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- PDB-7e19: Crystal structure of SAR-CoV-2 3CL protease complex with inhibito... -

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Entry
Database: PDB / ID: 7.0E+19
TitleCrystal structure of SAR-CoV-2 3CL protease complex with inhibitor SH-5
Components3C-like proteinase
KeywordsHYDROLASE / SARS-CoV-2 3CL protease
Function / homology
Function and homology information


Maturation of replicase proteins / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-2 sgRNAs / host cell endosome / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Translation of Replicase and Assembly of the Replication Transcription Complex / exoribonuclease activity / RNA phosphodiester bond hydrolysis, exonucleolytic / modulation by virus of host autophagy / mRNA methylation ...Maturation of replicase proteins / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-2 sgRNAs / host cell endosome / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Translation of Replicase and Assembly of the Replication Transcription Complex / exoribonuclease activity / RNA phosphodiester bond hydrolysis, exonucleolytic / modulation by virus of host autophagy / mRNA methylation / double membrane vesicle viral factory outer membrane / suppression by virus of host translation / ISG15-specific protease activity / host cell Golgi apparatus / Replication of the SARS-CoV-2 genome / suppression by virus of host type I interferon production / host cell endoplasmic reticulum / induction by virus of catabolism of host mRNA / SARS coronavirus main proteinase / cytoplasmic viral factory / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / G-quadruplex RNA binding / 3'-5'-exoribonuclease activity / suppression by virus of host ISG15-protein conjugation / host cell endoplasmic reticulum-Golgi intermediate compartment / protein K48-linked deubiquitination / suppression by virus of host toll-like receptor signaling pathway / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / transcription, RNA-templated / suppression by virus of host NF-kappaB cascade / modulation by virus of host protein ubiquitination / protein K63-linked deubiquitination / positive stranded viral RNA replication / protein autoprocessing / cysteine-type peptidase activity / mRNA (nucleoside-2'-O-)-methyltransferase activity / viral genome replication / suppression by virus of host TRAF activity / helicase activity / viral transcription / Transferases; Transferring one-carbon groups; Methyltransferases / ubiquitinyl hydrolase 1 / methyltransferase activity / DNA helicase / thiol-dependent deubiquitinase / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / DNA helicase activity / single-stranded RNA binding / host cell perinuclear region of cytoplasm / methylation / RNA helicase / induction by virus of host autophagy / endonuclease activity / RNA-directed RNA polymerase / RNA helicase activity / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed 5'-3' RNA polymerase activity / viral protein processing / suppression by virus of host type I interferon-mediated signaling pathway / Hydrolases; Acting on ester bonds / transcription, DNA-templated / host cell cytoplasm / protein dimerization activity / protein homodimerization activity / zinc ion binding / integral component of membrane / ATP binding / identical protein binding / cytosol
Similarity search - Function
RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nonstructural protein 14, betacoronavirus / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nonstructural protein 14, betacoronavirus / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Viral (Superfamily 1) RNA helicase / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Non-structural protein NSP15, middle domain superfamily / Non-structural protein 14, coronavirus / Non-structural protein NSP16, coronavirus-like / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / RNA polymerase, N-terminal, coronavirus / Coronavirus replicase NSP15, N-terminal oligomerisation / Coronavirus replicase NSP15, middle domain / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein 2, SARS-CoV-like / Non-structural protein NSP1 superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Polyprotein cleavage domain PL2pro superfamily, coronavirus / Betacoronavirus replicase NSP3, N-terminal / Non-structural protein NSP3, N-terminal, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / Endoribonuclease EndoU-like / Carbamoyl-phosphate synthase subdomain signature 2. / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Betacoronavirus Nsp3c-M domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / Betacoronavirus Nsp3c-C domain profile. / (+)RNA virus helicase core domain profile. / (+) RNA virus helicase core domain / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Replicase polyprotein, nucleic acid-binding domain superfamily / Non-structural protein NSP1, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus single-stranded poly(A) binding domain / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Coronavirus (CoV) Nsp1 globular domain profile. / Non-structural protein 6, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3A domain-like superfamily / Papain-like protease, N-terminal domain superfamily, coronavirus / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Papain-like protease, thumb domain superfamily, coronavirus / Lipocalin signature. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Coronavirus Nsp3d Ubl domain profile. / Coronavirus Nsp3a Ubl domain profile. / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Peptidase family C16 domain profile. / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein NSP7, coronavirus / Coronavirus replicase NSP7 / Coronavirus endopeptidase C30 / Non-structural protein NSP8, coronavirus-like / RNA synthesis protein NSP10, coronavirus / Coronavirus papain-like peptidase / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus main protease (M-pro) domain profile. / Coronavirus replicase NSP6 / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / Coronavirus replicase NSP4, N-terminal / Non-structural protein NSP8 superfamily, coronavirus / Peptidase C30, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Coronavirus replicase NSP3, C-terminal
Similarity search - Domain/homology
Chem-HUO / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsSenda, M. / Konno, S. / Hayashi, Y. / Senda, T.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED)JP20am0101001 Japan
CitationJournal: J.Med.Chem. / Year: 2021
Title: 3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV-2 Agents.
Authors: Konno, S. / Kobayashi, K. / Senda, M. / Funai, Y. / Seki, Y. / Tamai, I. / Schakel, L. / Sakata, K. / Pillaiyar, T. / Taguchi, A. / Taniguchi, A. / Gutschow, M. / Muller, C.E. / Takeuchi, K. ...Authors: Konno, S. / Kobayashi, K. / Senda, M. / Funai, Y. / Seki, Y. / Tamai, I. / Schakel, L. / Sakata, K. / Pillaiyar, T. / Taguchi, A. / Taniguchi, A. / Gutschow, M. / Muller, C.E. / Takeuchi, K. / Hirohama, M. / Kawaguchi, A. / Kojima, M. / Senda, T. / Shirasaka, Y. / Kamitani, W. / Hayashi, Y.
History
DepositionFeb 1, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 23, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 11, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4612
Polymers33,8261
Non-polymers6361
Water2,216123
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,9234
Polymers67,6512
Non-polymers1,2722
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
Buried area3100 Å2
ΔGint-14 kcal/mol
Surface area24540 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)45.111, 63.286, 106.697
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

