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- PDB-7k0f: 1.65 A resolution structure of SARS-CoV-2 3CL protease in complex... -

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Basic information

Entry
Database: PDB / ID: 7k0f
Title1.65 A resolution structure of SARS-CoV-2 3CL protease in complex with a deuterated GC376 alpha-ketoamide analog (compound 5)
Components3C-like proteinase
KeywordsHYDROLASE / COVID-19 / PROTEASE / severe acute respiratory syndrome coronavirus 2 / SARS-CoV-2 3CL protease Inhhibitors / deuterated hydrolase inhibitor
Function / homology
Function and homology information


Maturation of replicase proteins / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-2 sgRNAs / host cell endosome / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Translation of Replicase and Assembly of the Replication Transcription Complex / 5'-3' RNA helicase activity / RNA phosphodiester bond hydrolysis, exonucleolytic / Lyases; Phosphorus-oxygen lyases / mRNA methylation ...Maturation of replicase proteins / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-2 sgRNAs / host cell endosome / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Translation of Replicase and Assembly of the Replication Transcription Complex / 5'-3' RNA helicase activity / RNA phosphodiester bond hydrolysis, exonucleolytic / Lyases; Phosphorus-oxygen lyases / mRNA methylation / modulation by virus of host autophagy / double membrane vesicle viral factory outer membrane / suppression by virus of host translation / ISG15-specific protease activity / host cell Golgi apparatus / Replication of the SARS-CoV-2 genome / suppression by virus of host type I interferon production / host cell endoplasmic reticulum / SARS coronavirus main proteinase / induction by virus of catabolism of host mRNA / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 3'-5'-exoribonuclease activity / cytoplasmic viral factory / host cell endoplasmic reticulum-Golgi intermediate compartment / G-quadruplex RNA binding / suppression by virus of host ISG15-protein conjugation / protein K48-linked deubiquitination / suppression by virus of host toll-like receptor signaling pathway / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / transcription, RNA-templated / viral transcription / 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 / protein autoprocessing / cysteine-type peptidase activity / mRNA (nucleoside-2'-O-)-methyltransferase activity / viral genome replication / suppression by virus of host TRAF activity / helicase activity / ubiquitinyl hydrolase 1 / DNA helicase / thiol-dependent deubiquitinase / DNA helicase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / host cell perinuclear region of cytoplasm / viral protein processing / RNA helicase / induction by virus of host autophagy / endonuclease activity / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed 5'-3' RNA polymerase activity / suppression by virus of host type I interferon-mediated signaling pathway / transcription, DNA-templated / host cell cytoplasm / protein dimerization 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 15, middle domain, alpha/betacoronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nonstructural protein 14, betacoronavirus / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / 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. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nonstructural protein 14, betacoronavirus / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / 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. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) 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 / RNA polymerase, N-terminal, coronavirus / Coronavirus proofreading exoribonuclease / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP15, middle domain superfamily / Coronavirus RNA-dependent RNA polymerase, N-terminal / Coronavirus 2'-O-methyltransferase / Coronavirus replicase NSP15, N-terminal oligomerisation / Coronavirus replicase NSP15, middle domain / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / Endoribonuclease EndoU-like / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, coronavirus / Non-structural protein NSP1 superfamily, betacoronavirus / Betacoronavirus replicase NSP3, N-terminal / Non-structural protein 2, SARS-CoV-like / Betacoronavirus SUD-C domain / Non-structural protein NSP3, N-terminal, betacoronavirus / Carbamoyl-phosphate synthase subdomain signature 2. / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Betacoronavirus Nsp3c-M domain profile. / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Betacoronavirus replicase NSP1 / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Betacoronavirus single-stranded poly(A) binding domain / Non-structural protein NSP1, betacoronavirus / Coronavirus (CoV) Nsp1 globular domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / Betacoronavirus Nsp3c-C domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Replicase polyprotein, nucleic acid-binding domain superfamily / 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 / 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. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Lipocalin signature. / 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 Nsp3a Ubl domain profile. / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3d 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 / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Non-structural protein NSP7, coronavirus / Coronavirus replicase NSP4, C-terminal / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP8 / Coronavirus replicase NSP6 / Coronavirus papain-like peptidase / Non-structural protein NSP8, coronavirus-like / Coronavirus replicase NSP4, N-terminal / Coronavirus endopeptidase C30 / Coronavirus replicase NSP3, C-terminal / Coronavirus main protease (M-pro) domain profile. / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Non-structural protein 6, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / Non-structural protein NSP9, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus / Coronavirus replicase NSP4, N-terminal / Peptidase C16, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Peptidase C30, coronavirus / Non-structural protein NSP9 superfamily, coronavirus
Similarity search - Domain/homology
Chem-VR4 / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.65 Å
AuthorsLovell, S. / Kashipathy, M.M. / Battaile, K.P. / Chamandi, S.D. / Nguyen, H.N. / Kim, Y. / Chang, K.O. / Groutas, W.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI109039 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2021
Title: Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection.
Authors: Dampalla, C.S. / Zheng, J. / Perera, K.D. / Wong, L.R. / Meyerholz, D.K. / Nguyen, H.N. / Kashipathy, M.M. / Battaile, K.P. / Lovell, S. / Kim, Y. / Perlman, S. / Groutas, W.C. / Chang, K.O.
History
DepositionSep 4, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 7, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _citation_author.name
Revision 1.2Jul 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)69,4095
Polymers68,1382
Non-polymers1,2713
Water6,071337
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1850 Å2
ΔGint-10 kcal/mol
Surface area25060 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)55.246, 98.532, 58.962
Angle α, β, γ (deg.)90.000, 108.000, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein 3C-like proteinase / 3CL-PRO / 3CLp / SARS COV-2 virus main protease


