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- PDB-5pzn: CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA-DEPENDENT RNA... -

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Basic information

Entry
Database: PDB / ID: 5pzn
TitleCRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA-DEPENDENT RNA POLYMERASE IN COMPLEX WITH 5-[3-(TERT-BUTYLCARBAMOYL)PHENYL]-2-(4-FLUOROPHENYL)-N-METHYL-1-BENZOFURAN-3-CARBOXAMIDE
ComponentsRNA-directed RNA polymerase
KeywordsTRANSFERASE / NS5B / POLYMERASE / HCV / FINGERS / PALM / THUMB
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 / 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 / protein-containing complex / proteolysis / RNA binding / zinc ion binding / ATP binding / identical protein 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 / 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-23E / Chem-8XP / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus genotype 1b
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.25 Å
AuthorsSheriff, S.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.
Authors: Yeung, K.S. / Beno, B.R. / Parcella, K. / Bender, J.A. / Grant-Young, K.A. / Nickel, A. / Gunaga, P. / Anjanappa, P. / Bora, R.O. / Selvakumar, K. / Rigat, K. / Wang, Y.K. / Liu, M. / Lemm, ...Authors: Yeung, K.S. / Beno, B.R. / Parcella, K. / Bender, J.A. / Grant-Young, K.A. / Nickel, A. / Gunaga, P. / Anjanappa, P. / Bora, R.O. / Selvakumar, K. / Rigat, K. / Wang, Y.K. / Liu, M. / Lemm, J. / Mosure, K. / Sheriff, S. / Wan, C. / Witmer, M. / Kish, K. / Hanumegowda, U. / Zhuo, X. / Shu, Y.Z. / Parker, D. / Haskell, R. / Ng, A. / Gao, Q. / Colston, E. / Raybon, J. / Grasela, D.M. / Santone, K. / Gao, M. / Meanwell, N.A. / Sinz, M. / Soars, M.G. / Knipe, J.O. / Roberts, S.B. / Kadow, J.F.
History
DepositionFeb 27, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Feb 21, 2018Group: Structure summary / Category: pdbx_deposit_group / Item: _pdbx_deposit_group.group_type
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _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
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,04727
Polymers127,9232
Non-polymers4,12425
Water6,215345
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,06614
Polymers63,9621
Non-polymers2,10413
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,98113
Polymers63,9621
Non-polymers2,02012
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.000, 91.300, 234.300
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein RNA-directed RNA polymerase


Mass: 63961.516 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus genotype 1b (isolate Con1)
Strain: isolate Con1 / Plasmid: PET21b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q9WMX2, RNA-directed RNA polymerase

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Non-polymers , 5 types, 370 molecules

#2: Chemical ChemComp-23E / (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid


Mass: 630.732 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C38H38N4O5
#3: Chemical ChemComp-8XP / 5-[3-(tert-butylcarbamoyl)phenyl]-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide


Mass: 444.497 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H25FN2O3
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 345 / 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: 2.76 Å3/Da / Density % sol: 55.42 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.6 / Details: 100 mM sodium citrate, pH 5.6, 1.75 M (NH4)2SO4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.979 / Wavelength: 0.979 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jun 12, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.25→50 Å / Num. obs: 66014 / % possible obs: 96.8 % / Observed criterion σ(I): 0 / Redundancy: 4.4 % / Biso Wilson estimate: 39.99 Å2 / Rsym value: 0.067 / Net I/σ(I): 21.3
Reflection shellResolution: 2.25→2.33 Å / Redundancy: 3.2 % / Mean I/σ(I) obs: 3.2 / Rsym value: 0.328 / Rejects: 0 / % possible all: 84.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data collection
HKL-2000data scaling
AMoREphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NS5B/LIGAND+LIGAND

Resolution: 2.25→42.53 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.932 / SU R Cruickshank DPI: 0.237 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.24 / SU Rfree Blow DPI: 0.171 / SU Rfree Cruickshank DPI: 0.171
RfactorNum. reflection% reflectionSelection details
Rfree0.204 1387 2.1 %RANDOM
Rwork0.189 ---
obs0.189 65946 96.7 %-
Displacement parametersBiso max: 168.51 Å2 / Biso mean: 45.37 Å2 / Biso min: 16.3 Å2
Baniso -1Baniso -2Baniso -3
1--8.492 Å20 Å20 Å2
2--0.7898 Å20 Å2
3---7.7022 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: final / Resolution: 2.25→42.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8360 0 276 345 8981
Biso mean--50.54 43.1 -
Num. residues----1085
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3031SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes161HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1488HARMONIC5
X-RAY DIFFRACTIONt_it8990HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1146SEMIHARMONIC5
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_contact10480SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8990HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12325HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion3.16
X-RAY DIFFRACTIONt_other_torsion15.55
LS refinement shellResolution: 2.25→2.31 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2446 84 2.09 %
Rwork0.222 3941 -
all0.2225 4025 -
obs--80.96 %

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