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- PDB-6xhm: Covalent complex of SARS-CoV-2 main protease with N-[(2S)-1-({(2S... -

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Entry
Database: PDB / ID: 6xhm
TitleCovalent complex of SARS-CoV-2 main protease with N-[(2S)-1-({(2S,3S)-3,4-dihydroxy-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide
Components3C-like proteinase
KeywordsVIRAL PROTEIN / coronavirus protease 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 / modulation by virus of host autophagy ...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 / modulation by virus of host autophagy / mRNA methylation / 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 / cytoplasmic viral factory / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 3'-5'-exoribonuclease activity / G-quadruplex RNA binding / host cell endoplasmic reticulum-Golgi intermediate compartment / 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 / suppression by virus of host NF-kappaB cascade / viral transcription / modulation by virus of host protein ubiquitination / protein K63-linked deubiquitination / methyltransferase cap1 / positive stranded viral RNA replication / protein autoprocessing / cysteine-type peptidase activity / viral genome replication / mRNA (nucleoside-2'-O-)-methyltransferase activity / 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 / Coronaviridae zinc-binding (CV ZBD) domain profile. / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Sarbecovirus Nsp3c-N domain profile. / Betacoronavirus replicase NSP3, N-terminal / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, coronavirus / Non-structural protein NSP1 superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Betacoronavirus SUD-C domain / Non-structural protein NSP3, N-terminal, betacoronavirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / NendoU domain, nidovirus / Endoribonuclease EndoU-like / 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 / Non-structural protein 6, betacoronavirus / Replicase polyprotein, nucleic acid-binding domain superfamily / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / 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. / Papain-like protease, N-terminal domain superfamily, coronavirus / Lipocalin signature. / Papain-like viral protease, palm and finger domains, coronavirus / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, N-terminal / Coronavirus Nsp3d Ubl domain profile. / Coronavirus Nsp3a Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / 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-V2M / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.406 Å
AuthorsGajiwala, K.S. / Ferre, R.A. / Ryan, K. / Stewart, A.E.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19.
Authors: Hoffman, R.L. / Kania, R.S. / Brothers, M.A. / Davies, J.F. / Ferre, R.A. / Gajiwala, K.S. / He, M. / Hogan, R.J. / Kozminski, K. / Li, L.Y. / Lockner, J.W. / Lou, J. / Marra, M.T. / ...Authors: Hoffman, R.L. / Kania, R.S. / Brothers, M.A. / Davies, J.F. / Ferre, R.A. / Gajiwala, K.S. / He, M. / Hogan, R.J. / Kozminski, K. / Li, L.Y. / Lockner, J.W. / Lou, J. / Marra, M.T. / Mitchell Jr., L.J. / Murray, B.W. / Nieman, J.A. / Noell, S. / Planken, S.P. / Rowe, T. / Ryan, K. / Smith 3rd, G.J. / Solowiej, J.E. / Steppan, C.M. / Taggart, B.
History
DepositionJun 19, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Refinement description / Category: citation / citation_author / software
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _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 / _software.name
Revision 1.2Nov 25, 2020Group: 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)68,6585
Polymers67,6512
Non-polymers1,0073
Water8,017445
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2750 Å2
ΔGint-5 kcal/mol
Surface area25380 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)55.15, 98.51, 59.11
Angle α, β, γ (deg.)90, 107.45, 90
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein 3C-like proteinase


Mass: 33825.547 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: N-[(2S)-1-({(2S,3S)-3,4-dihydroxy-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: rep, 1a-1b / Production host: Escherichia coli (E. coli)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-V2M / N-[(2S)-1-({(2S)-4-hydroxy-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide


Mass: 472.534 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H32N4O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 445 / 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: 2.3 Å3/Da / Density % sol: 46.49 %
Crystal growTemperature: 294 K / Method: vapor diffusion
Details: Precipitant: 25.0 %w/v (25.0 uL of stock 50.0 %w/v) PEG 1500, Buffer: 0.1 M (5.0 uL of stock 1.0 M) MMT (pH 4.00)

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Data collection

DiffractionMean temperature: 98 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: May 21, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.406→56.39 Å / Num. obs: 87382 / % possible obs: 75 % / Redundancy: 3.5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.047 / Net I/σ(I): 12.3
Reflection shellResolution: 1.406→1.526 Å / Rmerge(I) obs: 0.721 / Num. unique obs: 4369 / CC1/2: 0.59

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoPROCdata scaling
BUSTERphasing
autoPROCdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5R8T
Resolution: 1.406→56.39 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.954 / SU R Cruickshank DPI: 0.083 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.085 / SU Rfree Blow DPI: 0.08 / SU Rfree Cruickshank DPI: 0.08
RfactorNum. reflection% reflectionSelection details
Rfree0.2096 4163 -RANDOM
Rwork0.1908 ---
obs0.1916 87382 74.9 %-
Displacement parametersBiso mean: 24.33 Å2
Baniso -1Baniso -2Baniso -3
1--0.3019 Å20 Å20.5982 Å2
2--0.0414 Å20 Å2
3---0.2604 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: LAST / Resolution: 1.406→56.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4662 0 72 445 5179
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084984HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.986804HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1704SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes859HARMONIC5
X-RAY DIFFRACTIONt_it4984HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion647SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4637SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.94
X-RAY DIFFRACTIONt_other_torsion13.96
LS refinement shellResolution: 1.41→1.49 Å
RfactorNum. reflection% reflection
Rfree0.2202 110 -
Rwork0.2265 --
obs0.2261 1748 9.93 %

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