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- PDB-7jsu: Crystal structure of SARS-CoV-2 3CL protease in complex with GC376 -

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Basic information

Entry
Database: PDB / ID: 7jsu
TitleCrystal structure of SARS-CoV-2 3CL protease in complex with GC376
Components3C-like proteinase
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / SARS-CoV-2 3CL protease / 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 / exoribonuclease complex / viral RNA-directed RNA polymerase complex / viral replication complex formation and maintenance / endopeptidase complex / endoribonuclease complex / Transcription of SARS-CoV-2 sgRNAs / 5'-3' RNA helicase activity ...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 / exoribonuclease complex / viral RNA-directed RNA polymerase complex / viral replication complex formation and maintenance / endopeptidase complex / endoribonuclease complex / Transcription of SARS-CoV-2 sgRNAs / 5'-3' RNA helicase activity / mRNA cap methyltransferase complex / RNA phosphodiester bond hydrolysis, exonucleolytic / mRNA cap binding complex / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / Lyases; Phosphorus-oxygen lyases / positive regulation of RNA biosynthetic process / 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 / 3'-5'-exoribonuclease activity / host cell endosome / 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 / RNA-templated transcription / 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 stranded viral RNA replication / mRNA (nucleoside-2'-O-)-methyltransferase activity / positive regulation of viral genome replication / suppression by virus of host TRAF activity / protein autoprocessing / cysteine-type peptidase activity / helicase activity / ubiquitinyl hydrolase 1 / DNA helicase / cysteine-type deubiquitinase activity / DNA helicase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / protein processing / host cell perinuclear region of cytoplasm / viral protein processing / integral to membrane of host cell / 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 / DNA-templated transcription / host cell cytoplasm / protein dimerization activity / suppression by virus of host type I interferon-mediated signaling pathway / 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) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp15 N-terminal oligomerization 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) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / 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, N-terminal oligomerization / Non-structural protein NSP15, middle domain superfamily / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Nonstructural protein 15, middle domain, coronavirus / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / Coronavirus replicase NSP15, N-terminal oligomerisation / Coronavirus replicase NSP15, middle domain / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Coronavirus RNA-dependent RNA polymerase, N-terminal / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronaviridae zinc-binding (CV ZBD) domain profile. / Nonstructural protein 13, zinc-binding domain, coronavirus-like / 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 / Betacoronavirus replicase NSP3, N-terminal / NSP1 globular domain superfamily, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Non-structural protein NSP3, N-terminal, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Non-structural protein 2, SARS-CoV-like / (+)RNA virus helicase core domain profile. / (+) RNA virus helicase core domain / 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. / : / NSP1, globular domain, betacoronavirus / Betacoronavirus replicase NSP1 / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Betacoronavirus single-stranded poly(A) binding domain / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor 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 superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, N-terminal / Coronavirus replicase NSP2, C-terminal / Coronavirus Nsp3d Ubl domain profile. / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Papain-like protease, thumb domain superfamily, coronavirus / Non-structural protein NSP7, coronavirus / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Coronavirus endopeptidase C30 / Coronavirus replicase NSP4, C-terminal / Coronavirus main protease (M-pro) domain profile. / Coronavirus papain-like peptidase / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP3, C-terminal / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP6 / Coronavirus replicase NSP8 / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein NSP4, N-terminal, coronavirus / Peptidase C30, domain 3, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus
Similarity search - Domain/homology
PHOSPHATE ION / Chem-UED / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 Å
AuthorsIketani, S. / Forouhar, F. / Liu, H. / Hong, S.J. / Lin, F.-Y. / Nair, M.S. / Zask, A. / 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 1.1Mar 24, 2021Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.2Apr 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

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Assembly

Deposited unit
A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4214
Polymers33,8261
Non-polymers5953
Water3,261181
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,8428
Polymers67,6512
Non-polymers1,1916
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_557-x,y,-z+21
Buried area3830 Å2
ΔGint-46 kcal/mol
Surface area25100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.830, 80.225, 51.990
Angle α, β, γ (deg.)90.000, 114.310, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-402-

PO4

21A-403-

PO4

31A-585-

HOH

41A-631-

HOH

51A-670-

HOH

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Components

#1: Protein 3C-like proteinase / 3CL-PRO / 3CLp / Main protease / Mpro / Non-structural protein 5 / nsp5 / SARS-CoV-2 main proteinase


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-UED / N~2~-[(benzyloxy)carbonyl]-N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-L-leucinamide / GC373 bound form


Mass: 405.488 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H31N3O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 181 / 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: 2.78 Å3/Da / Density % sol: 55.7 %
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-C / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: May 7, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.83→59.9 Å / Num. obs: 31993 / % possible obs: 99 % / Redundancy: 6.9 % / CC1/2: 0.99 / Net I/σ(I): 12.7
Reflection shellResolution: 1.83→1.86 Å / Rmerge(I) obs: 0.61 / Num. unique obs: 3134 / CC1/2: 0.93

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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: D_1000251323

Resolution: 1.83→47.38 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.41 / Phase error: 22.24 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2028 3134 9.8 %
Rwork0.1693 28837 -
obs0.1726 31971 97.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 146.76 Å2 / Biso mean: 41.0112 Å2 / Biso min: 15.77 Å2
Refinement stepCycle: final / Resolution: 1.83→47.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2340 0 39 183 2562
Biso mean--38.53 47.86 -
Num. residues----303
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062431
X-RAY DIFFRACTIONf_angle_d0.8443305
X-RAY DIFFRACTIONf_dihedral_angle_d15.575866
X-RAY DIFFRACTIONf_chiral_restr0.05370
X-RAY DIFFRACTIONf_plane_restr0.005427
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 22

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.83-1.860.29581490.24991252140195
1.86-1.890.27891400.22361318145899
1.89-1.920.26251640.22541272143696
1.92-1.960.25771430.221283142698
1.96-1.990.28361260.21181333145997
1.99-2.030.21741440.20031283142799
2.03-2.080.27091250.18951323144897
2.08-2.130.23741320.19031339147199
2.13-2.180.23981510.18751258140997
2.18-2.240.23491320.17691318145096
2.24-2.310.22691320.18251294142698
2.31-2.380.21471500.17561319146998
2.38-2.460.24731660.16971304147099
2.47-2.560.20861510.18151297144899
2.56-2.680.22461290.17341345147499
2.68-2.820.21631330.18861342147599
2.82-30.23961380.18221313145199
3-3.230.20651390.18361301144096
3.23-3.550.20571320.17271348148099
3.56-4.070.15771460.15321319146599
4.07-5.130.15261660.12591323148999
5.13-47.380.17481460.1481353149998
Refinement TLS params.Method: refined / Origin x: -25.8143 Å / Origin y: 12.5961 Å / Origin z: 59.7233 Å
111213212223313233
T0.1584 Å2-0.0429 Å2-0.0132 Å2-0.1659 Å2-0.023 Å2--0.1815 Å2
L0.2914 °20.0968 °2-0.5263 °2-0.3652 °20.2893 °2--1.7918 °2
S0.0305 Å °-0.0701 Å °-0.0505 Å °-0.0194 Å °-0.0533 Å °-0.0198 Å °-0.1571 Å °-0.1065 Å °0.0317 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 303
2X-RAY DIFFRACTION1allA401 - 403
3X-RAY DIFFRACTION1allS1 - 183

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