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- PDB-3bsa: Crystal Structure of HCV NS5B Polymerase with a Novel Pyridazinon... -

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Entry
Database: PDB / ID: 3bsa
TitleCrystal Structure of HCV NS5B Polymerase with a Novel Pyridazinone Inhibitor
ComponentsRNA-directed RNA polymerase
KeywordsTRANSFERASE / PROTEIN-LIGAND COMPLEX / RNA replication / RNA-binding / RNA-directed RNA polymerase / Transcription / Transcription regulation / Transmembrane / Viral nucleoprotein
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-1PD / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsHan, Q. / Showalter, R.E. / Zhao, Q. / Kissinger, C.R.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda6-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 1: exploration of 7'-substitution of benzothiadiazine.
Authors: Zhou, Y. / Webber, S.E. / Murphy, D.E. / Li, L.S. / Dragovich, P.S. / Tran, C.V. / Sun, Z. / Ruebsam, F. / Shah, A.M. / Tsan, M. / Showalter, R.E. / Patel, R. / Li, B. / Zhao, Q. / Han, Q. / ...Authors: Zhou, Y. / Webber, S.E. / Murphy, D.E. / Li, L.S. / Dragovich, P.S. / Tran, C.V. / Sun, Z. / Ruebsam, F. / Shah, A.M. / Tsan, M. / Showalter, R.E. / Patel, R. / Li, B. / Zhao, Q. / Han, Q. / Hermann, T. / Kissinger, C.R. / Lebrun, L. / Sergeeva, M.V. / Kirkovsky, L.
History
DepositionDec 23, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 23, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / entity / pdbx_entity_nonpoly / struct_ref_seq_dif / struct_site
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.4Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)129,7294
Polymers128,6912
Non-polymers1,0372
Water3,171176
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8642
Polymers64,3461
Non-polymers5191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8642
Polymers64,3461
Non-polymers5191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.536, 103.905, 125.932
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 RNA-directed RNA polymerase / NS5B / p68


Mass: 64345.738 Da / Num. of mol.: 2
Fragment: HCV NS5B catalytic domain, residues 2420-2989 of polyprotein
Mutation: Q544R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus (isolate BK) / Strain: Genotype 1b BK / Plasmid: PET21A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)STAR / References: UniProt: P26663, RNA-directed RNA polymerase
#2: Chemical ChemComp-1PD / 2-({3-[5-hydroxy-2-(3-methylbutyl)-3-oxo-6-(1,3-thiazol-5-yl)-2,3-dihydropyridazin-4-yl]-1,1-dioxido-2H-1,2,4-benzothia diazin-7-yl}oxy)acetamide / 2-({3-[5-hydroxy-2-(3-methylbutyl)-3-oxo-6-(1,3-thiazol-5-yl)-2,3-dihydropyridazin-4-yl]-1,1-dioxo-2H-1,2,4-benzothiadi azin-7-yl}oxy)acetamide


Mass: 518.566 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H22N6O6S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 176 / 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: 2.17 Å3/Da / Density % sol: 43.43 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.6
Details: 20% PEG 4K, 50 mM ammonium sulfate, 100 mM sodium acetate pH 4.7, 5 mM DTT. Transferred to pH 7.6 for soaking., VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-ID-B
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Mar 4, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.3→41.9 Å / Num. all: 48377 / Num. obs: 48377 / % possible obs: 95.7 % / Observed criterion σ(F): 0

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
DENZOdata reduction
SCALEPACKdata scaling
EPMRphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: HCV POLYMERASE

Resolution: 2.3→41.88 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.89 / SU B: 10.087 / SU ML: 0.245 / Isotropic thermal model: ISOTROPIC / Cross valid method: THROUGHOUT / ESU R: 0.533 / ESU R Free: 0.313 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.299 2394 4.9 %RANDOM
Rwork0.242 ---
all0.244 ---
obs0.244 48337 95.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 38.183 Å2
Baniso -1Baniso -2Baniso -3
1--3.5 Å20 Å20 Å2
2--8.53 Å20 Å2
3----5.04 Å2
Refinement stepCycle: LAST / Resolution: 2.3→41.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8668 0 70 176 8914
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0228934
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1511.97312134
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.60651110
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.53222.873362
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.681151514
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9821570
X-RAY DIFFRACTIONr_chiral_restr0.0730.21368
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.026702
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2060.24300
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3090.36216
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1520.15728
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2040.265
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1550.1515
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5491.55698
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.95328982
X-RAY DIFFRACTIONr_scbond_it1.2533701
X-RAY DIFFRACTIONr_scangle_it1.9774.53152
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.364 161 -
Rwork0.297 3337 -
obs--94.46 %

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