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- PDB-4nld: Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA... -

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Entry
Database: PDB / ID: 4nld
TitleCrystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with BMS-791325 also known as (1aR,12bS)-8-cyclohexyl-n-(dimethylsulfamoyl)-11-methoxy-1a-{[(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide and 2-(4-fluorophenyl)-n-methyl-6-[(methylsulfonyl)amino]-5-(propan-2-yloxy)-1-benzofuran-3-carboxamide
ComponentsRNA-directed RNA polymerase
Keywordstransferase/transferase INHIBITOR / NS5B / polymerase / HCV / hepatitis C virus / fingers / palm / thumb / polymerase/polymerase inhibitor / transferase-transferase INHIBITOR complex
Function / homology
Function and homology information


positive stranded viral RNA replication / 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 / viral genome replication ...positive stranded viral RNA replication / 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 / viral genome replication / SH3 domain binding / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / 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 / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA helicase / ribonucleoprotein complex / induction by virus of host autophagy / 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 / host cell plasma membrane / structural molecule activity / virion membrane / ATP hydrolysis activity / protein-containing complex / proteolysis / RNA binding / zinc ion binding / ATP binding / identical protein 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 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. / 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-2N5 / Chem-2N7 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsSheriff, S.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase.
Authors: Gentles, R.G. / Ding, M. / Bender, J.A. / Bergstrom, C.P. / Grant-Young, K. / Hewawasam, P. / Hudyma, T. / Martin, S. / Nickel, A. / Regueiro-Ren, A. / Tu, Y. / Yang, Z. / Yeung, K.S. / ...Authors: Gentles, R.G. / Ding, M. / Bender, J.A. / Bergstrom, C.P. / Grant-Young, K. / Hewawasam, P. / Hudyma, T. / Martin, S. / Nickel, A. / Regueiro-Ren, A. / Tu, Y. / Yang, Z. / Yeung, K.S. / Zheng, X. / Chao, S. / Sun, J.H. / Beno, B.R. / Camac, D.M. / Chang, C.H. / Gao, M. / Morin, P.E. / Sheriff, S. / Tredup, J. / Wan, J. / Witmer, M.R. / Xie, D. / Hanumegowda, U. / Knipe, J. / Mosure, K. / Santone, K.S. / Parker, D.D. / Zhuo, X. / Lemm, J. / Liu, M. / Pelosi, L. / Rigat, K. / Voss, S. / Wang, Y. / Wang, Y.K. / Colonno, R.J. / Gao, M. / Roberts, S.B. / Gao, Q. / Ng, A. / Meanwell, N.A. / Kadow, J.F.
History
DepositionNov 14, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 19, 2014Provider: repository / Type: Initial release
Revision 1.1Mar 26, 2014Group: Database references
Revision 1.2Jul 29, 2020Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _chem_comp.mon_nstd_flag / _chem_comp.name ..._chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,0119
Polymers63,9621
Non-polymers2,0498
Water55831
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.000, 120.600, 201.500
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

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Protein / Sugars , 2 types, 3 molecules A

#1: Protein RNA-directed RNA polymerase / NS5B / p68


Mass: 63961.516 Da / Num. of mol.: 1 / Fragment: UNP Residues 2420-2992
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Strain: Bartenschlager / Gene: NS5B / Plasmid: pET21b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) STAR / References: UniProt: Q9WMX2, RNA-directed RNA polymerase
#5: Sugar ChemComp-BOG / octyl beta-D-glucopyranoside / Beta-Octylglucoside / octyl beta-D-glucoside / octyl D-glucoside / octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0

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Non-polymers , 4 types, 37 molecules

#2: Chemical ChemComp-2N7 / (1aR,12bS)-8-cyclohexyl-N-(dimethylsulfamoyl)-11-methoxy-1a-{[(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide


Mass: 659.838 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H45N5O5S / Comment: antivirus*YM
#3: Chemical ChemComp-2N5 / 2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-5-(propan-2-yloxy)-1-benzofuran-3-carboxamide


Mass: 420.455 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21FN2O5S
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / 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: 3.47 Å3/Da / Density % sol: 64.52 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 100 mM Sodium Citrate, 1.75 M (NH4)2SO4, pH 5.6, vapor diffusion, hanging drop, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Nov 10, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.75→50 Å / Num. obs: 22091 / % possible obs: 93 % / Observed criterion σ(I): 0 / Redundancy: 5.5 % / Biso Wilson estimate: 72.05 Å2 / Rmerge(I) obs: 0.081 / Net I/σ(I): 18.3
Reflection shellResolution: 2.75→2.85 Å / Redundancy: 5.5 % / Rmerge(I) obs: 0.499 / Mean I/σ(I) obs: 3.2 / % possible all: 94.7

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Processing

Software
NameVersionClassificationNB
BUSTER-TNTBUSTER 2.11.4refinement
PDB_EXTRACT3.11data extraction
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
AMoREphasing
BUSTER2.11.4refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NS5B/LIGAND COMPLEX

Resolution: 2.75→39.42 Å / Cor.coef. Fo:Fc: 0.9242 / Cor.coef. Fo:Fc free: 0.9014 / Occupancy max: 1 / Occupancy min: 0 / SU R Cruickshank DPI: 0.518 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.498 / SU Rfree Blow DPI: 0.302 / SU Rfree Cruickshank DPI: 0.306
RfactorNum. reflection% reflectionSelection details
Rfree0.2533 1030 4.73 %RANDOM
Rwork0.2129 ---
obs0.2147 21785 92.38 %-
Displacement parametersBiso max: 148.87 Å2 / Biso mean: 61.2733 Å2 / Biso min: 20.31 Å2
Baniso -1Baniso -2Baniso -3
1-4.8202 Å20 Å20 Å2
2---12.7696 Å20 Å2
3---7.9493 Å2
Refine analyzeLuzzati coordinate error obs: 0.402 Å
Refinement stepCycle: LAST / Resolution: 2.75→39.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3867 0 136 31 4034
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1431SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes76HARMONIC2
X-RAY DIFFRACTIONt_gen_planes658HARMONIC5
X-RAY DIFFRACTIONt_it4158HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion536SEMIHARMONIC5
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_contact4708SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4158HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg5716HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion2.89
X-RAY DIFFRACTIONt_other_torsion18.81
LS refinement shellResolution: 2.75→2.88 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2637 132 4.51 %
Rwork0.2444 2796 -
all0.2453 2928 -
obs--92.38 %

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