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

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Basic information

Entry
Database: PDB / ID: 7lku
Title1.65 A resolution structure of SARS-CoV-2 3CL protease in complex with inhibitor 3b (deuterated analog of inhibitor 2a)
Components3C-like proteinase
KeywordsHYDROLASE/INHIBITOR / COVID-19 / PROTEASE / severe acute respiratory syndrome coronavirus 2 / SARS-CoV-2 3CL protease Inhhibitors / HYDROLASE-INHIBITOR complex
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 / 3'-5'-exoribonuclease activity / cytoplasmic viral factory / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 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 (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. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nonstructural protein 14, betacoronavirus / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/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. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nonstructural protein 14, betacoronavirus / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) 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 / Coronavirus proofreading exoribonuclease / Coronavirus replicase NSP15, N-terminal oligomerisation / Coronavirus replicase NSP15, middle domain / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Coronavirus RNA-dependent RNA polymerase, N-terminal / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerisation / Coronavirus replicase NSP15, middle domain / Coronaviridae zinc-binding (CV ZBD) domain profile. / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / NendoU domain, nidovirus / Endoribonuclease EndoU-like / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, N-terminal, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, coronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / Non-structural protein NSP1 superfamily, betacoronavirus / Carbamoyl-phosphate synthase subdomain signature 2. / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / (+)RNA virus helicase core domain profile. / (+) RNA virus helicase core domain / Betacoronavirus Nsp3c-M domain profile. / Non-structural protein NSP1, betacoronavirus / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Betacoronavirus single-stranded poly(A) binding domain / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Betacoronavirus replicase NSP1 / Coronavirus (CoV) Nsp1 globular domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / 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 / Lipocalin signature. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / 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 / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Coronavirus replicase NSP6 / Coronavirus replicase NSP4, C-terminal / Coronavirus main protease (M-pro) domain profile. / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP8 / Coronavirus papain-like peptidase / Coronavirus endopeptidase C30 / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Peptidase C30, coronavirus / Non-structural protein NSP7 superfamily, coronavirus / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP4, C-terminal, coronavirus / Non-structural protein NSP8, coronavirus-like / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Coronavirus replicase NSP4, N-terminal / Non-structural protein 6, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus
Similarity search - Domain/homology
Chem-Y4D / Chem-Y5S / Chem-Y91 / Chem-Y8Y / 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. / Rathnayake, A.D. / Nguyen, H.N. / Baird, M.A. / Kim, Y. / Shadipeni, N. / 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)R01 AI109039 United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3CL Protease.
Authors: Dampalla, C.S. / Kim, Y. / Bickmeier, N. / Rathnayake, A.D. / Nguyen, H.N. / Zheng, J. / Kashipathy, M.M. / Baird, M.A. / Battaile, K.P. / Lovell, S. / Perlman, S. / Chang, K.O. / Groutas, W.C.
History
DepositionFeb 2, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 17, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 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_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Aug 4, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _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
B: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,2646
Polymers68,1382
Non-polymers2,1274
Water5,819323
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1950 Å2
ΔGint-13 kcal/mol
Surface area24580 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)54.911, 98.388, 58.186
Angle α, β, γ (deg.)90.000, 107.390, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 34068.805 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
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

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Non-polymers , 5 types, 327 molecules

#2: Chemical ChemComp-Y4D / (1R,2S)-2-((S)-2-(((((1R,3s,5S)-bicyclo[3.3.1]nonan-3-yl)methoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonic acid


Mass: 531.663 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H41N3O8S
#3: Chemical ChemComp-Y5S / (1S,2S)-2-((S)-2-(((((1R,3s,5S)-bicyclo[3.3.1]nonan-3-yl)methoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonic acid


Mass: 531.663 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H41N3O8S
#4: Chemical ChemComp-Y8Y / (1R,2S)-2-((S)-2-(((((1R,3r,5S)-bicyclo[3.3.1]nonan-3-yl)methoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonic acid


Mass: 531.663 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H41N3O8S
#5: Chemical ChemComp-Y91 / (1S,2S)-2-((S)-2-(((((1R,3r,5S)-bicyclo[3.3.1]nonan-3-yl)methoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonic acid


Mass: 531.663 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H41N3O8S
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 323 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.2 Å3/Da / Density % sol: 44.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 20% w/v PEG4000, 100 mM Tris

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Nov 28, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.65→49.19 Å / Num. obs: 70811 / % possible obs: 99.9 % / Redundancy: 3.5 % / Biso Wilson estimate: 22.5 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.054 / Net I/σ(I): 9.8 / Num. measured all: 246165 / Scaling rejects: 145
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.5 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Net I/σ(I) obs% possible all
1.65-1.680.5531248035340.8831.9100
9.04-49.190.05315864560.99425.499.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIXrefinement
XDSdata reduction
Aimless0.7.4data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6XMK
Resolution: 1.65→31.66 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1 / Phase error: 24.61 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2107 3470 4.91 %
Rwork0.1775 67198 -
obs0.1791 70668 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 90.95 Å2 / Biso mean: 31.5616 Å2 / Biso min: 15.51 Å2
Refinement stepCycle: final / Resolution: 1.65→31.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4502 0 128 323 4953
Biso mean--35.17 39.28 -
Num. residues----599
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 (%)
1.65-1.670.34051560.282226952851100
1.67-1.70.29061500.266226442794100
1.7-1.720.28081480.255726572805100
1.72-1.750.28481620.236126382800100
1.75-1.780.26231410.23182683282499
1.78-1.810.26541600.211626542814100
1.81-1.840.26691390.209726622801100
1.84-1.880.22511300.207727062836100
1.88-1.910.27751360.204826862822100
1.91-1.960.22531650.206826612826100
1.96-20.24671300.202126692799100
2-2.050.25051510.207626772828100
2.05-2.110.26421360.199326832819100
2.11-2.170.24721570.183226962853100
2.17-2.240.20821310.186527002831100
2.24-2.320.21591260.183126752801100
2.32-2.410.22071120.181327272839100
2.41-2.520.1991440.180326782822100
2.52-2.650.22431750.179826512826100
2.65-2.820.21631150.179127112826100
2.82-3.040.2221030.17427622865100
3.04-3.340.21591230.180326832806100
3.34-3.830.18141100.155727242834100
3.83-4.820.14841170.136127382855100
4.82-31.660.18061530.166127382891100

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