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- PDB-5uj2: Crystal structure of HCV NS5B genotype 2A JFH-1 isolate with S15G... -

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Basic information

Entry
Database: PDB / ID: 5uj2
TitleCrystal structure of HCV NS5B genotype 2A JFH-1 isolate with S15G E86Q E87Q C223H V321I mutations and Delta8 neta hairpoin loop deletion in complex with GS-639476 (diphsohate version of GS-9813), Mn2+ and symmetrical primer template 5'-AUAAAUUU
Components
  • Genome polyprotein
  • RNA (5'-R(*AP*UP*AP*AP*AP*UP*UP*U)-3')
Keywordsimmune system/RNA / HCV / VIRAL / NS5B / RDRP / RESISTANCE MUTATION / SOFOSBUVIR / SOVALDI / VIRUNON / GS7977-DP / GS-639476 / TEMPLATE / PRIMER / immune system-RNA complex
Function / homology
Function and homology information


negative regulation of autophagy of mitochondrion / : / hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / Dectin-2 family / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity ...negative regulation of autophagy of mitochondrion / : / hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / Dectin-2 family / 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 / ribonucleoside triphosphate phosphatase activity / lipid droplet / negative regulation of autophagy / SH3 domain binding / : / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / clathrin-dependent endocytosis of virus by host cell / viral nucleocapsid / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / RNA helicase / induction by virus of host autophagy / ribonucleoprotein complex / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane / identical protein binding / plasma membrane / cytoplasm
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 non-structural protein NS4b ...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. / 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-8B4 / : / RNA / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Hepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.9 Å
AuthorsEdwards, T.E. / Fox III, D. / Appleby, T.C. / Murakami, E. / Rey, A. / McGrath, M.E.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Discovery of a 2'-fluoro-2'-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties.
Authors: Kirschberg, T.A. / Metobo, S. / Clarke, M.O. / Aktoudianakis, V. / Babusis, D. / Barauskas, O. / Birkus, G. / Butler, T. / Byun, D. / Chin, G. / Doerffler, E. / Edwards, T.E. / Fenaux, M. / ...Authors: Kirschberg, T.A. / Metobo, S. / Clarke, M.O. / Aktoudianakis, V. / Babusis, D. / Barauskas, O. / Birkus, G. / Butler, T. / Byun, D. / Chin, G. / Doerffler, E. / Edwards, T.E. / Fenaux, M. / Lee, R. / Lew, W. / Mish, M.R. / Murakami, E. / Park, Y. / Squires, N.H. / Tirunagari, N. / Wang, T. / Whitcomb, M. / Xu, J. / Yang, H. / Ye, H. / Zhang, L. / Appleby, T.C. / Feng, J.Y. / Ray, A.S. / Cho, A. / Kim, C.U.
History
DepositionJan 16, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 22, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 12, 2017Group: Database references
Revision 1.2Oct 4, 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
T: RNA (5'-R(*AP*UP*AP*AP*AP*UP*UP*U)-3')
P: RNA (5'-R(*AP*UP*AP*AP*AP*UP*UP*U)-3')
A: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,4988
Polymers68,8543
Non-polymers6435
Water45025
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4230 Å2
ΔGint-56 kcal/mol
Surface area22420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.760, 141.760, 91.110
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

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RNA chain / Protein , 2 types, 3 molecules TPA

#1: RNA chain RNA (5'-R(*AP*UP*AP*AP*AP*UP*UP*U)-3')


Mass: 2496.529 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli) / Plasmid: VCID 6258 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): ROSETTA(DE3)
#2: Protein Genome polyprotein


Mass: 63861.336 Da / Num. of mol.: 1 / Mutation: S15G E86Q E87Q C223H V321I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Production host: Escherichia coli (E. coli) / References: UniProt: R9TEU1, UniProt: Q99IB8*PLUS

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Non-polymers , 4 types, 30 molecules

#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-8B4 / (1S)-1-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1,4-anhydro-2-deoxy-2-fluoro-5-O-[(S)-hydroxy(phosphonooxy)phosphoryl]-2-methyl-D-ribitol


Mass: 443.219 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H16FN5O9P2
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 25 / 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: 4.1 Å3/Da / Density % sol: 70 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 6.6
Details: NS5B AT 5.1 MG/ML IN 5 MM TRIS PH 7.5, 200 MM NH4OAC, 1 MM EDTA, 1 MM DTT AGAINST 25% PEG 550

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Dec 12, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 23027 / % possible obs: 99.2 % / Observed criterion σ(I): -3 / Redundancy: 3.6 % / Biso Wilson estimate: 54.08 Å2 / Rmerge(I) obs: 0.085 / Net I/σ(I): 15.77

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMACrefinement
XSCALEdata scaling
PHASERphasing
PDB_EXTRACT3.22data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WT9

4wt9


Resolution: 2.9→50 Å / SU B: 14.568 / SU ML: 0.256 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.543 / ESU R Free: 0.3 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.227 1167 5.1 %RANDOM
Rwork0.184 ---
obs0.186 23025 99.2 %-
Displacement parametersBiso mean: 57.85 Å2
Baniso -1Baniso -2Baniso -3
1-1.7 Å20.85 Å20 Å2
2--1.7 Å20 Å2
3----5.52 Å2
Refinement stepCycle: LAST / Resolution: 2.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4056 252 32 25 4365

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