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- PDB-7jt0: Crystal structure of SARS-CoV-2 3CL protease in complex with MAC5576 -

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Basic information

Entry
Database: PDB / ID: 7jt0
TitleCrystal structure of SARS-CoV-2 3CL protease in complex with MAC5576
Components3C-like proteinase
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / SARS-CoV-2 3CL protease / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / exoribonuclease complex / viral RNA-directed RNA polymerase complex / endoribonuclease complex / Transcription of SARS-CoV-2 sgRNAs / endopeptidase complex / 5'-3' RNA helicase activity / mRNA cap methyltransferase complex ...Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / exoribonuclease complex / viral RNA-directed RNA polymerase 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 / modulation by virus of host autophagy / Lyases; Phosphorus-oxygen lyases / 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 / Nonstructural protein 14, betacoronavirus / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / 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. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / 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. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) 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 / Nonstructural protein 15, middle domain, coronavirus / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP15, middle domain superfamily / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Coronavirus replicase NSP15, middle domain / Coronavirus 2'-O-methyltransferase / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / 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 NSP3, N-terminal, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Non-structural protein NSP1 superfamily, betacoronavirus / Betacoronavirus replicase NSP3, N-terminal / Betacoronavirus SUD-C domain / (+) 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 / Betacoronavirus single-stranded poly(A) binding domain / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Non-structural protein NSP1, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / Betacoronavirus Nsp3c-C domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 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 / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3d Ubl domain profile. / 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 / Non-structural protein NSP7, coronavirus / Peptidase family C16 domain profile. / Coronavirus replicase NSP7 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP8 / Coronavirus endopeptidase C30 / Coronavirus papain-like peptidase / Coronavirus main protease (M-pro) domain profile. / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus replicase NSP6 / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein 6, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP8, coronavirus / RNA synthesis protein NSP10, coronavirus
Similarity search - Domain/homology
thiophene-2-carbaldehyde / PHOSPHATE ION / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.73 Å
AuthorsIketani, S. / Forouhar, F. / Liu, H. / Hong, S.J. / Lin, F.-Y. / Nair, M.S. / Zask, A. / Huang, Y. / Xing, L. / Stockwell, B.R. ...Iketani, S. / Forouhar, F. / Liu, H. / Hong, S.J. / Lin, F.-Y. / Nair, M.S. / Zask, A. / Huang, Y. / Xing, L. / Stockwell, B.R. / Chavez, A. / Ho, D.D.
CitationJournal: Nat Commun / Year: 2021
Title: Lead compounds for the development of SARS-CoV-2 3CL protease inhibitors.
Authors: Iketani, S. / Forouhar, F. / Liu, H. / Hong, S.J. / Lin, F.Y. / Nair, M.S. / Zask, A. / Huang, Y. / Xing, L. / Stockwell, B.R. / Chavez, A. / Ho, D.D.
History
DepositionAug 16, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 10, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 14, 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 / _citation_author.identifier_ORCID / _citation_author.name

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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)34,0333
Polymers33,8261
Non-polymers2072
Water4,234235
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,0656
Polymers67,6512
Non-polymers4144
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_557-x,y,-z+21
Buried area3150 Å2
ΔGint-31 kcal/mol
Surface area25360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.329, 82.496, 51.821
Angle α, β, γ (deg.)90.000, 114.830, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-543-

HOH

21A-634-

HOH

31A-696-

HOH

41A-720-

HOH

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Components

#1: Protein 3C-like proteinase / SARS-CoV-2 3CL protease


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
Gene: rep, 1a-1b / Cell (production host): BL21 (DE3) / Production host: Escherichia coli (E. coli)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-LW1 / thiophene-2-carbaldehyde / Thiophene-2-carboxaldehyde


Mass: 112.150 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4OS / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 235 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Nonpolymer detailsMAC5576 is a slowly hydrolyzed, unnatural substrate of 3CL, as confirmed by biochemical studies

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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: 2.82 Å3/Da / Density % sol: 56.38 %
Crystal growTemperature: 277 K / Method: microbatch / pH: 6
Details: 0.1 M sodium phosphate-monobasic, 0.1 M MES (pH 6), and 20% (w/v) PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 30, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.73→60.6 Å / Num. obs: 38900 / % possible obs: 99.2 % / Redundancy: 6.8 % / CC1/2: 1 / Rmerge(I) obs: 0.04 / Net I/σ(I): 23.5
Reflection shellResolution: 1.73→1.75 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.69 / Num. unique obs: 3899 / CC1/2: 0.9 / % possible all: 88.3

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7JST
Resolution: 1.73→47.03 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.39 / Phase error: 20.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1917 3899 10.03 %
Rwork0.1666 34980 -
obs0.1691 38879 99.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 150.59 Å2 / Biso mean: 42.403 Å2 / Biso min: 17.56 Å2
Refinement stepCycle: final / Resolution: 1.73→47.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2333 0 12 241 2586
Biso mean--41.06 49.9 -
Num. residues----302
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062397
X-RAY DIFFRACTIONf_angle_d0.8383258
X-RAY DIFFRACTIONf_dihedral_angle_d17.635855
X-RAY DIFFRACTIONf_chiral_restr0.051365
X-RAY DIFFRACTIONf_plane_restr0.006423
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 28

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.73-1.750.26521370.26591241137899
1.75-1.770.28121560.257712331389100
1.77-1.80.30091500.23961251140199
1.8-1.820.24651410.21081217135899
1.82-1.850.22421420.19141269141199
1.85-1.870.20271370.17931236137399
1.87-1.90.20481400.17061232137299
1.9-1.940.19451480.17421213136199
1.94-1.970.1961380.17351235137399
1.97-20.22181290.16891292142199
2-2.040.19391350.17791189132498
2.04-2.080.23761420.18141230137297
2.08-2.130.1791130.17331276138999
2.13-2.180.20971270.170212751402100
2.18-2.230.20351350.166312431378100
2.23-2.290.23271570.177412471404100
2.29-2.360.22591320.182112741406100
2.36-2.440.23751350.184612571392100
2.44-2.530.24111380.185312461384100
2.53-2.630.21221270.18612791406100
2.63-2.750.21891300.18621252138299
2.75-2.890.21631620.1841231139399
2.89-3.070.21151410.1781233137498
3.07-3.310.1971470.177412441391100
3.31-3.640.19091370.17412631400100
3.64-4.170.18141390.1441266140599
4.17-5.250.14161520.12821259141199
5.25-47.030.13921320.14741297142999
Refinement TLS params.Method: refined / Origin x: -26.4727 Å / Origin y: 12.6631 Å / Origin z: 59.5781 Å
111213212223313233
T0.1748 Å2-0.0114 Å2-0.0041 Å2-0.2118 Å2-0.0168 Å2--0.2282 Å2
L0.5906 °20.4179 °2-0.099 °2-1.2068 °20.4978 °2--1.9393 °2
S0.0243 Å °-0.025 Å °-0.0419 Å °-0.0085 Å °0.0094 Å °-0.096 Å °0.0155 Å °-0.0352 Å °-0.0009 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 302
2X-RAY DIFFRACTION1allA401 - 402
3X-RAY DIFFRACTION1allS1 - 241

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