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- PDB-4jtw: Crystal structure of HCV NS5B polymerase in complex with coupound 1 -

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Basic information

Entry
Database: PDB / ID: 4jtw
TitleCrystal structure of HCV NS5B polymerase in complex with coupound 1
ComponentsGenome polyprotein
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / RNA-DIRECTED RNA POLYMERASE / TRANSFERASE / 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 / channel activity / monoatomic ion transmembrane transport / viral nucleocapsid / clathrin-dependent endocytosis of virus by host cell / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / molecular adaptor activity / 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 / 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. / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-1NU / Genome polyprotein
Similarity search - Component
Biological speciesHEPATITIS C VIRUS
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsCoulombe, R.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Molecular Dynamics Simulations and Structure-Based Rational Design Lead to Allosteric HCV NS5B Polymerase Thumb Pocket 2 Inhibitor with Picomolar Cellular Replicon Potency.
Authors: Hucke, O. / Coulombe, R. / Bonneau, P. / Bertrand-Laperle, M. / Brochu, C. / Gillard, J. / Joly, M.A. / Landry, S. / Lepage, O. / Llinas-Brunet, M. / Pesant, M. / Poirier, M. / Poirier, M. / ...Authors: Hucke, O. / Coulombe, R. / Bonneau, P. / Bertrand-Laperle, M. / Brochu, C. / Gillard, J. / Joly, M.A. / Landry, S. / Lepage, O. / Llinas-Brunet, M. / Pesant, M. / Poirier, M. / Poirier, M. / McKercher, G. / Marquis, M. / Kukolj, G. / Beaulieu, P.L. / Stammers, T.A.
History
DepositionMar 24, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 26, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)129,75310
Polymers128,5712
Non-polymers1,1828
Water5,729318
1
A: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8775
Polymers64,2861
Non-polymers5914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8775
Polymers64,2861
Non-polymers5914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)106.430, 108.000, 134.920
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 / Core protein p21 / Capsid protein C / p21 / Core protein p19 / Envelope glycoprotein E1 / gp32 / ...Core protein p21 / Capsid protein C / p21 / Core protein p19 / Envelope glycoprotein E1 / gp32 / gp35 / Envelope glycoprotein E2 / NS1 / gp68 / gp70 / p7 / Protease NS2-3 / p23 / Serine protease NS3 / Hepacivirin / NS3P / p70 / Non-structural protein 4A / NS4A / p8 / Non-structural protein 4B / NS4B / p27 / Non-structural protein 5A / NS5A / p56 / RNA-directed RNA polymerase / NS5B / p68


Mass: 64285.637 Da / Num. of mol.: 2
Fragment: RNA-DIRECTED RNA POLYMERASE, UNP RESIDUES 2420-2989
Source method: isolated from a genetically manipulated source
Details: PROTEIN CONSTRUCT ID 001 / Source: (gene. exp.) HEPATITIS C VIRUS / Strain: 1BJ4 / Gene: NS5B / Plasmid: PET29B / Production host: Escherichia coli (E. coli) / Strain (production host): JM109(DE3)
References: UniProt: O92972, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases, hepacivirin, nucleoside-triphosphate phosphatase, RNA helicase, RNA-directed RNA polymerase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-1NU / 1-(2,4,6-trifluorobenzyl)-6-[2-(trifluoromethyl)phenoxy]quinazolin-4(1H)-one


Mass: 450.333 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H12F6N2O2
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 318 / 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: 3.02 Å3/Da / Density % sol: 59.21 %
Crystal growTemperature: 284 K / Method: vapor diffusion, hanging drop / pH: 5.4
Details: 100 mM MES, 21% PEGmme 5000, 400 mM Ammonium sulfate, 10% glycerol, pH 5.4, VAPOR DIFFUSION, HANGING DROP, temperature 284K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Mar 6, 2009 / Details: hires2
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 3→40 Å / Num. obs: 31347 / % possible obs: 98.1 % / Observed criterion σ(I): 1 / Redundancy: 6.6 % / Rmerge(I) obs: 0.149 / Net I/σ(I): 10.84
Reflection shellResolution: 3→3.11 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.536 / Mean I/σ(I) obs: 2.2 / Num. unique all: 2653 / % possible all: 84.2

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
CNX2002refinement
HKL-2000data reduction
SCALEPACKdata scaling
CNX2002phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3MWV

3mwv


Resolution: 3→40 Å / σ(F): 1 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.274 3118 RANDOM
Rwork0.2 --
obs-31135 -
Refinement stepCycle: LAST / Resolution: 3→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8724 0 80 318 9122
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006792
X-RAY DIFFRACTIONc_angle_deg1.28864

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