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- PDB-3d28: Crystal structure of hcv ns5b polymerase with a novel benzisothia... -

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Basic information

Entry
Database: PDB / ID: 3d28
TitleCrystal structure of hcv ns5b polymerase with a novel benzisothiazole inhibitor
ComponentsRNA-directed RNA polymeraseRNA-dependent RNA polymerase
KeywordsTRANSFERASE / Protein-Ligand Complex / RNA-DIRECTED RNA POLYMERASE / NUCLEOTIDYLTRANSFERASE / NUCLEOTIDE-BINDING / TRANSCRIPTION / HYDROLASE
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-B34 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsHan, Q. / Showalter, R.E. / Zhao, Q. / Kissinger, C.R.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase.
Authors: Kim, S.H. / Tran, M.T. / Ruebsam, F. / Xiang, A.X. / Ayida, B. / McGuire, H. / Ellis, D. / Blazel, J. / Tran, C.V. / Murphy, D.E. / Webber, S.E. / Zhou, Y. / Shah, A.M. / Tsan, M. / ...Authors: Kim, S.H. / Tran, M.T. / Ruebsam, F. / Xiang, A.X. / Ayida, B. / McGuire, H. / Ellis, D. / Blazel, J. / Tran, C.V. / Murphy, D.E. / Webber, S.E. / Zhou, Y. / Shah, A.M. / Tsan, M. / Showalter, R.E. / Patel, R. / Gobbi, A. / LeBrun, L.A. / Bartkowski, D.M. / Nolan, T.G. / Norris, D.A. / Sergeeva, M.V. / Kirkovsky, L. / Zhao, Q. / Han, Q. / Kissinger, C.R.
History
DepositionMay 7, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 19, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Category: 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
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)129,4844
Polymers128,6912
Non-polymers7932
Water2,450136
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7422
Polymers64,3461
Non-polymers3961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7422
Polymers64,3461
Non-polymers3961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)83.979, 104.881, 126.008
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 / RNA-dependent RNA polymerase / NS5B / p68


Mass: 64345.738 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN, RESIDUES 2420-2989 / Mutation: R2963Q
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-B34 / (5S)-1-benzyl-3-(1,1-dioxido-1,2-benzisothiazol-3-yl)-4-hydroxy-5-(1-methylethyl)-1,5-dihydro-2H-pyrrol-2-one


Mass: 396.460 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H20N2O4S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 136 / 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: 2.16 Å3/Da / Density % sol: 42.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.6
Details: 20% PEG 4K, 50 MM AMMONIUM SULFATE, 100 MM SODIUM ACETATE, 5 MM DTT, PH 4.7, TRANSFERRED to PH 7.6 FOR SOAKING AND DATA COLLECTION, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Nov 7, 2005 / Details: MIRRORS
RadiationMonochromator: OSMIC MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→28.72 Å / Num. all: 43492 / Num. obs: 43492 / % possible obs: 86.7 % / Observed criterion σ(F): 0 / Redundancy: 2.7 % / Rmerge(I) obs: 0.143 / Net I/σ(I): 7.5
Reflection shellResolution: 2.3→2.38 Å / % possible all: 65.6

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Processing

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

Resolution: 2.3→28.72 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.887 / SU B: 11.8 / SU ML: 0.288 / Isotropic thermal model: ISOTROPIC / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.781 / ESU R Free: 0.356 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.3125 2228 5.1 %RANDOM
Rwork0.2572 ---
all0.26 43461 --
obs0.26 43461 86.73 %-
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: 59.011 Å2
Baniso -1Baniso -2Baniso -3
1--1.34 Å20 Å20 Å2
2--4.48 Å20 Å2
3----3.14 Å2
Refinement stepCycle: LAST / Resolution: 2.3→28.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8668 0 56 136 8860
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0228918
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0421.97112112
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.17751110
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.96622.873362
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.333151514
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8761570
X-RAY DIFFRACTIONr_chiral_restr0.0630.21370
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.026662
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1870.24463
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.2920.26171
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.140.2439
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1970.279
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1090.29
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8333.55721
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.31748978
X-RAY DIFFRACTIONr_scbond_it1.0834.53680
X-RAY DIFFRACTIONr_scangle_it1.46153134
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.357 110 -
Rwork0.326 2135 -
obs--61.63 %

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