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- PDB-7cut: Crystal structure of the SARS-CoV-2 (COVID-19) main protease in c... -

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Basic information

Entry
Database: PDB / ID: 7cut
TitleCrystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with Z-VAD-FMK
Components
  • 3C protein
  • Z-VAD(OMe)-FMK
KeywordsVIRAL PROTEIN / SARS-CoV-2 / 3CL / inhibitor / complex
Function / homology
Function and homology information


Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / 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 / modulation by virus of host autophagy / RNA phosphodiester bond hydrolysis, exonucleolytic / mRNA methylation ...Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / 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 / modulation by virus of host autophagy / RNA phosphodiester bond hydrolysis, exonucleolytic / 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 / G-quadruplex RNA binding / suppression by virus of host ISG15-protein conjugation / suppression by virus of host toll-like receptor signaling pathway / protein K48-linked deubiquitination / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 3'-5'-exoribonuclease activity / host cell endoplasmic reticulum-Golgi intermediate compartment / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / suppression by virus of host NF-kappaB cascade / modulation by virus of host protein ubiquitination / transcription, RNA-templated / protein K63-linked deubiquitination / positive stranded viral RNA replication / protein autoprocessing / viral genome replication / cysteine-type peptidase activity / suppression by virus of host TRAF activity / mRNA (nucleoside-2'-O-)-methyltransferase activity / helicase activity / ubiquitinyl hydrolase 1 / Transferases; Transferring one-carbon groups; Methyltransferases / viral transcription / DNA helicase / methyltransferase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / thiol-dependent deubiquitinase / 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 / suppression by virus of host type I interferon-mediated signaling pathway / viral protein processing / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed 5'-3' RNA polymerase activity / RNA helicase activity / transcription, DNA-templated / Hydrolases; Acting on ester bonds / 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 Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / 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 / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / 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 / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, N-terminal, betacoronavirus / DPUP/SUD, C-terminal, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Betacoronavirus SUD-C domain / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, coronavirus / Betacoronavirus replicase NSP3, N-terminal / Non-structural protein NSP1 superfamily, betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / Viral (Superfamily 1) RNA helicase / NSP15, NendoU domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronaviral / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus proofreading exoribonuclease / Coronavirus replicase NSP15, middle domain / Coronavirus RNA-dependent RNA polymerase, N-terminal / Coronavirus 2'-O-methyltransferase / Coronavirus replicase NSP15, N-terminal oligomerisation / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Betacoronavirus Nsp3c-M domain profile. / Coronaviridae zinc-binding (CV ZBD) domain profile. / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / Betacoronavirus Nsp3c-C domain profile. / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / NendoU domain, nidovirus / Endoribonuclease EndoU-like / Carbamoyl-phosphate synthase subdomain signature 2. / Coronavirus (CoV) Nsp1 globular domain profile. / Betacoronavirus single-stranded poly(A) binding domain / Betacoronavirus replicase NSP1 / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Non-structural protein NSP1, betacoronavirus / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Replicase polyprotein, nucleic acid-binding domain superfamily / Non-structural protein 6, betacoronavirus / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Papain-like protease, N-terminal domain superfamily, coronavirus / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Betacoronavirus nucleic acid-binding (NAR) / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Papain-like protease, thumb domain superfamily, coronavirus / Coronavirus Nsp3d Ubl domain profile. / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Non-structural protein NSP3A domain-like superfamily / (+)RNA virus helicase core domain profile. / (+) RNA virus helicase core domain / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Lipocalin signature. / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Non-structural protein NSP7 superfamily, coronavirus / Coronavirus replicase NSP7 / Non-structural protein NSP7, coronavirus / Peptidase family C16 domain profile. / Coronavirus endopeptidase C30 / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / 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 / Coronavirus papain-like peptidase / Coronavirus replicase NSP4, N-terminal / Papain-like viral protease, palm and finger domains, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP8, coronavirus-like / Peptidase C16, coronavirus / Peptidase C30, coronavirus / Peptidase C30, domain 3, coronavirus
Similarity search - Domain/homology
Z-VAD(OMe)-FMK / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å
AuthorsLu, M. / Yang, H.T. / Wang, Z.Y. / Zhao, Y. / Xing, Y.F.
Funding support China, 7items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81520108019 China
National Natural Science Foundation of China (NSFC)813300237 China
Other governmentClinical Research Program of Ruijin Hospital (2018CR006) China
Other governmentShanghai Youth Talent Development Program (2017275) China
Other governmentShanghai Medical and Health Excellent Discipline Leader Development Plan (2018BR36) China
Other governmentShanghai Collaborative Innovation Center for Translational Medicine (TM201902) China
Other governmentFoundation of National Facility for Translational Medicine (Shanghai) (TMSK-2020-003) China
CitationJournal: Signal Transduct Target Ther / Year: 2021
Title: Identification of proteasome and caspase inhibitors targeting SARS-CoV-2 M pro .
Authors: Wang, Z. / Zhao, Y. / Wang, Q. / Xing, Y. / Feng, L. / Kong, J. / Peng, C. / Zhang, L. / Yang, H. / Lu, M.
History
DepositionAug 24, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 23, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 7, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C protein
B: Z-VAD(OMe)-FMK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6666
Polymers34,3112
Non-polymers3544
Water3,225179
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
γ
α
β
Length a, b, c (Å)98.220, 82.650, 51.740
Angle α, β, γ (deg.)90.000, 115.280, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-675-

