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

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Basic information

Entry
Database: PDB / ID: 4mia
TitleHepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with RG7109 (N-{4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-2,5-dihydropyridin-3-yl)quinolin-3-yl]phenyl}methanesulfonamide)
ComponentsRNA-directed RNA polymeraseRNA-dependent RNA polymerase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / polymerase / 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 / 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 / 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 / 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-28L / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.8 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)127,8556
Polymers126,7092
Non-polymers1,1464
Water4,143230
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,9283
Polymers63,3551
Non-polymers5732
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,9283
Polymers63,3551
Non-polymers5732
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)84.981, 104.816, 125.284
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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-28L / N-{4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-2,5-dihydropyridin-3-yl)quinolin-3-yl]phenyl}methanesulfonamide


Mass: 507.601 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H29N3O5S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 230 / 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: 2.2 Å3/Da / Density % sol: 44.14 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 4.64
Details: 24% peg 4000, 7.5% glycerol, 50 mM sodium citrate pH 4.64, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 14, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 28541 / % possible obs: 99.7 % / Redundancy: 6.7 % / Biso Wilson estimate: 63.07 Å2 / Rmerge(I) obs: 0.186 / Χ2: 1.038 / Net I/σ(I): 4.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.8-2.95.60.94427650.982199
2.9-3.026.50.79328141.02199.5
3.02-3.156.80.65528151.055199.5
3.15-3.326.90.4828121.055199.8
3.32-3.5370.30728191.055199.9
3.53-3.870.20928331.0451100
3.8-4.1870.14428451.0261100
4.18-4.7970.10928911.0181100
4.79-6.036.90.12629031.0791100
6.03-506.50.05930441.032199.5

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
BUSTER-TNTBUSTER 2.11.4refinement
PDB_EXTRACT3.11data extraction
HKL-3000data reduction
BUSTER2.11.4refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.8→38.8 Å / Cor.coef. Fo:Fc: 0.9277 / Cor.coef. Fo:Fc free: 0.8792 / Occupancy max: 1 / Occupancy min: 0.5 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2788 1432 5.09 %RANDOM
Rwork0.2021 ---
obs0.206 28155 99.75 %-
Displacement parametersBiso max: 210.42 Å2 / Biso mean: 48.4331 Å2 / Biso min: 10.81 Å2
Baniso -1Baniso -2Baniso -3
1--0.2999 Å20 Å20 Å2
2---5.3493 Å20 Å2
3---5.6491 Å2
Refine analyzeLuzzati coordinate error obs: 0.318 Å
Refinement stepCycle: LAST / Resolution: 2.8→38.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8508 0 74 230 8812
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3063SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes170HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1373HARMONIC5
X-RAY DIFFRACTIONt_it8866HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_chiral_improper_torsion1166SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact10836SEMIHARMONIC4
X-RAY DIFFRACTIONo_bond_d8866HARMONIC20.009
X-RAY DIFFRACTIONo_angle_deg12055HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion2.6
X-RAY DIFFRACTIONt_other_torsion18.44
LS refinement shellResolution: 2.8→2.91 Å / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.2882 144 4.97 %
Rwork0.2227 2756 -
all0.226 2900 -
obs--99.75 %

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