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- PDB-4mib: Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex wit... -

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Basic information

Entry
Database: PDB / ID: 4mib
TitleHepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48 (N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide)
ComponentsRNA-DIRECTED RNA POLYMERASERNA-dependent RNA polymerase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / polymerase / transferase / ns5b / TRANSFERASE-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 / : ...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 / clathrin-dependent endocytosis of virus by host cell / viral nucleocapsid / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / 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 / host cell nucleus / structural molecule activity / virion attachment to host cell / host cell plasma membrane / virion membrane / 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 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 / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-28M / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 Å
AuthorsHarris, S.F. / Villasenor, A.G.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of N-[4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]phenyl]methanesulfonamide (RG7109), a potent inhibitor of the hepatitis C virus NS5B polymerase.
Authors: Talamas, F.X. / Abbot, S.C. / Anand, S. / Brameld, K.A. / Carter, D.S. / Chen, J. / Davis, D. / de Vicente, J. / Fung, A.D. / Gong, L. / Harris, S.F. / Inbar, P. / Labadie, S.S. / Lee, E.K. ...Authors: Talamas, F.X. / Abbot, S.C. / Anand, S. / Brameld, K.A. / Carter, D.S. / Chen, J. / Davis, D. / de Vicente, J. / Fung, A.D. / Gong, L. / Harris, S.F. / Inbar, P. / Labadie, S.S. / Lee, E.K. / Lemoine, R. / Le Pogam, S. / Leveque, V. / Li, J. / McIntosh, J. / Najera, I. / Park, J. / Railkar, A. / Rajyaguru, S. / Sangi, M. / Schoenfeld, R.C. / Staben, L.R. / Tan, Y. / Taygerly, J.P. / Villasenor, A.G. / Weller, P.E.
History
DepositionAug 30, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 7, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_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)127,7575
Polymers126,7092
Non-polymers1,0473
Water8,863492
1
A: RNA-DIRECTED RNA POLYMERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,9173
Polymers63,3551
Non-polymers5632
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-DIRECTED RNA POLYMERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,8392
Polymers63,3551
Non-polymers4851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.413, 105.549, 126.006
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 RNA-DIRECTED RNA POLYMERASE / RNA-dependent RNA polymerase / NS5B / p68


Mass: 63354.719 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 2421-2989
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Strain: 1b BK / Gene: NS5B / Production host: Escherichia coli (E. coli) / References: UniProt: P26663, RNA-directed RNA polymerase
#2: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-28M / N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide


Mass: 484.611 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H32N4O4S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 492 / 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: 2.27 Å3/Da / Density % sol: 45.76 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 4.9
Details: 26% PEG 4000, 7.5% glycerol, 50 mM Na Citrate pH 4.9, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 22, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 50500 / % possible obs: 97.4 % / Redundancy: 6.3 % / Biso Wilson estimate: 33.85 Å2 / Rmerge(I) obs: 0.143 / Χ2: 0.992 / Net I/σ(I): 6.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.3-2.386.20.57251180.984199.7
2.38-2.486.20.49850851.025199.4
2.48-2.596.20.38450521.041199.2
2.59-2.736.30.31250761.083198.8
2.73-2.96.30.24350391.013198.2
2.9-3.126.30.19150270.971197.8
3.12-3.446.30.14450430.911197.2
3.44-3.936.30.10950220.987196.5
3.93-4.956.30.09150120.922195.5
4.95-506.30.06550260.982191.8

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
BUSTER-TNTBUSTER 2.11.4refinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
BUSTER2.11.4refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.3→45.85 Å / Cor.coef. Fo:Fc: 0.9305 / Cor.coef. Fo:Fc free: 0.9064 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.392 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2485 2547 5.05 %RANDOM
Rwork0.2 ---
obs0.2024 50446 97.2 %-
Displacement parametersBiso max: 132.93 Å2 / Biso mean: 32.1425 Å2 / Biso min: 6.86 Å2
Baniso -1Baniso -2Baniso -3
1-1.8844 Å20 Å20 Å2
2---8.9489 Å20 Å2
3---7.0644 Å2
Refine analyzeLuzzati coordinate error obs: 0.273 Å
Refinement stepCycle: LAST / Resolution: 2.3→45.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8680 0 72 492 9244
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3145SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes172HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1388HARMONIC5
X-RAY DIFFRACTIONt_it9072HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1193SEMIHARMONIC5
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_contact11107SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9072HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg12344HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion2.91
X-RAY DIFFRACTIONt_other_torsion16.59
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2546 207 5.63 %
Rwork0.2188 3469 -
all0.2208 3676 -
obs--97.2 %

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