HOH

21A-710-

HOH

31A-711-

HOH

41A-770-

HOH

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Components

#1: Protein 3C protein / main protease


Mass: 33825.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: SF file contains Friedel pairs.
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: rep, 1a-1b / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Protein/peptide Z-VAD(OMe)-FMK


Type: Peptide-like / Class: Inhibitor / Mass: 485.933 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: Z-VAD(OMe)-FMK
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 179 / 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: 3 Å3/Da / Density % sol: 58.98 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1 M HEPES pH 7.5, 10% w/v PEG6000, 5% v/v MPD

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97913 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 8, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97913 Å / Relative weight: 1
ReflectionResolution: 1.82→44.41 Å / Num. obs: 60523 / % possible obs: 97 % / Redundancy: 1.9 % / CC1/2: 0.998 / Net I/σ(I): 14
Reflection shellResolution: 1.82→1.86 Å / Redundancy: 1.9 % / Num. unique obs: 1974 / CC1/2: 0.85 / % possible all: 99.3

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6LU7
Resolution: 1.82→44.41 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 27.07 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2232 3705 6.12 %
Rwork0.1823 56818 -
obs0.1848 60523 91.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 101.89 Å2 / Biso mean: 41.4431 Å2 / Biso min: 17.53 Å2
Refinement stepCycle: final / Resolution: 1.82→44.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2329 0 54 179 2562
Biso mean--57.89 47.27 -
Num. residues----301
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 26

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.82-1.840.31531510.30622335248695
1.84-1.870.3451430.28022214235796
1.87-1.90.32361510.2872318246995
1.9-1.920.33671340.30882114224890
1.92-1.950.31181530.2792238239195
1.95-1.990.32961570.25912299245696
1.99-2.020.30821480.24542262241095
2.02-2.060.33321490.24782270241995
2.06-2.10.25071390.2372141228091
2.1-2.140.22281530.23182333248696
2.14-2.190.25331510.2242286243796
2.19-2.240.30021450.2282253239895
2.24-2.290.28811460.2262188233491
2.29-2.360.28981430.22182268241195
2.36-2.420.27931470.21362298244597
2.42-2.50.23761480.21292293244195
2.5-2.590.25291440.19372206235093
2.59-2.70.22931370.20032155229290
2.7-2.820.27521420.20042144228691
2.82-2.970.27521360.1912134227090
2.97-3.150.23251340.1842080221487
3.15-3.40.22591310.17312031216284
3.4-3.740.19261290.15561951208082
3.74-4.280.19281240.13171982210683
4.28-5.390.14931380.13232009214785
5.39-44.410.14771320.14962016214885

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