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Basic information

Entry
Database: PDB / ID: 6wtj
TitleFeline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
Components3C-like proteinase
KeywordsHydrolase/Hydrolase Inhibitor / COVID-19 / SARS-CoV-2 / 3CLpro / coronavirus / main protease / kinetics / SARS / VIRAL PROTEIN / Hydrolase-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 / viral RNA-directed RNA polymerase complex / exoribonuclease 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 / viral RNA-directed RNA polymerase complex / exoribonuclease 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 / positive regulation of RNA biosynthetic process / 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 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
main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nonstructural protein 14, betacoronavirus ...main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nonstructural protein 14, betacoronavirus / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) 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, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP16, coronavirus-like / Nonstructural protein 15, middle domain, coronavirus / Coronavirus RNA-dependent RNA polymerase, N-terminal / Coronavirus replicase NSP15, N-terminal oligomerization / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / RNA polymerase, N-terminal, coronavirus / Non-structural protein 14, coronavirus / Non-structural protein NSP15, middle domain superfamily / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / 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, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / NSP1 globular domain superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Non-structural protein NSP3, N-terminal, betacoronavirus / Betacoronavirus replicase NSP3, N-terminal / (+)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. / : / Betacoronavirus replicase NSP1 / NSP1, globular domain, betacoronavirus / Betacoronavirus single-stranded poly(A) binding domain / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / Betacoronavirus Nsp3c-C 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 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 / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, N-terminal / Coronavirus replicase NSP2, C-terminal / Coronavirus Nsp3d Ubl domain profile. / Coronavirus Nsp3a Ubl domain profile. / Non-structural protein 2, C-terminal domain, coronavirus / 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 / Peptidase family C16 domain profile. / Coronavirus replicase NSP7 / Coronavirus endopeptidase C30 / RNA synthesis protein NSP10, coronavirus / Coronavirus RNA synthesis protein NSP10 / Non-structural protein NSP8, coronavirus / Coronavirus replicase NSP8 / Coronavirus replicase NSP3, C-terminal / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus main protease (M-pro) domain profile. / Non-structural protein NSP4, N-terminal, coronavirus
Similarity search - Domain/homology
Chem-K36 / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsKhan, M.B. / Arutyunova, E. / Young, H.S. / Lemieux, M.J.
Funding support Canada, 2items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR) Canada
Natural Sciences and Engineering Research Council (NSERC, Canada)549297-2019 Canada
CitationJournal: Nat Commun / Year: 2020
Title: Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication.
Authors: Vuong, W. / Khan, M.B. / Fischer, C. / Arutyunova, E. / Lamer, T. / Shields, J. / Saffran, H.A. / McKay, R.T. / van Belkum, M.J. / Joyce, M.A. / Young, H.S. / Tyrrell, D.L. / Vederas, J.C. / Lemieux, M.J.
History
DepositionMay 2, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2020Provider: repository / Type: Initial release
Revision 1.1May 27, 2020Group: Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen ...pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Item: _pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details ..._pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details / _pdbx_struct_assembly.oligomeric_count / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.oper_expression
Revision 1.2Sep 9, 2020Group: 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

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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)34,3112
Polymers33,8261
Non-polymers4861
Water1,04558
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6224
Polymers67,6512
Non-polymers9712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area2980 Å2
ΔGint-15 kcal/mol
Surface area25170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)114.970, 53.810, 45.500
Angle α, β, γ (deg.)90.000, 101.742, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11A-549-

HOH

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Components

#1: Protein 3C-like proteinase / 3CL-PRO / 3CLp


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
Production host: Escherichia coli O103:H2 str. 12009 (bacteria)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-K36 / (1S,2S)-2-({N-[(benzyloxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid / GC376 / GC376


Type: peptide-like / Mass: 485.551 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H31N3O8S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antivirus*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 58 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Nonpolymer detailsThe protein was co-crystallized with GC376

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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: 2.04 Å3/Da / Density % sol: 39.61 %
Crystal growTemperature: 295 K / Method: vapor diffusion / pH: 7
Details: 0.2 M Sodium chloride 0.1 M HEPES pH 7.0 20 % w/v PEG 6000.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 16, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.9→34.36 Å / Num. obs: 21581 / % possible obs: 97.9 % / Redundancy: 3.429 % / Biso Wilson estimate: 42.56 Å2 / CC1/2: 0.996 / Net I/σ(I): 7.18
Reflection shellResolution: 1.9→1.95 Å / Num. unique obs: 2925 / CC1/2: 0.25

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6Y7M
Resolution: 1.9→34.36 Å / SU ML: 0.3347 / Cross valid method: FREE R-VALUE / σ(F): 0.78 / Phase error: 29.4565
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2348 2738 6.63 %
Rwork0.1986 38582 -
obs0.2011 41320 98.13 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 57.7 Å2
Refinement stepCycle: LAST / Resolution: 1.9→34.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2367 0 29 58 2454
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092472
X-RAY DIFFRACTIONf_angle_d1.19343362
X-RAY DIFFRACTIONf_chiral_restr0.0643378
X-RAY DIFFRACTIONf_plane_restr0.0066437
X-RAY DIFFRACTIONf_dihedral_angle_d16.9066341
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.930.40651360.36481941X-RAY DIFFRACTION98.06
1.93-1.970.34471350.36781920X-RAY DIFFRACTION96.57
1.97-2.010.41341260.37641772X-RAY DIFFRACTION91.47
2.01-2.050.32971370.35961939X-RAY DIFFRACTION98.62
2.05-2.090.31251390.30191958X-RAY DIFFRACTION99.71
2.09-2.140.32171390.27691960X-RAY DIFFRACTION99.24
2.14-2.190.2931380.26981937X-RAY DIFFRACTION99
2.19-2.250.26061380.25431975X-RAY DIFFRACTION99.2
2.25-2.320.33411380.25041894X-RAY DIFFRACTION99.12
2.32-2.390.27971380.23961952X-RAY DIFFRACTION98.86
2.39-2.480.26131380.23941941X-RAY DIFFRACTION98.3
2.48-2.580.25581310.24381854X-RAY DIFFRACTION94.3
2.58-2.70.28821400.22911940X-RAY DIFFRACTION99
2.7-2.840.27521400.2281978X-RAY DIFFRACTION99.34
2.84-3.010.31591360.20951945X-RAY DIFFRACTION99.14
3.02-3.250.26391390.21661957X-RAY DIFFRACTION99.53
3.25-3.570.22151370.18981919X-RAY DIFFRACTION98.09
3.57-4.090.22581380.17431895X-RAY DIFFRACTION97.46
4.09-5.150.18251380.14171958X-RAY DIFFRACTION99.67
5.15-34.360.15931370.15171947X-RAY DIFFRACTION98.07
Refinement TLS params.Method: refined / Origin x: -16.8879261929 Å / Origin y: 12.8098910952 Å / Origin z: 17.4944498739 Å
111213212223313233
T0.251064881343 Å20.0173061592583 Å20.0320514965699 Å2-0.289359530137 Å2-0.012594056074 Å2--0.275316634827 Å2
L1.94818495636 °20.415698604245 °20.955285636608 °2-2.04260165451 °20.910102232574 °2--2.06354409596 °2
S0.0143779661683 Å °-0.0666553410213 Å °0.139110953559 Å °0.0457778284667 Å °-0.0265501230819 Å °0.121292906813 Å °0.0304779205261 Å °-0.0686141608014 Å °-0.0224961058304 Å °
Refinement TLS groupSelection details: all

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