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Entry
Database: PDB / ID: 2gz8
TitleStructure-Based Drug Design and Structural Biology Study of Novel Nonpeptide Inhibitors of SARS-CoV Main Protease
ComponentsReplicase polyprotein 1ab
KeywordsHYDROLASE / SARS CoV main protease
Function / homology
Function and homology information


positive regulation of ubiquitin-specific protease activity / Maturation of replicase proteins / Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-1 sgRNAs / Lys48-specific deubiquitinase activity / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-1 genome / mRNA (guanine-N7-)-methyltransferase activity / Transferases; Transferring one-carbon groups; Methyltransferases / viral RNA-directed RNA polymerase complex ...positive regulation of ubiquitin-specific protease activity / Maturation of replicase proteins / Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-1 sgRNAs / Lys48-specific deubiquitinase activity / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-1 genome / mRNA (guanine-N7-)-methyltransferase activity / Transferases; Transferring one-carbon groups; Methyltransferases / viral RNA-directed RNA polymerase complex / exoribonuclease complex / viral replication complex formation and maintenance / endopeptidase complex / endoribonuclease complex / 5'-3' RNA helicase activity / mRNA cap methyltransferase complex / RNA phosphodiester bond hydrolysis, exonucleolytic / positive regulation of RNA biosynthetic process / Lyases; Phosphorus-oxygen lyases / mRNA methylation / double membrane vesicle viral factory outer membrane / suppression by virus of host translation / ISG15-specific peptidase activity / SARS coronavirus main proteinase / suppression by virus of host type I interferon production / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 3'-5'-exoribonuclease activity / host cell endosome / host cell endoplasmic reticulum-Golgi intermediate compartment / induction by virus of catabolism of host mRNA / cytoplasmic viral factory / protein K48-linked deubiquitination / G-quadruplex RNA binding / suppression by virus of host ISG15-protein conjugation / 7-methylguanosine mRNA capping / RNA-templated transcription / viral transcription / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / suppression by virus of host toll-like receptor signaling pathway / host cell Golgi apparatus / host cell endoplasmic reticulum / suppression by virus of host NF-kappaB cascade / modulation by virus of host protein ubiquitination / protein K63-linked deubiquitination / methyltransferase cap1 / positive stranded viral RNA replication / mRNA (nucleoside-2'-O-)-methyltransferase activity / positive regulation of viral genome replication / suppression by virus of host TRAF activity / protein autoprocessing / helicase activity / double-stranded RNA binding / ubiquitinyl hydrolase 1 / DNA helicase / cysteine-type deubiquitinase activity / DNA helicase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / protein processing / host cell perinuclear region of cytoplasm / viral protein processing / integral to membrane of host cell / RNA helicase / lyase activity / induction by virus of host autophagy / RNA-directed RNA polymerase / suppression by virus of host gene expression / endonuclease activity / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed 5'-3' RNA polymerase activity / DNA-templated transcription / host cell cytoplasm / protein dimerization activity / suppression by virus of host type I interferon-mediated signaling pathway / ATP hydrolysis activity / zinc ion binding / integral component of membrane / ATP binding / identical protein binding
Similarity search - Function
Non-structural protein 3, SUD-N macrodomain, SARS-CoV / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Nonstructural protein 14, betacoronavirus ...Non-structural protein 3, SUD-N macrodomain, SARS-CoV / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Nonstructural protein 14, betacoronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / Viral (Superfamily 1) RNA helicase / NSP15, NendoU domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nonstructural protein 15, middle domain, coronavirus / Non-structural protein NSP16, coronavirus-like / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Coronavirus replicase NSP15, N-terminal oligomerization / Non-structural protein 14, coronavirus / Non-structural protein NSP15, middle domain superfamily / RNA polymerase, N-terminal, coronavirus / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / NendoU domain, nidovirus / Endoribonuclease EndoU-like / Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus / Sarbecovirus Nsp3c-N domain profile. / NSP1 globular domain superfamily, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Betacoronavirus replicase NSP3, N-terminal / Non-structural protein 2, SARS-CoV-like / Non-structural protein NSP3, N-terminal, betacoronavirus / Betacoronavirus SUD-C domain / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / : / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / : / : / : / Coronavirus (CoV) Nsp1 globular domain profile. / Betacoronavirus Nsp3c-M domain profile. / : / Non-structural protein NSP3, SUD-M domain, betacoronavirus / NSP1, globular domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus single-stranded poly(A) binding domain / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / Betacoronavirus Nsp3c-C domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3A domain-like superfamily / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, N-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Coronavirus Nsp3d Ubl domain profile. / Coronavirus Nsp3a Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Papain-like protease, thumb domain superfamily, coronavirus / Non-structural protein NSP7, coronavirus / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Coronavirus endopeptidase C30 / Non-structural protein NSP9 superfamily, coronavirus / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus replicase NSP6 / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus main protease (M-pro) domain profile. / Coronavirus replicase NSP4, C-terminal / Coronavirus papain-like peptidase / Coronavirus replicase NSP3, C-terminal / RNA synthesis protein NSP10 superfamily, coronavirus
Similarity search - Domain/homology
Chem-F3F / Replicase polyprotein 1ab / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSARS coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.97 Å
AuthorsLu, I.L. / Wu, S.Y.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Structure-Based Drug Design and Structural Biology Study of Novel Nonpeptide Inhibitors of Severe Acute Respiratory Syndrome Coronavirus Main Protease
Authors: Lu, I.L. / Mahindroo, N. / Liang, P.H. / Peng, Y.H. / Kuo, C.J. / Tsai, K.C. / Hsieh, H.P. / Chao, Y.S. / Wu, S.Y.
History
DepositionMay 11, 2006Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Aug 29, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Replicase polyprotein 1ab
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2402
Polymers33,8771
Non-polymers3631
Water3,495194
1
A: Replicase polyprotein 1ab
hetero molecules

