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- PDB-4eo6: HCV NS5B polymerase inhibitors: Tri-substituted acylhydrazines as... -

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Basic information

Entry
Database: PDB / ID: 4eo6
TitleHCV NS5B polymerase inhibitors: Tri-substituted acylhydrazines as tertiary amide bioisosteres
ComponentsRNA-directed RNA polymerase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / HCV / NS5B / RNA / RNA polymerase / polymerase inhibitor / Thumb Site 2 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 transformation of host cell / symbiont-mediated suppression of host TRAF-mediated signal transduction / 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 transformation of host cell / symbiont-mediated suppression of host TRAF-mediated signal transduction / 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 / viral nucleocapsid / monoatomic ion transmembrane transport / 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 / ribonucleoprotein complex / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / serine-type endopeptidase activity / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / 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. / 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-0S2 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.791 Å
AuthorsAppleby, T.C. / Canales, E. / Watkins, W.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Tri-substituted acylhydrazines as tertiary amide bioisosteres: HCV NS5B polymerase inhibitors.
Authors: Canales, E. / Carlson, J.S. / Appleby, T. / Fenaux, M. / Lee, J. / Tian, Y. / Tirunagari, N. / Wong, M. / Watkins, W.J.
History
DepositionApr 13, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 27, 2012Provider: repository / Type: Initial release
Revision 1.1Sep 13, 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
Revision 1.2Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)129,0684
Polymers128,2892
Non-polymers7792
Water20,3031127
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,5342
Polymers64,1451
Non-polymers3901
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,5342
Polymers64,1451
Non-polymers3901
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.833, 105.714, 127.016
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: 64144.520 Da / Num. of mol.: 2 / Fragment: UNP residues 2422-2989 / Mutation: T329V, V338A, R544Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus (isolate BK) / Strain: BK / Gene: NS5B / Production host: Escherichia coli (E. coli) / References: UniProt: P26663, RNA-directed RNA polymerase
#2: Chemical ChemComp-0S2 / 5-(3,3-dimethylbut-1-yn-1-yl)-3-{[(trans-4-methylcyclohexyl)carbonyl](propan-2-yl)amino}thiophene-2-carboxylic acid


Mass: 389.551 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H31NO3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1127 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 45.23 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 15-20% PEG 4000, 10 % glycerol, 100 mM sodium acetate, pH 4.8-5.0, VAPOR DIFFUSION, SITTING DROP, temperature 293K
PH range: 4.8-5.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9773 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 7, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9773 Å / Relative weight: 1
ReflectionResolution: 1.791→48.8 Å / Num. all: 102794 / Num. obs: 102794 / % possible obs: 94.26 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 5 % / Rsym value: 0.085 / Net I/σ(I): 18

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
PHENIX(phenix.refine: 1.7_650)refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1C2P

1c2p


Resolution: 1.791→48.8 Å / SU ML: 0.2 / σ(F): 0 / Phase error: 23.42 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2212 1918 1.87 %
Rwork0.1801 --
obs0.1808 102794 94.26 %
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 41.095 Å2 / ksol: 0.368 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-1.6932 Å20 Å2-0 Å2
2--2.3938 Å20 Å2
3----4.087 Å2
Refinement stepCycle: LAST / Resolution: 1.791→48.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8696 0 54 1127 9877
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0068946
X-RAY DIFFRACTIONf_angle_d0.99412145
X-RAY DIFFRACTIONf_dihedral_angle_d11.9333275
X-RAY DIFFRACTIONf_chiral_restr0.0671370
X-RAY DIFFRACTIONf_plane_restr0.0051541
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.791-1.83580.2681080.2275611X-RAY DIFFRACTION75
1.8358-1.88540.23221300.20796684X-RAY DIFFRACTION88
1.8854-1.94090.25181320.18896909X-RAY DIFFRACTION91
1.9409-2.00350.29421320.18427085X-RAY DIFFRACTION93
2.0035-2.07510.20511340.1817148X-RAY DIFFRACTION95
2.0751-2.15820.23131390.17677297X-RAY DIFFRACTION96
2.1582-2.25640.21511420.17927330X-RAY DIFFRACTION97
2.2564-2.37540.24331340.18497363X-RAY DIFFRACTION97
2.3754-2.52420.24481420.18937422X-RAY DIFFRACTION97
2.5242-2.71910.23211440.19057463X-RAY DIFFRACTION98
2.7191-2.99270.23951430.18237527X-RAY DIFFRACTION98
2.9927-3.42570.18361450.17777589X-RAY DIFFRACTION98
3.4257-4.31560.2211440.15487645X-RAY DIFFRACTION98
4.3156-48.81820.18431490.18197803X-RAY DIFFRACTION97

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