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- PDB-4mz4: Discovery of an Irreversible HCV NS5B Polymerase Inhibitor -

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Basic information

Entry
Database: PDB / ID: 4mz4
TitleDiscovery of an Irreversible HCV NS5B Polymerase Inhibitor
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 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 / molecular adaptor activity / 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. / 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-2F3 / PHOSPHATE ION / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.63 Å
AuthorsZeng, Q. / Anilkumar, G.N. / Rosenblum, S.B. / Huang, H.-C. / Lesburg, C.A. / Jiang, Y. / Selyutin, O. / Chan, T.-Y. / Bennett, F. / Chen, K.X. ...Zeng, Q. / Anilkumar, G.N. / Rosenblum, S.B. / Huang, H.-C. / Lesburg, C.A. / Jiang, Y. / Selyutin, O. / Chan, T.-Y. / Bennett, F. / Chen, K.X. / Venkatraman, S. / Sannigrahi, M. / Velazquez, F. / Duca, J.S. / Gavalas, S. / Huang, Y. / Pu, H. / Wang, L. / Pinto, P. / Vibulbhan, B. / Agrawal, S. / Ferrari, E. / Jiang, C.-K. / Li, C. / Hesk, D. / Gesell, J. / Sorota, S. / Shih, N.-Y. / Njoroge, F.G. / Kozlowski, J.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of an irreversible HCV NS5B polymerase inhibitor.
Authors: Zeng, Q. / Nair, A.G. / Rosenblum, S.B. / Huang, H.C. / Lesburg, C.A. / Jiang, Y. / Selyutin, O. / Chan, T.Y. / Bennett, F. / Chen, K.X. / Venkatraman, S. / Sannigrahi, M. / Velazquez, F. / ...Authors: Zeng, Q. / Nair, A.G. / Rosenblum, S.B. / Huang, H.C. / Lesburg, C.A. / Jiang, Y. / Selyutin, O. / Chan, T.Y. / Bennett, F. / Chen, K.X. / Venkatraman, S. / Sannigrahi, M. / Velazquez, F. / Duca, J.S. / Gavalas, S. / Huang, Y. / Pu, H. / Wang, L. / Pinto, P. / Vibulbhan, B. / Agrawal, S. / Ferrari, E. / Jiang, C.K. / Li, C. / Hesk, D. / Gesell, J. / Sorota, S. / Shih, N.Y. / Njoroge, F.G. / Kozlowski, J.A.
History
DepositionSep 29, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2013Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2013Group: Database references
Revision 1.2Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / 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_conn.pdbx_leaving_atom_flag / _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

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)129,5927
Polymers128,3832
Non-polymers1,2095
Water29,8331656
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9385
Polymers64,1921
Non-polymers7474
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,6532
Polymers64,1921
Non-polymers4621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)89.986, 106.596, 134.602
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: 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: O92972, RNA-directed RNA polymerase
#2: Chemical ChemComp-2F3 / 1-[(2-chloroquinolin-3-yl)methyl]-6-fluoro-5-methyl-3-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxylic acid


Mass: 461.872 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H17ClFN3O3
#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.: 1656 / 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: 2.51 Å3/Da / Density % sol: 51.08 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 5.9
Details: 14.0 %w/v PEG 3350 100.0 mM Sodium citrate, pH 5.9, 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 210r / Detector: CCD / Date: Oct 18, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.63→20 Å / Num. obs: 159667 / % possible obs: 92.7 % / Biso Wilson estimate: 22.28 Å2
Reflection shellResolution: 1.63→1.66 Å / % possible all: 98.2

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Processing

Software
NameVersionClassification
HKL-2000data collection
BUSTER2.11.2refinement
HKL-2000data reduction
HKL-2000data scaling
BUSTER2.11.2phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.63→19.92 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.9491 / SU R Cruickshank DPI: 0.086 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2038 8018 5.02 %RANDOM
Rwork0.1749 ---
obs0.1763 159667 99 %-
Displacement parametersBiso mean: 27.66 Å2
Baniso -1Baniso -2Baniso -3
1--2.5666 Å20 Å20 Å2
2---2.4853 Å20 Å2
3---5.0519 Å2
Refine analyzeLuzzati coordinate error obs: 0.179 Å
Refinement stepCycle: LAST / Resolution: 1.63→19.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8749 0 79 1656 10484
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3159SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes197HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1481HARMONIC5
X-RAY DIFFRACTIONt_it9172HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1218SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact12588SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9172HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12487HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion3.54
X-RAY DIFFRACTIONt_other_torsion16.14
LS refinement shellResolution: 1.63→1.67 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2555 577 5.24 %
Rwork0.2154 10444 -
all0.2174 11021 -
obs--99 %

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