A: Replicase polyprotein 1ab
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,4804
Polymers67,7532
Non-polymers7272
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Unit cell
Length a, b, c (Å)108.279, 82.107, 53.407
Angle α, β, γ (deg.)90.00, 104.66, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-459-

HOH

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Components

#1: Protein Replicase polyprotein 1ab / SARS-CoV main protease / pp1ab / ORF1AB


Mass: 33876.637 Da / Num. of mol.: 1 / Fragment: 3C-like proteinase
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) SARS coronavirus / Genus: Coronavirus / Strain: sarsSevere acute respiratory syndrome / Plasmid: pET32Xa/LIC / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: P59641, UniProt: P0C6X7*PLUS, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Chemical ChemComp-F3F / S-[5-(TRIFLUOROMETHYL)-4H-1,2,4-TRIAZOL-3-YL] 5-(PHENYLETHYNYL)FURAN-2-CARBOTHIOATE


Mass: 363.314 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H8F3N3O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 194 / 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: 3.39 Å3/Da / Density % sol: 63.7 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 2mM DTT, 6% PEG 6000, 0.1M Mes, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL12B2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Dec 6, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.97→30 Å / Num. all: 29584 / Num. obs: 31161 / % possible obs: 96.939 % / Observed criterion σ(F): 48.23 / Observed criterion σ(I): 24.09
Reflection shellResolution: 1.967→2.018 Å / % possible all: 94.712

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
MOLREPphasing
REFMAC5.2.0005refinement
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1UK4; chain_id A
Resolution: 1.97→30 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.24057 1577 RANDOM
Rwork0.21486 --
all0.2161 29584 -
obs0.2161 31161 -
Refinement stepCycle: LAST / Resolution: 1.97→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2370 0 25 194 2589
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONr_bond_refined_d0.006
X-RAY DIFFRACTIONr_angle_refined_deg1.337

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