Mass: 34068.805 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: N-terminal hexahistidine tag
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: rep, 1a-1b / Plasmid: pET28 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-VR4 / N-{(2S,3R)-4-(benzylamino)-3-hydroxy-4-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}-N~2~-[(benzyloxy)carbonyl]-L-leucinamide / GC376 alpha-ketoamide analog (bound form)


Mass: 538.635 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H38N4O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 337 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Nonpolymer detailsVR4 is deuterated at C33

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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: 2.24 Å3/Da / Density % sol: 45.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 28% PEG 2000 MME, 0.1 M Bis-Tris

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.9201 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 2, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 1.65→46.36 Å / Num. obs: 70687 / % possible obs: 98.3 % / Redundancy: 3.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.061 / Net I/σ(I): 10.7 / Num. measured all: 247132 / Scaling rejects: 8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Net I/σ(I) obs% possible all
1.65-1.683.50.791214034430.6761.696.9
9.04-46.363.40.03415854600.99830.998

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation6.3 Å46.36 Å

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.7.4data scaling
PHASER2.8.3phasing
PHENIXdev_3959refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6XMK
Resolution: 1.65→46.36 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.01 / Phase error: 23.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2252 3463 4.9 %
Rwork0.1805 67180 -
obs0.1826 70643 98.07 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 74.12 Å2 / Biso mean: 29.6206 Å2 / Biso min: 12.74 Å2
Refinement stepCycle: final / Resolution: 1.65→46.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4461 0 91 337 4889
Biso mean--33.74 36.01 -
Num. residues----596
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 25

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.65-1.670.32421430.27412635277897
1.67-1.70.2711570.25172619277698
1.7-1.720.30871400.25272650279096
1.72-1.750.26611630.25622625278898
1.75-1.780.28551370.2572686282397
1.78-1.810.29641640.24042626279097
1.81-1.840.30271310.2252684281598
1.84-1.880.25661310.2152646277797
1.88-1.910.27471410.20832663280498
1.91-1.960.2371560.20452674283098
1.96-20.2411430.20042655279898
2-2.050.25941360.22726286298
2.05-2.110.24921410.20192659280098
2.11-2.170.24121580.18512674283298
2.17-2.240.22331350.18982683281898
2.24-2.320.25131350.18692712284798
2.32-2.410.22961030.18412735283899
2.41-2.520.22671530.18122694284799
2.52-2.650.21681650.18122672283799
2.66-2.820.24661200.17392728284898
2.82-3.040.24031040.17752727283198
3.04-3.340.21031260.18532728285498
3.34-3.830.19231090.15982743285299
3.83-4.820.17071170.1372766288399
4.82-46.360.20861550.16592770292599

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