#1: Protein 3C-like proteinase / 3CL-PRO / 3CLp / Main protease / Mpro / Non-structural protein 5 / nsp5 / SARS coronavirus main proteinase


Mass: 33825.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-HUO / (phenylmethyl) N-[(2S)-1-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-1-oxidanylidene-3-[(3S)-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]amino]-3-methyl-1-oxidanylidene-butan-2-yl]carbamate


Mass: 635.774 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H41N5O6S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 123 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.25 Å3/Da / Density % sol: 45.37 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 17.5% PEG4000 0.1M sodium acetate pH 4.6 0.2 M ammonium acetate

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-17A / Wavelength: 0.98 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 23, 2020
RadiationMonochromator: Si111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.15→44.55 Å / Num. obs: 17272 / % possible obs: 100 % / Redundancy: 13.3 % / Biso Wilson estimate: 21.64 Å2 / Rmerge(I) obs: 0.231 / Net I/σ(I): 12.63
Reflection shellResolution: 2.15→2.27 Å / Rmerge(I) obs: 0.971 / Mean I/σ(I) obs: 3.47 / Num. unique obs: 2559

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Processing

Software
NameVersionClassification
PHENIX1.19_4092refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6Y2F
Resolution: 2.15→41.55 Å / SU ML: 0.2432 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 22.8147
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2346 864 5 %
Rwork0.1913 16406 -
obs0.1934 17270 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.43 Å2
Refinement stepCycle: LAST / Resolution: 2.15→41.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2339 0 45 123 2507
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00762439
X-RAY DIFFRACTIONf_angle_d0.9563316
X-RAY DIFFRACTIONf_chiral_restr0.0537375
X-RAY DIFFRACTIONf_plane_restr0.0088429
X-RAY DIFFRACTIONf_dihedral_angle_d11.0416380
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.280.24531410.20492678X-RAY DIFFRACTION100
2.28-2.460.28591400.21242666X-RAY DIFFRACTION100
2.46-2.710.27981420.21392698X-RAY DIFFRACTION100
2.71-3.10.24771440.21182723X-RAY DIFFRACTION100
3.1-3.910.22331440.18292750X-RAY DIFFRACTION100
3.91-41.550.19811530.16712891X-RAY DIFFRACTION99.93
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
11.280248792280.598662144956-0.1171686105771.259340299470.2909745663892.35643796873-0.06917116219480.2248302371670.0955711386882-0.08099043022210.0737866897824-0.0876250679551-0.1999289033180.026329419683-0.001402175215430.138307268606-0.0025161299588-0.01377614114790.1465039156070.04069985061320.1432660144579.97410237469-17.3273571376-34.1804328999
22.872274042370.0950879585206-0.1071373608152.4039043544-0.6599926601911.96948115211-0.0483408815110.00162730370412-0.002580757023770.0728755617128-0.01840202148520.026334981848-0.01180253772030.009752237227510.05229248876190.1156007118710.01599832766540.001087317795370.0997791303926-0.02189540420410.116099484923-12.6147159741-21.5933637619-11.2240294636
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 1 through 200 )1 - 2001 - 200
22chain 'A' and (resid 201 through 305 )201 - 305201 - 305

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