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- PDB-4eo8: HCV NS5B polymerase inhibitors: Tri-substituted acylhydrazines as... -

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Basic information

Entry
Database: PDB / ID: 4eo8
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 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-0S3 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.798 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 16, 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)129,0704
Polymers128,2892
Non-polymers7812
Water19,5821087
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,5352
Polymers64,1451
Non-polymers3911
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,5352
Polymers64,1451
Non-polymers3911
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.590, 105.930, 126.720
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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-0S3 / 5-(3,3-dimethylbut-1-yn-1-yl)-3-{2,2-dimethyl-1-[(trans-4-methylcyclohexyl)carbonyl]hydrazinyl}thiophene-2-carboxylic acid


Mass: 390.540 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N2O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1087 / 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: 2.24 Å3/Da / Density % sol: 45.06 %
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: 1.798→48.868 Å / Num. obs: 103856 / % possible obs: 96.55 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 6 % / Biso Wilson estimate: 16.44 Å2 / Rsym value: 0.068 / Net I/σ(I): 24

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Processing

Software
NameVersionClassificationNB
PHENIX1.7_650refinement
PDB_EXTRACT3.11data extraction
BOSdata collection
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1C2P

1c2p


Resolution: 1.798→48.868 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8399 / SU ML: 0.2 / σ(F): 0 / Phase error: 22.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2203 1936 1.86 %
Rwork0.1794 --
obs0.1802 103856 96.55 %
Solvent computationShrinkage radii: 0.95 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 43.094 Å2 / ksol: 0.376 e/Å3
Displacement parametersBiso max: 59.73 Å2 / Biso mean: 20.0188 Å2 / Biso min: 6.93 Å2
Baniso -1Baniso -2Baniso -3
1--1.2025 Å20 Å2-0 Å2
2--5.4156 Å20 Å2
3----4.2132 Å2
Refinement stepCycle: LAST / Resolution: 1.798→48.868 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8696 0 54 1087 9837
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0068945
X-RAY DIFFRACTIONf_angle_d0.96812145
X-RAY DIFFRACTIONf_chiral_restr0.0641366
X-RAY DIFFRACTIONf_plane_restr0.0041541
X-RAY DIFFRACTIONf_dihedral_angle_d11.4993275
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7975-1.84250.281230.2066589671288
1.8425-1.89230.25291300.2036811694191
1.8923-1.9480.24171300.19266986711694
1.948-2.01090.25351330.18697116724995
2.0109-2.08270.22871390.18357183732297
2.0827-2.16610.21711400.17857305744597
2.1661-2.26470.2361390.17567371751098
2.2647-2.38410.21961410.17467327746898
2.3841-2.53350.24421410.1817350749198
2.5335-2.72910.23641390.18247387752698
2.7291-3.00370.23981430.18757462760599
3.0037-3.43820.21331430.17327539768299
3.4382-4.33140.17641450.158676157760100
4.3314-48.88620.20561500.18657879802999

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