miller, J. / Price, D.J. / Maynard, A. / Voitenleitner, C. / Mathis, A. / Williams, S. / Pouliot, J.J. / Creech, K. / Wang, F. / Fang, J. / Zhang, H. / Tai, V. ...Authors: Chong, P.Y. / Shotwell, J.B. / Miller, J. / Price, D.J. / Maynard, A. / Voitenleitner, C. / Mathis, A. / Williams, S. / Pouliot, J.J. / Creech, K. / Wang, F. / Fang, J. / Zhang, H. / Tai, V.W. / Turner, E. / Kahler, K.M. / Crosby, R. / Peat, A.J.
#1: Journal: J. Med. Chem. / Year: 2014
Title: Discovery of a potent boronic acid derived inhibitor of the HCV RNA-dependent RNA polymerase.
Authors: Maynard, A. / Crosby, R.M. / Ellis, B. / Hamatake, R. / Hong, Z. / Johns, B.A. / Kahler, K.M. / Koble, C. / Leivers, A. / Leivers, M.R. / Mathis, A. / Peat, A.J. / Pouliot, J.J. / Roberts, C. ...Authors: Maynard, A. / Crosby, R.M. / Ellis, B. / Hamatake, R. / Hong, Z. / Johns, B.A. / Kahler, K.M. / Koble, C. / Leivers, A. / Leivers, M.R. / Mathis, A. / Peat, A.J. / Pouliot, J.J. / Roberts, C.D. / Samano, V. / Schmidt, R.M. / Smith, G.K. / Spaltenstein, A. / Stewart, E.L. / Thommes, P. / Turner, E.M. / Voitenleitner, C. / Walker, J.T. / Waitt, G. / Weatherhead, J. / Weaver, K. / Williams, S. / Wright, L. / Xiong, Z.Z. / Haigh, D. / Shotwell, J.B.
History
DepositionOct 26, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 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: HCV Polymerase
B: HCV Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)125,9864
Polymers124,9572
Non-polymers1,0292
Water8,035446
1
A: HCV Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,9932
Polymers62,4791
Non-polymers5141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: HCV Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,9932
Polymers62,4791
Non-polymers5141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.811, 106.565, 126.509
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 HCV Polymerase


Mass: 62478.605 Da / Num. of mol.: 2 / Mutation: F101Y, K114R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus subtype 1b / Plasmid: pET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q99AU2
#2: Chemical ChemComp-K4M / (4-{1-[5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)-1-benzofuran-6-yl]-1H-1,2,4-triazol-5-yl}-2-fluorophenyl)boronic acid


Mass: 514.288 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H21BF2N4O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 446 / 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: 2.31 Å3/Da / Density % sol: 46.86 % / Mosaicity: 0.991 °
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5 / Details: 0.1M Na Citrate pH5.0, 10% glycerol, 15% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.987 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Aug 23, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.07→50 Å / Num. obs: 72869 / % possible obs: 99.6 % / Redundancy: 6 % / Rmerge(I) obs: 0.088 / Χ2: 1 / Net I/σ(I): 5.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.07-2.1460.59971600.847199.3
2.14-2.2360.46172010.861199.4
2.23-2.3360.3871610.903199.5
2.33-2.4560.28572250.931199.5
2.45-2.616.10.21272260.929199.6
2.61-2.816.10.15572600.944199.8
2.81-3.096.10.11272721.025199.9
3.09-3.546.10.07573401.118199.9
3.54-4.466.10.04973901.13199.9
4.46-505.80.04876341.299199.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
REFMAC5.6.0081refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.14→29.68 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.945 / SU B: 9.9 / SU ML: 0.118 / SU R Cruickshank DPI: 0.0596 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.06 / ESU R Free: 0.042
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.2376 4659 7.2 %RANDOM
Rwork0.2103 ---
obs0.2123 59756 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 71.09 Å2 / Biso mean: 34.16 Å2 / Biso min: 22.32 Å2
Baniso -1Baniso -2Baniso -3
1--41.46 Å20 Å20 Å2
2--53.8 Å20 Å2
3----12.35 Å2
Refinement stepCycle: final / Resolution: 2.14→29.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8439 0 76 446 8961
Biso mean--38.26 41.42 -
Num. residues----1105
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0228735
X-RAY DIFFRACTIONr_bond_other_d0.0020.025802
X-RAY DIFFRACTIONr_angle_refined_deg1.1361.97111907
X-RAY DIFFRACTIONr_angle_other_deg1.117314146
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.08751111
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.89823.097339
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.303151400
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.9741558
X-RAY DIFFRACTIONr_chiral_restr0.0510.21358
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219718
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021768
Refine LS restraints NCSNCS model details: RESTRAINTS / Rms dev Biso : 0 Å2 / Rms dev position: 0 Å / Weight Biso : 0 / Weight position: 0
LS refinement shellResolution: 2.139→2.194 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.295 331 -
Rwork0.255 4240 -
all-4571 -
obs--97.65 %
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)
10.2403-0.08390.28210.0441-0.11160.64270.038-0.01620.0005-0.0102-0.0017-0.0050.0477-0.0202-0.03630.3202-0.0198-0.00770.00490.00350.309311.26845.90647.254
20.25910.04690.13270.03740.03260.36870.02170.0347-0.00090.0106-0.00050.00670.02550.0336-0.02120.31830.0129-0.0060.0074-0.00230.318-11.36245.915-7.925
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 563
2X-RAY DIFFRACTION1A601
3X-RAY DIFFRACTION2B1 - 563
4X-RAY DIFFRACTION2B601

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