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- PDB-5w2e: HCV NS5B RNA-dependent RNA polymerase in complex with non-nucleos... -

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Basic information

Entry
Database: PDB / ID: 5w2e
TitleHCV NS5B RNA-dependent RNA polymerase in complex with non-nucleoside inhibitor MK-8876
ComponentsGenome polyprotein
KeywordsTRANSFERASE/INHIBITOR / antiviral inhibitor / HCV / polymerase / VIRAL PROTEIN / TRANSFERASE-INHIBITOR complex
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 / channel activity / monoatomic ion transmembrane transport / 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 / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / ribonucleoprotein complex / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / serine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / virion attachment to host cell / apoptotic process / host cell plasma membrane / structural molecule activity / virion membrane / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / 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 NS2, C-terminal domain / 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, 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 NS2, C-terminal domain / Hepatitis C virus core protein, chain A superfamily / : / Hepatitis C virus non-structural protein NS4b / Hepatitis C virus capsid protein / 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 zinc finger domain / Hepatitis C virus non-structural 5a domain 1b / Hepatitis C virus, Non-structural protein NS2 / : / NS3 RNA helicase, C-terminal helical domain / Hepacivirus nonstructural protein 2 (NS2) protease domain profile. / Hepatitis C virus non-structural 5a protein membrane anchor / 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 / Hepacivirus/Pegivirus NS3 protease domain profile. / Hepatitis C virus NS3 protease / 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 / 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-9VY / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus genotype 1b
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsLesburg, C.A. / Ummat, A.
CitationJournal: ChemMedChem / Year: 2017
Title: Development of a New Structural Class of Broadly Acting HCV Non-Nucleoside Inhibitors Leading to the Discovery of MK-8876.
Authors: McComas, C.C. / Palani, A. / Chang, W. / Holloway, M.K. / Lesburg, C.A. / Li, P. / Liverton, N. / Meinke, P.T. / Olsen, D.B. / Peng, X. / Soll, R.M. / Ummat, A. / Wu, J. / Wu, J. / Zorn, N. / Ludmerer, S.W.
History
DepositionJun 6, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 16, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 4, 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

Downloads & links

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Assembly

Deposited unit
A: Genome polyprotein
B: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,3684
Polymers128,1392
Non-polymers1,2292
Water4,666259
1
A: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,6842
Polymers64,0691
Non-polymers6151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,6842
Polymers64,0691
Non-polymers6151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)86.092, 106.418, 126.091
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Genome polyprotein


Mass: 64069.387 Da / Num. of mol.: 2 / Fragment: UNP residues 3-570
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus genotype 1b (isolate BK)
Strain: isolate BK / Production host: Escherichia coli (E. coli)
References: UniProt: P26663, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases, hepacivirin, nucleoside-triphosphate phosphatase, RNA helicase, RNA-directed RNA polymerase
#2: Chemical ChemComp-9VY / 2-(4-fluorophenyl)-5-(11-fluoro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-[methyl(methylsulfonyl)amino]-1-benzofuran-3-carboxamide


Mass: 614.619 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H24F2N4O5S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 259 / 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: 2.25 Å3/Da / Density % sol: 45.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 14.0 w/v polyethylene glycol 4000 0.1 M MES pH 5.8 5mM DTT 10.0 w/v glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 20, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→34.15 Å / Num. obs: 29250 / % possible obs: 100 % / Redundancy: 6.6 % / Biso Wilson estimate: 58.69 Å2 / Rmerge(I) obs: 0.149 / Net I/σ(I): 10.1
Reflection shellResolution: 2.8→2.95 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.667 / Num. unique obs: 4208 / % possible all: 99.6

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1c2p

1c2p


Resolution: 2.8→34.15 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.897 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.37
RfactorNum. reflection% reflectionSelection details
Rfree0.239 1480 5.07 %RANDOM
Rwork0.181 ---
obs0.184 29173 100 %-
Displacement parametersBiso mean: 45.77 Å2
Baniso -1Baniso -2Baniso -3
1-2.9025 Å20 Å20 Å2
2---10.0828 Å20 Å2
3---7.1802 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: 1 / Resolution: 2.8→34.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8698 0 88 259 9045
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.019047HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1412333HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3089SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes174HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1442HARMONIC5
X-RAY DIFFRACTIONt_it9047HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.86
X-RAY DIFFRACTIONt_other_torsion19.48
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1177SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact10630SEMIHARMONIC4
LS refinement shellResolution: 2.8→2.9 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.3045 148 5.25 %
Rwork0.1961 2672 -
all0.2016 2820 -
obs--99.93 %
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)
12.00710.45390.21160.54550.06040.71410.0167-0.10670.0237-0.0791-0.03390.11590.0644-0.05030.0172-0.0999-0.0810.01360.0153-0.0381-0.0282-29.7776-13.89916.0383
20.88230.06290.14431.04770.49781.47760.05310.0150.095-0.0111-0.03930.0167-0.0029-0.0809-0.0137-0.10620.0197-0.02240.0393-0.0147-0.1682-10.8215-1.818927.4511
300.4131-1.07430.51960.59020.89970.03690.0441-0.04570.0207-0.0252-0.06120.1480.0329-0.01170.04860.1062-0.0871-0.0058-0.0241-0.06871.4581-21.237723.2705
42.9103-0.94040.29161.31630.06453.95650.00680.0763-0.010.10040.04010.0170.15890.2065-0.0469-0.11220.0799-0.05050.0286-0.0211-0.1761-13.239-9.3765-0.1833
52.1707-0.246-1.01891.65990.44161.4950.02390.2538-0.0283-0.177-0.0314-0.0241-0.04990.09480.0075-0.10730.055-0.02810.16810.076-0.1639-10.4931-2.0155-5.7017
61.3635-0.17971.65470.0595-0.50710.56040.00870.0401-0.03270.0066-0.01810.0869-0.0305-0.03560.0093-0.06530.0225-0.00780.0023-0.0338-0.027513.31313.96157.6168
71.3078-0.0362-0.11561.28860.48981.48060.07010.0597-0.07090.0073-0.00140.086-0.02750.011-0.0688-0.09950.00160.0138-0.00780.0022-0.182132.06821.9164-3.93
80-0.93390.75271.59692.31262.68920.0337-0.08840.0761-0.03670.0062-0.0767-0.1550.0433-0.03990.0767-0.12080.1052-0.032-0.0369-0.087744.091821.48470.0393
93.74730.39110.75231.1838-0.37623.9458-0.0258-0.10260.0032-0.15520.08870.0679-0.1380.264-0.0629-0.1142-0.06270.08780.0565-0.0966-0.197329.96949.507523.727
101.48890.46830.89921.2634-0.15171.89810.0229-0.26810.03130.13860.014-0.02640.01870.09-0.0369-0.1075-0.04480.04810.24550.0049-0.182132.91011.734728.9835
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|1 - 47 }
2X-RAY DIFFRACTION2{ A|48 - 292 }
3X-RAY DIFFRACTION3{ A|293 - 368 }
4X-RAY DIFFRACTION4{ A|369 - 497 }
5X-RAY DIFFRACTION5{ A|498 - 564 }
6X-RAY DIFFRACTION6{ B|1 - 47 }
7X-RAY DIFFRACTION7{ B|48 - 292 }
8X-RAY DIFFRACTION8{ B|293 - 368 }
9X-RAY DIFFRACTION9{ B|369 - 497 }
10X-RAY DIFFRACTION10{ B|498 - 564 }

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