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

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Basic information

Entry
Database: PDB / ID: 4mka
TitleHepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with inhibitor 13 (N-{2-[3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydropyridin-3-yl)phenyl]-1,3-benzoxazol-5-yl}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 / ribonucleoprotein complex / RNA-directed RNA polymerase / 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 / 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 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-2AY / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.05 Å
AuthorsHarris, S.F. / Wong, A.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B.
Authors: Schoenfeld, R.C. / Bourdet, D.L. / Brameld, K.A. / Chin, E. / de Vicente, J. / Fung, A. / Harris, S.F. / Lee, E.K. / Le Pogam, S. / Leveque, V. / Li, J. / Lui, A.S. / Najera, I. / Rajyaguru, ...Authors: Schoenfeld, R.C. / Bourdet, D.L. / Brameld, K.A. / Chin, E. / de Vicente, J. / Fung, A. / Harris, S.F. / Lee, E.K. / Le Pogam, S. / Leveque, V. / Li, J. / Lui, A.S. / Najera, I. / Rajyaguru, S. / Sangi, M. / Steiner, S. / Talamas, F.X. / Taygerly, J.P. / Zhao, J.
History
DepositionSep 4, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2014Group: Database references
Revision 1.2Feb 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)127,9617
Polymers126,7092
Non-polymers1,2515
Water16,790932
1
A: RNA-DIRECTED RNA POLYMERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,9413
Polymers63,3551
Non-polymers5872
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-DIRECTED RNA POLYMERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,0204
Polymers63,3551
Non-polymers6653
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.944, 105.463, 126.161
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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-2AY / N-{3-[3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydropyridin-3-yl)phenyl]-1-oxo-1H-isochromen-7-yl}methanesulfonamide


Mass: 494.559 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H26N2O6S
#4: 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
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 932 / 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: 2.26 Å3/Da / Density % sol: 45.58 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 26% PEG 4000, 7.5% glycerol, 50 Tris pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 24, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. obs: 72251 / % possible obs: 100 % / Redundancy: 4.8 % / Biso Wilson estimate: 25.31 Å2 / Rmerge(I) obs: 0.168 / Χ2: 1.1 / Net I/σ(I): 5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.05-2.124.20.87671111.036199.8
2.12-2.214.60.771611.0451100
2.21-2.314.80.63171521.1621100
2.31-2.434.90.48371251.0841100
2.43-2.584.90.37771851.0641100
2.58-2.784.90.27771641.1041100
2.78-3.064.90.18872201.11100
3.06-3.514.90.11872511.11100
3.51-4.424.80.07473061.2311100
4.42-504.70.04575761.056199.9

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
BUSTER-TNTBUSTER 2.11.4refinement
PDB_EXTRACT3.11data extraction
BUSTER2.11.4refinement
RefinementResolution: 2.05→45.81 Å / Cor.coef. Fo:Fc: 0.9551 / Cor.coef. Fo:Fc free: 0.9403 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.206 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.226 / SU Rfree Blow DPI: 0.172 / SU Rfree Cruickshank DPI: 0.167
RfactorNum. reflection% reflectionSelection details
Rfree0.2169 3529 5 %RANDOM
Rwork0.178 ---
obs0.1799 70525 97.2 %-
Displacement parametersBiso max: 128.51 Å2 / Biso mean: 29.2851 Å2 / Biso min: 11.04 Å2
Baniso -1Baniso -2Baniso -3
1-0.3848 Å20 Å20 Å2
2---1.066 Å20 Å2
3---0.6812 Å2
Refine analyzeLuzzati coordinate error obs: 0.215 Å
Refinement stepCycle: LAST / Resolution: 2.05→45.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8680 0 86 932 9698
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3150SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes173HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1413HARMONIC5
X-RAY DIFFRACTIONt_it9128HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1196SEMIHARMONIC5
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_contact11798SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9128HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12427HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion3.31
X-RAY DIFFRACTIONt_other_torsion15.64
LS refinement shellResolution: 2.05→2.1 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.254 215 5.27 %
Rwork0.2204 3866 -
all0.2221 4081 -
obs--97.2 %

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