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- PDB-2ijn: Isothiazoles as active-site inhibitors of HCV NS5B polymerase -

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Basic information

Entry
Database: PDB / ID: 2ijn
TitleIsothiazoles as active-site inhibitors of HCV NS5B polymerase
ComponentsRNA polymerase NS5B
KeywordsTRANSCRIPTION / TRANSFERASE / HCV / NS5B / Viral RNA directed RNA polymerase / RDRP / active site / covalent inhibitor
Function / homology
Function and homology information


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 / lipid droplet / ribonucleoside triphosphate phosphatase activity / channel activity ...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 / lipid droplet / ribonucleoside triphosphate phosphatase activity / channel activity / monoatomic ion transmembrane transport / viral nucleocapsid / clathrin-dependent endocytosis of virus by host cell / 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 / induction by virus of host autophagy / ribonucleoprotein complex / 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 / proteolysis / RNA binding / zinc ion binding / ATP binding / plasma membrane / cytoplasm
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-221 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus subtype 1b
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsYan, S. / Yao, N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Isothiazoles as active-site inhibitors of HCV NS5B polymerase
Authors: Yan, S. / Appleby, T. / Gunic, E. / Shim, J.H. / Tasu, T. / Kim, H. / Rong, F. / Chen, H. / Hamatake, R. / Wu, J.Z. / Hong, Z. / Yao, N.
History
DepositionSep 29, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 28, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RNA polymerase NS5B
B: RNA polymerase NS5B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,7414
Polymers128,0272
Non-polymers7152
Water4,864270
1
A: RNA polymerase NS5B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,3712
Polymers64,0131
Non-polymers3571
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: RNA polymerase NS5B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,3712
Polymers64,0131
Non-polymers3571
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)85.507, 105.272, 126.458
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 polymerase NS5B


Mass: 64013.324 Da / Num. of mol.: 2 / Fragment: residues 2422-2989 of HCV polyprotein
Source method: isolated from a genetically manipulated source
Details: cyclic precursor of inhibitor 221 forms an S-S brigde to CYS 366 upon binding
Source: (gene. exp.) Hepatitis C virus subtype 1b / Genus: Hepacivirus / Species: Hepatitis C virus / Strain: subtype 1b / Production host: Escherichia coli (E. coli) / References: UniProt: Q99AU2, RNA-directed RNA polymerase
#2: Chemical ChemComp-221 / (2R,3R)-3-{[3,5-BIS(TRIFLUOROMETHYL)PHENYL]AMINO}-2-CYANO-3-THIOXOPROPANAMIDE


Mass: 357.275 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H9F6N3OS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 270 / 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: 2.22 Å3/Da / Density % sol: 44.64 %
Crystal growTemperature: 295 K / Method: evaporation / pH: 5
Details: 20% PEG 4000, 5mM DTT, 0.5M MES, 1.0M NaCl, pH 5.0, Microbatch, EVAPORATION, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Dec 7, 2004 / Details: Osmic blue mirror
RadiationMonochromator: y / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→500 Å / Num. all: 58598 / Num. obs: 57634 / % possible obs: 98.4 % / Observed criterion σ(I): -1 / Redundancy: 14.8 % / Rsym value: 0.075 / Net I/σ(I): 20
Reflection shellResolution: 2.2→2.28 Å / Rsym value: 0.251 / % possible all: 97.2

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Processing

Software
NameVersionClassification
CrystalClear(MSC/RIGAKU)data collection
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→500 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.261 5742 -Random
Rwork0.222 ---
all-58633 --
obs-56389 96.2 %-
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-0.006 Å20 Å20 Å2
2--0.205 Å20 Å2
3----0.211 Å2
Refinement stepCycle: LAST / Resolution: 2.2→500 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8721 0 46 270 9037
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.0058
X-RAY DIFFRACTIONc_angle_deg1.123
X-RAY DIFFRACTIONc_mcbond_it1.3161.5
X-RAY DIFFRACTIONc_mcangle_it2.0672
X-RAY DIFFRACTIONc_scbond_it2.1362
X-RAY DIFFRACTIONc_scangle_it3.0452.5

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