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- PDB-3skh: I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- C... -

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Entry
Database: PDB / ID: 3skh
TitleI. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles
ComponentsHCV NS5B RNA_DEPENDENT RNA POLYMERASE
Keywordstransferase/transferase INHIBITOR / RNA-dependent RNA polymerase / 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 / : ...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 / molecular adaptor activity / 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. / 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-058 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus isolate HC-J4
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.5 Å
AuthorsLesburg, C.A. / Anilkumar, G.N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles.
Authors: Anilkumar, G.N. / Lesburg, C.A. / Selyutin, O. / Rosenblum, S.B. / Zeng, Q. / Jiang, Y. / Chan, T.Y. / Pu, H. / Vaccaro, H. / Wang, L. / Bennett, F. / Chen, K.X. / Duca, J. / Gavalas, S. / ...Authors: Anilkumar, G.N. / Lesburg, C.A. / Selyutin, O. / Rosenblum, S.B. / Zeng, Q. / Jiang, Y. / Chan, T.Y. / Pu, H. / Vaccaro, H. / Wang, L. / Bennett, F. / Chen, K.X. / Duca, J. / Gavalas, S. / Huang, Y. / Pinto, P. / Sannigrahi, M. / Velazquez, F. / Venkatraman, S. / Vibulbhan, B. / Agrawal, S. / Butkiewicz, N. / Feld, B. / Ferrari, E. / He, Z. / Jiang, C.K. / Palermo, R.E. / McMonagle, P. / Huang, H.C. / Shih, N.Y. / Njoroge, G. / Kozlowski, J.A.
History
DepositionJun 22, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2011Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2012Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: HCV NS5B RNA_DEPENDENT RNA POLYMERASE
B: HCV NS5B RNA_DEPENDENT RNA POLYMERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,1434
Polymers128,3832
Non-polymers7602
Water8,107450
1
A: HCV NS5B RNA_DEPENDENT RNA POLYMERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,5712
Polymers64,1921
Non-polymers3801
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: HCV NS5B RNA_DEPENDENT RNA POLYMERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,5712
Polymers64,1921
Non-polymers3801
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)90.440, 107.630, 136.070
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 HCV NS5B RNA_DEPENDENT RNA POLYMERASE / RNA-directed RNA polymerase / NS5B


Mass: 64191.582 Da / Num. of mol.: 2 / Fragment: unp residues 2420-2989
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus isolate HC-J4 / Strain: HC-J4 / Production host: Escherichia coli (E. coli) / References: UniProt: O92972, RNA-directed RNA polymerase
#2: Chemical ChemComp-058 / 1-benzyl-5-chloro-3-(2-fluorophenyl)-1H-indole-2-carboxylic acid


Mass: 379.811 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H15ClFNO2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 450 / 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: 2.58 Å3/Da / Density % sol: 52.31 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 15.0 w/v PEG 3350, 0.1 M sodium citrate pH 5.0, VAPOR DIFFUSION, HANGING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54182 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jan 13, 2005
RadiationMonochromator: Varimax HR / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54182 Å / Relative weight: 1
ReflectionResolution: 2.5→50.04 Å / Num. all: 46716 / Num. obs: 46105 / % possible obs: 98.7 % / Observed criterion σ(F): -5 / Observed criterion σ(I): -5 / Redundancy: 3.47 % / Biso Wilson estimate: 52.7 Å2 / Rmerge(I) obs: 0.088 / Net I/σ(I): 9
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 3.22 % / Rmerge(I) obs: 0.36 / Mean I/σ(I) obs: 3 / Num. unique all: 4591 / % possible all: 98.7

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Processing

Software
NameClassification
CrystalCleardata collection
BUSTERrefinement
CrystalCleardata reduction
CrystalCleardata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.5→50.04 Å / Cor.coef. Fo:Fc: 0.902 / Cor.coef. Fo:Fc free: 0.854 / SU R Cruickshank DPI: 0.498 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.265 2285 4.96 %RANDOM
Rwork0.1994 ---
obs0.2026 46045 98.7 %-
all-46661 --
Displacement parametersBiso mean: 49.5 Å2
Baniso -1Baniso -2Baniso -3
1--22.7752 Å20 Å20 Å2
2--10.0431 Å20 Å2
3---12.7321 Å2
Refine analyzeLuzzati coordinate error obs: 0.326 Å
Refinement stepCycle: LAST / Resolution: 2.5→50.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8694 0 54 450 9198
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018950HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0912092HARMONIC2
LS refinement shellResolution: 2.5→2.56 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3106 147 4.58 %
Rwork0.2294 3064 -
all0.2332 3211 -
obs-3211 98.7 %

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