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- PDB-7tob: Crystal structure of the SARS-CoV-2 Omicron main protease (Mpro) ... -

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Basic information

Entry
Database: PDB / ID: 7tob
TitleCrystal structure of the SARS-CoV-2 Omicron main protease (Mpro) in complex with inhibitor GC376
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN/INHIBITOR / omicron / main protease / 3cl / 3-chemotrypsin like protease / sars-cov-2 / COVID / GC376 / inhibitor / covalent / antiviral / NSP5 / VIRAL PROTEIN / VIRAL PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


viral genome replication / methyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase ...viral genome replication / methyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / host cell endosome / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / endonuclease activity / ubiquitinyl hydrolase 1 / methylation / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / host cell perinuclear region of cytoplasm / single-stranded RNA binding / host cell endoplasmic reticulum membrane / viral protein processing / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / viral translational frameshifting / cysteine-type endopeptidase activity / virus-mediated perturbation of host defense response / lipid binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / proteolysis / zinc ion binding / membrane
Similarity search - Function
Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, N-terminal, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / NSP1 globular domain superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Carbamoyl-phosphate synthase subdomain signature 2. ...Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, N-terminal, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / NSP1 globular domain superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Carbamoyl-phosphate synthase subdomain signature 2. / Betacoronavirus Nsp3c-M domain profile. / NSP1, globular domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus single-stranded poly(A) binding domain / NSP1, C-terminal domain, betacoronavirus / : / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Non-structural protein NSP3, nucleic acid-binding domain superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Papain-like viral protease, palm and finger domains, coronavirus / Papain-like protease, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP2, N-terminal / : / Coronavirus replicase NSP2, C-terminal / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp2 middle domain profile. / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / Nonstructural protein 2, N-terminal domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / : / Coronavirus 3Ecto domain profile. / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / : / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / 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. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP7, coronavirus / Non-structural protein NSP8, coronavirus / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Papain-like protease, thumb domain superfamily, coronavirus / Peptidase C30, domain 3, coronavirus / Non-structural protein 6, coronavirus / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus endopeptidase C30 / Coronavirus papain-like peptidase / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus main protease (M-pro) domain profile. / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Macro domain / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-K36 / DI(HYDROXYETHYL)ETHER / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsSacco, M.D. / Wang, J. / Chen, Y.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI158775 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI147325 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI157046 United States
CitationJournal: Cell Res. / Year: 2022
Title: The P132H mutation in the main protease of Omicron SARS-CoV-2 decreases thermal stability without compromising catalysis or small-molecule drug inhibition.
Authors: Sacco, M.D. / Hu, Y. / Gongora, M.V. / Meilleur, F. / Kemp, M.T. / Zhang, X. / Wang, J. / Chen, Y.
History
DepositionJan 24, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 2, 2022Provider: repository / Type: Initial release
Revision 1.1May 4, 2022Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 18, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5644
Polymers33,8671
Non-polymers6983
Water3,567198
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,1298
Polymers67,7332
Non-polymers1,3966
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area3280 Å2
ΔGint-16 kcal/mol
Surface area25940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.186, 52.987, 113.006
Angle α, β, γ (deg.)90.000, 100.500, 90.000
Int Tables number5
Space group name H-MI121

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Components

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


Mass: 33866.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Variant: Omicron
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P0DTC1, SARS coronavirus main proteinase
#2: Chemical ChemComp-K36 / (1S,2S)-2-({N-[(benzyloxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid / GC376


Type: peptide-like / Mass: 485.551 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H31N3O8S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antivirus*YM
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 198 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 1.96 Å3/Da / Density % sol: 37.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 20% PEG 3350, 0.2 M KNO3

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54056 Å
DetectorType: DECTRIS EIGER R 4M / Detector: PIXEL / Date: Jan 20, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54056 Å / Relative weight: 1
ReflectionResolution: 2.05→26.21 Å / Num. obs: 16446 / % possible obs: 99.2 % / Redundancy: 3.3 % / CC1/2: 0.992 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.05 / Rrim(I) all: 0.092 / Net I/σ(I): 9.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.05-2.112.90.499365112520.6920.3520.6132.298.4
8.94-26.22.30.0624361860.9590.0550.08319.989.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
Aimless0.7.7data scaling
PDB_EXTRACT3.27data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7lyh

7lyh


Resolution: 2.05→26.21 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.948 / SU B: 5.444 / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.258 / ESU R Free: 0.183 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2135 829 5 %RANDOM
Rwork0.1716 ---
obs0.1737 15614 98.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 92.5 Å2 / Biso mean: 30.736 Å2 / Biso min: 16.25 Å2
Baniso -1Baniso -2Baniso -3
1--1.28 Å20 Å2-0.3 Å2
2---0.31 Å20 Å2
3---1.6 Å2
Refinement stepCycle: final / Resolution: 2.05→26.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2363 0 43 198 2604
Biso mean--37.77 39.35 -
Num. residues----306
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0132480
X-RAY DIFFRACTIONr_bond_other_d0.0040.0152295
X-RAY DIFFRACTIONr_angle_refined_deg1.5431.6483357
X-RAY DIFFRACTIONr_angle_other_deg1.6781.595270
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6035307
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.17123.279122
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.59415390
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.8931511
X-RAY DIFFRACTIONr_chiral_restr0.0710.2319
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022850
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02588
LS refinement shellResolution: 2.05→2.103 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.264 71 -
Rwork0.268 1108 -
all-1179 -
obs--98.09 %

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