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- PDB-2yoj: HCV NS5B polymerase complexed with pyridonylindole compound -

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Basic information

Entry
Database: PDB / ID: 2yoj
TitleHCV NS5B polymerase complexed with pyridonylindole compound
ComponentsRNA-DIRECTED RNA POLYMERASE
KeywordsTRANSFERASE / INHIBITOR
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 / molecular adaptor activity / 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 / 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-8Y6 / PHOSPHATE ION / Genome polyprotein
Similarity search - Component
Biological speciesHEPATITIS C VIRUS
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.76 Å
AuthorsChen, K.X. / Venkatraman, S. / Anilkumar, G.N. / Zeng, Q. / Lesburg, C.A. / Vibulbhan, B. / Yang, W. / Velazquez, F. / Chan, T.-Y. / Bennett, F. ...Chen, K.X. / Venkatraman, S. / Anilkumar, G.N. / Zeng, Q. / Lesburg, C.A. / Vibulbhan, B. / Yang, W. / Velazquez, F. / Chan, T.-Y. / Bennett, F. / Sannigrahi, M. / Jiang, Y. / Duca, J.S. / Pinto, P. / Gavalas, S. / Huang, Y. / Wu, W. / Selyutin, O. / Agrawal, S. / Feld, B. / Huang, H.-C. / Li, C. / Cheng, K.-C. / Shih, N.-Y. / Kozlowski, J.A. / Rosenblum, S.B. / Njoroge, F.G.
CitationJournal: Acs Med.Chem.Lett. / Year: 2014
Title: Discovery of Sch 900188: A Potent Hepatitis C Virus Ns5B Polymerase Inhibitor Prodrug as a Development Candidate
Authors: Chen, K.X. / Venkatraman, S. / Anilkumar, G.N. / Zeng, Q. / Lesburg, C.A. / Vibulbhan, B. / Velazquez, F. / Chan, T.-Y. / Bennett, F. / Jiang, Y. / Pinto, P. / Huang, Y. / Selyutin, O. / ...Authors: Chen, K.X. / Venkatraman, S. / Anilkumar, G.N. / Zeng, Q. / Lesburg, C.A. / Vibulbhan, B. / Velazquez, F. / Chan, T.-Y. / Bennett, F. / Jiang, Y. / Pinto, P. / Huang, Y. / Selyutin, O. / Agrawal, S. / Huang, H.-C. / Li, C. / Cheng, K.-C. / Shih, N.-Y. / Kozlowski, J.A. / Rosenblum, S.B. / Njoroge, F.G.
History
DepositionOct 24, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 9, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2014Group: Database references
Revision 1.2Aug 23, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.type
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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)131,9968
Polymers130,6402
Non-polymers1,3576
Water28,3381573
1
A: RNA-DIRECTED RNA POLYMERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,9984
Polymers65,3201
Non-polymers6783
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-DIRECTED RNA POLYMERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,9984
Polymers65,3201
Non-polymers6783
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)90.271, 106.227, 134.553
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (-0.904052, -0.318902, 0.284589), (-0.278312, -0.066127, -0.958212), (0.324394, -0.945478, -0.028972)
Vector: 47.339, 53.123, 37.229)

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Components

#1: Protein RNA-DIRECTED RNA POLYMERASE / NS5B / P68


Mass: 65319.805 Da / Num. of mol.: 2 / Fragment: NS5B, RESIDUES 2420-2989
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HEPATITIS C VIRUS / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: O92972, RNA-directed RNA polymerase
#2: Chemical ChemComp-8Y6 / 4-fluoranyl-6-[(7-fluoranyl-4-oxidanylidene-3H-quinazolin-6-yl)methyl]-8-(2-oxidanylidene-1H-pyridin-3-yl)furo[2,3-e]indole-7-carboxylic acid


Mass: 488.399 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H14F2N4O5
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1573 / 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: 2.47 Å3/Da / Density % sol: 50.18 % / Description: NONE
Crystal growDetails: 14.0 %W/V PEG 3350, 100.0 MM DI-SODIUM CITRATE PH 5.9

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 11, 2007 / Details: BIMORPH
RadiationMonochromator: SI111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.76→20 Å / Num. obs: 125012 / % possible obs: 97 % / Observed criterion σ(I): 2 / Redundancy: 4.9 % / Biso Wilson estimate: 24.71 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 29.7
Reflection shellResolution: 1.76→1.79 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 3.1 / % possible all: 93

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.76→19.91 Å / Cor.coef. Fo:Fc: 0.9557 / Cor.coef. Fo:Fc free: 0.9431 / SU R Cruickshank DPI: 0.112 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.123 / SU Rfree Blow DPI: 0.113 / SU Rfree Cruickshank DPI: 0.108
RfactorNum. reflection% reflectionSelection details
Rfree0.2089 6195 5 %RANDOM
Rwork0.1767 ---
obs0.1783 123931 96.58 %-
Displacement parametersBiso mean: 29.13 Å2
Baniso -1Baniso -2Baniso -3
1--3.0709 Å20 Å20 Å2
2---2.2601 Å20 Å2
3---5.331 Å2
Refine analyzeLuzzati coordinate error obs: 0.196 Å
Refinement stepCycle: LAST / Resolution: 1.76→19.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8735 0 92 1573 10400
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.019072HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9912334HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3112SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes202HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1489HARMONIC5
X-RAY DIFFRACTIONt_it9072HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.42
X-RAY DIFFRACTIONt_other_torsion16.57
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1200SEMIHARMONIC5
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_contact12195SEMIHARMONIC4
LS refinement shellResolution: 1.76→1.81 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2707 454 5.16 %
Rwork0.2375 8337 -
all0.2391 8791 -
obs--96.58 %

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