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

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Basic information

Entry
Database: PDB / ID: 7jpz
TitleStructure of the SARS-CoV-2 main protease in complex with inhibitor MPI1
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


Maturation of replicase proteins / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / viral RNA-directed RNA polymerase complex / exoribonuclease complex / endoribonuclease complex / Transcription of SARS-CoV-2 sgRNAs / endopeptidase complex / 5'-3' RNA helicase activity / mRNA cap methyltransferase complex ...Maturation of replicase proteins / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / viral RNA-directed RNA polymerase complex / exoribonuclease complex / endoribonuclease complex / Transcription of SARS-CoV-2 sgRNAs / endopeptidase complex / 5'-3' RNA helicase activity / mRNA cap methyltransferase complex / RNA phosphodiester bond hydrolysis, exonucleolytic / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / positive regulation of RNA biosynthetic process / Lyases; Phosphorus-oxygen lyases / modulation by virus of host autophagy / 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 / host cell endosome / 3'-5'-exoribonuclease activity / 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 / transcription, RNA-templated / 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 regulation of viral genome replication / mRNA (nucleoside-2'-O-)-methyltransferase activity / positive stranded viral RNA replication / suppression by virus of host TRAF activity / protein autoprocessing / cysteine-type peptidase activity / helicase activity / ubiquitinyl hydrolase 1 / DNA helicase / DNA helicase activity / cysteine-type deubiquitinase activity / single-stranded RNA binding / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / protein processing / host cell perinuclear region of cytoplasm / viral protein processing / 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 / transcription, DNA-templated / suppression by virus of host type I interferon-mediated signaling pathway / host cell cytoplasm / protein dimerization activity / host cell nucleus / ATP hydrolysis 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 / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization 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 / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization 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. / Viral (Superfamily 1) RNA helicase / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus proofreading exoribonuclease / Coronavirus replicase NSP15, N-terminal oligomerisation / Coronavirus replicase NSP15, middle domain / Non-structural protein NSP16, coronavirus-like / Coronavirus RNA-dependent RNA polymerase, N-terminal / Non-structural protein 14, coronavirus / Nonstructural protein 15, middle domain, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerisation / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / NendoU domain, nidovirus / Endoribonuclease EndoU-like / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus / Non-structural protein NSP1 superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / Non-structural protein NSP3, N-terminal, betacoronavirus / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Carbamoyl-phosphate synthase subdomain signature 2. / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / Lipocalin signature. / Coronavirus (CoV) Nsp1 globular domain profile. / Betacoronavirus Nsp3c-M domain profile. / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Betacoronavirus single-stranded poly(A) binding domain / Non-structural protein NSP1, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Non-structural protein 6, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain superfamily, 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 / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3d Ubl domain profile. / Coronavirus replicase NSP2, C-terminal / Coronavirus Nsp3a Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Papain-like protease, thumb domain superfamily, coronavirus / Peptidase family C16 domain profile. / Coronavirus replicase NSP7 / Non-structural protein NSP7, coronavirus / Coronavirus main protease (M-pro) domain profile. / Coronavirus replicase NSP8 / Coronavirus endopeptidase C30 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP3, C-terminal / Coronavirus papain-like peptidase / Coronavirus replicase NSP4, N-terminal / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Non-structural protein NSP7 superfamily, coronavirus / Coronavirus replicase NSP3, C-terminal / Peptidase C30, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP8, coronavirus / Non-structural protein 6, coronavirus
Similarity search - Domain/homology
Chem-GHX / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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

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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)34,2972
Polymers33,8581
Non-polymers4401
Water2,792155
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,5944
Polymers67,7152
Non-polymers8792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area3190 Å2
ΔGint-16 kcal/mol
Surface area24940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)114.240, 53.790, 45.040
Angle α, β, γ (deg.)90.000, 101.310, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-621-

HOH

21A-627-

HOH

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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-GHX / (phenylmethyl) N-[(2S)-1-oxidanylidene-1-[[(2S)-1-oxidanyl-3-[(3S)-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]-3-phenyl-propan-2-yl]carbamate


Mass: 439.504 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H29N3O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 155 / 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 Å3/Da / Density % sol: 38.62 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.2 M Ammonium phosphate dibasic, 17% w/v PEG3350, pH8.0, with a protein concentration of 14 mg/ml

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Data collection

DiffractionMean temperature: 120 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→56.01 Å / Num. obs: 34758 / % possible obs: 97.9 % / Redundancy: 3.7 % / CC1/2: 0.998 / Net I/σ(I): 8.8
Reflection shellResolution: 1.6→1.63 Å / Num. unique obs: 1698 / CC1/2: 0.377

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874-000refinement
PDB_EXTRACT3.25data extraction
iMOSFLMdata reduction
pointlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6Y2E

6y2e


Resolution: 1.6→56.01 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 28.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2409 1744 5.02 %
Rwork0.2057 32992 -
obs0.2074 34736 97.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 108.74 Å2 / Biso mean: 40.0819 Å2 / Biso min: 16.36 Å2
Refinement stepCycle: final / Resolution: 1.6→56.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2369 0 32 155 2556
Biso mean--71.77 42.74 -
Num. residues----306
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072493
X-RAY DIFFRACTIONf_angle_d1.0763390
X-RAY DIFFRACTIONf_dihedral_angle_d24.267358
X-RAY DIFFRACTIONf_chiral_restr0.057377
X-RAY DIFFRACTIONf_plane_restr0.006443
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6-1.650.36641480.35472696284497
1.65-1.70.33741360.30252722285897
1.7-1.760.27891570.27362693285097
1.76-1.830.27281370.26422701283897
1.83-1.910.28671570.26882716287396
1.91-2.020.31861420.25522711285397
2.02-2.140.27061430.23812759290298
2.14-2.310.30821500.23942720287099
2.31-2.540.2561380.22932800293899
2.54-2.910.3171460.21282789293599
2.91-3.660.21381440.18662807295199
3.66-56.010.17561460.15872878302499
Refinement TLS params.Method: refined / Origin x: -16.6454 Å / Origin y: 1.7936 Å / Origin z: 17.2561 Å
111213212223313233
T0.1938 Å20.0187 Å20.037 Å2-0.1913 Å2-0.018 Å2--0.1962 Å2
L1.7231 °2-0.0439 °20.7473 °2-0.9075 °20.2845 °2--1.6468 °2
S0.0402 Å °-0.0254 Å °0.1271 Å °0.0536 Å °-0.0238 Å °-0.0058 Å °0.1448 Å °-0.0242 Å °-0.051 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 401
2X-RAY DIFFRACTION1allA501
3X-RAY DIFFRACTION1allS1 - 154

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