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- PDB-7jq3: Structure of the SARS-CoV-2 main protease in complex with inhibit... -

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Basic information

Entry
Database: PDB / ID: 7jq3
TitleStructure of the SARS-CoV-2 main protease in complex with inhibitor MPI6
Components3C-like proteinase
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / COVID-19 / SARS-CoV-2 / main protease / reversible covalent inhibitors / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity, producing 3'-phosphomonoesters / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 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 ...protein guanylyltransferase activity / RNA endonuclease activity, producing 3'-phosphomonoesters / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 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 / TRAF3-dependent IRF activation pathway / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / snRNP Assembly / double membrane vesicle viral factory outer membrane / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / SARS coronavirus main proteinase / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase activity / symbiont-mediated suppression of host NF-kappaB cascade / host cell endosome / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / mRNA (guanine-N7)-methyltransferase / omega peptidase activity / methyltransferase cap1 / 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 / DNA helicase / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / ubiquitinyl hydrolase 1 / 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 / lyase activity / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / copper ion binding / RNA-directed RNA polymerase / viral translational frameshifting / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / lipid binding / DNA-templated transcription / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / : / : / : / Coronavirus Nonstructural protein 13, 1B domain ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / : / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Coronavirus Nsp12 Interface domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerization / Nonstructural protein 15, middle domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Nidovirus 2-O-methyltransferase / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Nidovirus 3'-5' exoribonuclease domain / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / : / Lipocalin signature. / DNA2/NAM7 helicase-like, C-terminal / AAA domain / 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 / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / 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.
Similarity search - Domain/homology
Chem-VHP / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsYang, K. / Liu, W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM121584 United States
CitationJournal: Chemmedchem / Year: 2021
Title: A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors*.
Authors: Yang, K.S. / Ma, X.R. / Ma, Y. / Alugubelli, Y.R. / Scott, D.A. / Vatansever, E.C. / Drelich, A.K. / Sankaran, B. / Geng, Z.Z. / Blankenship, L.R. / Ward, H.E. / Sheng, Y.J. / Hsu, J.C. / ...Authors: Yang, K.S. / Ma, X.R. / Ma, Y. / Alugubelli, Y.R. / Scott, D.A. / Vatansever, E.C. / Drelich, A.K. / Sankaran, B. / Geng, Z.Z. / Blankenship, L.R. / Ward, H.E. / Sheng, Y.J. / Hsu, J.C. / Kratch, K.C. / Zhao, B. / Hayatshahi, H.S. / Liu, J. / Li, P. / Fierke, C.A. / Tseng, C.K. / Xu, S. / Liu, W.R.
History
DepositionAug 10, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 23, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 31, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.4Oct 16, 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

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4202
Polymers33,8581
Non-polymers5631
Water1,892105
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,8404
Polymers67,7152
Non-polymers1,1252
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,y,-z1
Buried area3220 Å2
ΔGint-17 kcal/mol
Surface area25200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.240, 53.760, 113.822
Angle α, β, γ (deg.)90.000, 101.130, 90.000
Int Tables number5
Space group name H-MI121

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Components

#1: Protein 3C-like proteinase / SARS-CoV-2 Main Protease


Mass: 33857.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
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: Chemical ChemComp-VHP / N-[(benzyloxy)carbonyl]-O-tert-butyl-L-threonyl-N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-L-leucinamide


Mass: 562.698 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H46N4O7 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 105 / 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: 2.01 Å3/Da / Density % sol: 38.67 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.2 M Ammonium phosphate dibasic, 17% w/v PEG3350, pH 8.0, with a protein concentration of 14 mg/ml

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Data collection

DiffractionMean temperature: 120 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU R-AXIS IV / Wavelength: 1.5 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jul 3, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5 Å / Relative weight: 1
ReflectionResolution: 2.1→48.44 Å / Num. obs: 15795 / % possible obs: 99.9 % / Redundancy: 4.2 % / CC1/2: 0.995 / Net I/σ(I): 8.8
Reflection shellResolution: 2.1→2.16 Å / Num. unique obs: 1265 / CC1/2: 0.633

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Processing

Software
NameVersionClassification
PHENIX1.18.2refinement
PDB_EXTRACT3.25data extraction
iMOSFLMdata reduction
pointlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6Y2E

6y2e


Resolution: 2.1→48.44 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 32.65 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2544 814 5.16 %
Rwork0.2066 --
obs0.2094 15762 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 177.22 Å2 / Biso mean: 60.3828 Å2 / Biso min: 25.18 Å2
Refinement stepCycle: final / Resolution: 2.1→48.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2369 0 40 105 2514
Biso mean--89.05 71.06 -
Num. residues----306
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092487
X-RAY DIFFRACTIONf_angle_d1.1773383
X-RAY DIFFRACTIONf_dihedral_angle_d20.868358
X-RAY DIFFRACTIONf_chiral_restr0.058380
X-RAY DIFFRACTIONf_plane_restr0.006439
Refinement TLS params.Method: refined / Origin x: 24.9596 Å / Origin y: 1.891 Å / Origin z: -12.861 Å
111213212223313233
T0.2267 Å20.057 Å2-0.0589 Å2-0.2704 Å20.037 Å2--0.2109 Å2
L2.4966 °2-0.6895 °2-1.0904 °2-2.8983 °2-0.0698 °2--3.4467 °2
S0.0082 Å °0.1544 Å °-0.0566 Å °-0.1408 Å °-0.0241 Å °-0.0713 Å °-0.2629 Å °-0.1099 Å °0.0477 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 401
2X-RAY DIFFRACTION1allS1 - 39
3X-RAY DIFFRACTION1allB1 - 66

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