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- PDB-3tyq: SAR development and discovery of potent indole-based inhibitors o... -

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Basic information

Entry
Database: PDB / ID: 3tyq
TitleSAR development and discovery of potent indole-based inhibitors of the hepatitis c virus NS5B polymerase
ComponentsRNA-directed 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 / 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 / molecular adaptor activity / 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, 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 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 core protein, chain A superfamily / : / 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 / NS3 RNA helicase, C-terminal helical domain / 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-HI4 / PHOSPHATE ION / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.6 Å
AuthorsLesburg, C.A. / Chen, K.X.
CitationJournal: J.Med.Chem. / Year: 2012
Title: A Novel Class of Highly Potent Irreversible Hepatitis C Virus NS5B Polymerase Inhibitors.
Authors: Chen, K.X. / Lesburg, C.A. / Vibulbhan, B. / Yang, W. / Chan, T.Y. / Venkatraman, S. / Velazquez, F. / Zeng, Q. / Bennett, F. / Anilkumar, G.N. / Duca, J. / Jiang, Y. / Pinto, P. / Wang, L. ...Authors: Chen, K.X. / Lesburg, C.A. / Vibulbhan, B. / Yang, W. / Chan, T.Y. / Venkatraman, S. / Velazquez, F. / Zeng, Q. / Bennett, F. / Anilkumar, G.N. / Duca, J. / Jiang, Y. / Pinto, P. / Wang, L. / Huang, Y. / Selyutin, O. / Gavalas, S. / Pu, H. / Agrawal, S. / Feld, B. / Huang, H.C. / Li, C. / Cheng, K.C. / Shih, N.Y. / Kozlowski, J.A. / Rosenblum, S.B. / Njoroge, F.G.
History
DepositionSep 26, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 1, 2012Provider: repository / Type: Initial release
Revision 1.1Mar 21, 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: RNA-directed RNA polymerase
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,5397
Polymers128,3832
Non-polymers1,1565
Water29,1301617
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8174
Polymers64,1921
Non-polymers6253
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7223
Polymers64,1921
Non-polymers5302
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)90.034, 106.863, 134.547
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 / RNA-dependent RNA polymerase


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 / Strain: HC-J4 / Gene: NS5B / Production host: Escherichia coli (E. coli) / References: UniProt: O92972, RNA-directed RNA polymerase
#2: Chemical ChemComp-HI4 / 5-ethyl-1-(2-fluoro-5-nitrobenzyl)-3-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxylic acid


Mass: 435.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H18FN3O5
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1617 / 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: 2.52 Å3/Da / Density % sol: 51.21 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 5.2
Details: 15.0% w/v Miralax (PEG3350), 0.1 M citrate, pH 5.2, VAPOR DIFFUSION, HANGING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 18, 2007
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→50 Å / Num. all: 170899 / Num. obs: 169874 / % possible obs: 99.4 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 5.3 % / Biso Wilson estimate: 20.608 Å2 / Rmerge(I) obs: 0.046 / Net I/σ(I): 32
Reflection shellResolution: 1.6→1.66 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.317 / Mean I/σ(I) obs: 4.8 / Num. unique all: 16510 / % possible all: 99.7

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Processing

Software
NameVersionClassification
JDirectordata collection
BUSTER-TNT2.1.1refinement
HKL-2000data reduction
HKL-2000data scaling
BUSTER-TNT2.1.1phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.6→20 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.1953 8505 5.01 %RANDOM
Rwork0.1682 ---
all0.1696 169668 --
obs0.1696 169668 99.13 %-
Displacement parametersBiso mean: 24.91 Å2
Baniso -1Baniso -2Baniso -3
1--3.51844006 Å20 Å20 Å2
2---1.08863536 Å20 Å2
3---4.60707542 Å2
Refinement stepCycle: LAST / Resolution: 1.6→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8735 0 77 1617 10429
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONt_angle_deg1.28
X-RAY DIFFRACTIONt_bond_d0.011
X-RAY DIFFRACTIONt_dihedral_angle_d16.358
LS refinement shellResolution: 1.6→1.7 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2189 1314 4.96 %
Rwork0.1879 25153 -
all0.1894 26467 -
obs-26467 99.13 %

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