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- PDB-6mvo: HCV NS5B 1A Y316 bound to Compound 49 -

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Basic information

Entry
Database: PDB / ID: 6mvo
TitleHCV NS5B 1A Y316 bound to Compound 49
ComponentsRNA-directed RNA polymeraseRNA-dependent RNA polymerase
KeywordsVIRAL PROTEIN / Hepatitus C / NS5B / REPLICATION
Function / homology
Function and homology information


hepacivirin / 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 / SH3 domain binding / nucleoside-triphosphate phosphatase ...hepacivirin / 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 / SH3 domain binding / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / viral nucleocapsid / clathrin-dependent endocytosis of virus by host cell / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA helicase / ribonucleoprotein complex / induction by virus of host autophagy / RNA-directed RNA polymerase / virus-mediated perturbation of host defense response / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / nucleotide binding / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
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 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 / helicase superfamily c-terminal 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 / Alpha-Beta Plaits / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / 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-K4P / Genome polyprotein / RNA-directed RNA polymerase
Similarity search - Component
Biological speciesHepacivirus C
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.95 Å
Model detailsHCV NS5B 1A Y316 bound to Compound 49
AuthorsWilliams, S.P. / Kahler, K. / Price, D.J. / Peat, A.J.
CitationJournal: 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.
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 / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RNA-directed RNA polymerase
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)125,80811
Polymers123,9982
Non-polymers1,8109
Water7,152397
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,8565
Polymers61,9991
Non-polymers8574
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,9526
Polymers61,9991
Non-polymers9535
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.225, 61.202, 91.773
Angle α, β, γ (deg.)89.700, 86.980, 80.920
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: HIS / End label comp-ID: HIS / Refine code: 0 / Auth seq-ID: 1 - 562 / Label seq-ID: 1 - 562

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein RNA-directed RNA polymerase / RNA-dependent RNA polymerase


Mass: 61998.988 Da / Num. of mol.: 2 / Mutation: F101Y, C110S, R113S, K114R, C316Y
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepacivirus C / Plasmid: pET21 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q66N85, UniProt: P26664*PLUS, RNA-directed RNA polymerase
#2: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-K4P / 6-[(7-chloro-1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide


Mass: 568.809 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H23BClFN2O6S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 397 / 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: 2.38 Å3/Da / Density % sol: 48.26 % / Mosaicity: 0.443 °
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: CLSI / Beamline: 08ID-1 / Wavelength: 0.987 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Sep 28, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.89→50 Å / Num. obs: 88656 / % possible obs: 97.9 % / Redundancy: 3.9 % / Rmerge(I) obs: 0.102 / Χ2: 1 / Net I/σ(I): 5.9 / Num. measured all: 349545
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.89-1.963.80.59687341.151196.4
1.96-2.043.90.40688530.797196.9
2.04-2.1340.30587340.727197.1
2.13-2.2440.24288210.726197.3
2.24-2.3840.18988120.7197.7
2.38-2.5740.14389250.682198
2.57-2.8240.10988760.827198.3
2.82-3.2340.08689531.145198.6
3.23-4.0740.06689621.604198.9
4.07-503.90.05489861.643199.4

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation29.28 Å2.07 Å

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Processing

Software
NameVersionClassificationNB
REFMAC5.6.0081refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREP11.0.02phasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→29.28 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.923 / WRfactor Rfree: 0.2288 / WRfactor Rwork: 0.2101 / FOM work R set: 0.8699 / SU B: 5.915 / SU ML: 0.084 / SU R Cruickshank DPI: 0.044 / SU Rfree: 0.0345 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.044 / ESU R Free: 0.034 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2352 5906 7.2 %RANDOM
Rwork0.2166 ---
obs0.218 75663 97.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 57.07 Å2 / Biso mean: 23.838 Å2 / Biso min: 13.14 Å2
Baniso -1Baniso -2Baniso -3
1-21.58 Å2-3.02 Å212.24 Å2
2---22.61 Å2-1.81 Å2
3---1.02 Å2
Refinement stepCycle: final / Resolution: 1.95→29.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8543 0 113 397 9053
Biso mean--29.75 25.46 -
Num. residues----1124
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.028871
X-RAY DIFFRACTIONr_bond_other_d0.0020.025928
X-RAY DIFFRACTIONr_angle_refined_deg1.0981.97412102
X-RAY DIFFRACTIONr_angle_other_deg1.112314400
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.70851132
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.94822.493345
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.548151390
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.241570
X-RAY DIFFRACTIONr_chiral_restr0.0590.21371
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219901
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021855
Refine LS restraints NCS

Ens-ID: 1 / Number: 19770 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.1 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.949→2 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.313 433 -
Rwork0.267 5452 -
all-5885 -
obs--94.89 %
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)
10.0839-0.0318-0.01130.51250.0020.10320.0013-0.0008-0.0163-0.01920.0154-0.0454-0.01380.0008-0.01670.00490.01140.00580.09-0.0020.0156-9.342-14.02121.681
20.0554-0.008-0.01020.55440.08080.023-0.01480.0060.0157-0.0390.01430.03570.00560.00060.00050.020.0205-0.00450.10410.01230.00799.27414.096-22.094
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 562
2X-RAY DIFFRACTION1A604
3X-RAY DIFFRACTION2B1 - 562
4X-RAY DIFFRACTION2B605

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