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- PDB-2hwi: HCV NS5B allosteric inhibitor complex -

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Basic information

Entry
Database: PDB / ID: 2hwi
TitleHCV NS5B allosteric inhibitor complex
ComponentsRNA-directed RNA polymerase (NS5B) (p68)
KeywordsTRANSFERASE / HCV / NS5B / Viral RNA-directed RNA polymerase / RdRP / Allosteric inhibitor / HCV 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 / 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-VRX / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsYao, N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Structure-based design of a novel thiazolone scaffold as HCV NS5B polymerase allosteric inhibitors.
Authors: Yan, S. / Appleby, T. / Larson, G. / Wu, J.Z. / Hamatake, R. / Hong, Z. / Yao, N.
History
DepositionAug 1, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 7, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 30, 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 / 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
Remark 999Sequence According to author, these are due to viral strand differences

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RNA-directed RNA polymerase (NS5B) (p68)
B: RNA-directed RNA polymerase (NS5B) (p68)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,7754
Polymers128,0272
Non-polymers7492
Water7,206400
1
A: RNA-directed RNA polymerase (NS5B) (p68)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,3882
Polymers64,0131
Non-polymers3741
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: RNA-directed RNA polymerase (NS5B) (p68)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,3882
Polymers64,0131
Non-polymers3741
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)84.997, 106.585, 127.200
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: 64013.324 Da / Num. of mol.: 2 / Fragment: HCV NS5B
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Genus: Hepacivirus / Production host: Escherichia coli (E. coli) / References: UniProt: P26663, RNA-directed RNA polymerase
#2: Chemical ChemComp-VRX / (2S)-({(5Z)-5-[(5-ETHYL-2-FURYL)METHYLENE]-4-OXO-4,5-DIHYDRO-1,3-THIAZOL-2-YL}AMINO)(4-FLUOROPHENYL)ACETIC ACID


Mass: 374.386 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H15FN2O4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 400 / 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: 2.25 Å3/Da / Density % sol: 45.31 %
Crystal growTemperature: 295 K / Method: evaporation / pH: 5
Details: 20%PEG4000, 5mM DTT, 0.5M MES, 1.0M NaCl, PH5, Micro batch, pH 5.0, 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: Jan 1, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→20 Å / Num. all: 78204 / Num. obs: 74324 / % possible obs: 94.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -1 / Redundancy: 5.3 % / Rmerge(I) obs: 0.067 / Net I/σ(I): 16
Reflection shellResolution: 2→2.07 Å / Rmerge(I) obs: 0.276 / Mean I/σ(I) obs: 3.64 / Num. unique all: 7254 / % possible all: 93.6

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Processing

Software
NameClassification
CNSrefinement
DENZOdata reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB Entry: 1C2P

1c2p


Resolution: 2→20 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.259 7275 -random
Rwork0.223 ---
all0.223 78678 --
obs0.223 72022 91.5 %-
Refinement stepCycle: LAST / Resolution: 2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8721 0 52 400 9173
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.0053
X-RAY DIFFRACTIONc_angle_deg1.1111

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