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- PDB-6xfn: Crystal structure of the SARS-CoV-2 (COVID-19) main protease in c... -

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Basic information

Entry
Database: PDB / ID: 6xfn
TitleCrystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with UAW243
Components
  • 3C-like proteinase
  • UAW243
KeywordsHYDROLASE / COVID / COVID19 / COVID-19 / SARS / SARS COV2 / COV / NCOV 19 / CORONAVIRUS / MAIN PROTEASE / 3CL / MPRO / PRO / VIRAL PROTEIN / GC376 / calpain inhibitor II / calpain inhibitor XII / 12 / calpain inhibitor 12 / leupeptin / calpain / aldehyde / GC-376 / 3cl-like / a-ketoamide / alpheketoamide / alpha / ketoamide / PEPTIDOMIMETIC / PROTEASE / CYSTEINE
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 / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nonstructural protein 14, betacoronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization 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 / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nonstructural protein 14, betacoronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization 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 / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Coronavirus proofreading exoribonuclease / Coronavirus 2'-O-methyltransferase / Coronavirus replicase NSP15, middle domain / Coronavirus RNA-dependent RNA polymerase, N-terminal / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / 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. / Non-structural protein NSP1 superfamily, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Non-structural protein NSP3, N-terminal, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, coronavirus / Non-structural protein 2, SARS-CoV-like / Betacoronavirus replicase NSP3, N-terminal / Betacoronavirus SUD-C domain / 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 profile. / (+) RNA virus helicase core domain / Betacoronavirus Nsp3c-M domain profile. / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus single-stranded poly(A) binding domain / Non-structural protein NSP3, SUD-M domain, betacoronavirus / 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) Nsp7 cofactor domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 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 Nsp3a Ubl domain profile. / Coronavirus Nsp3d 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 / Peptidase family C16 domain profile. / Coronavirus replicase NSP7 / Non-structural protein NSP7, coronavirus / Coronavirus endopeptidase C30 / Coronavirus papain-like peptidase / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / RNA synthesis protein NSP10, coronavirus / Non-structural protein 6, coronavirus / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP9, coronavirus / Coronavirus replicase NSP3, C-terminal / Coronavirus replicase NSP4, N-terminal / Non-structural protein NSP4, C-terminal, coronavirus / Coronavirus replicase NSP4, C-terminal / RNA synthesis protein NSP10 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP7 superfamily, coronavirus / Peptidase C30, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Peptidase C16, coronavirus / Coronavirus main protease (M-pro) domain profile.
Similarity search - Domain/homology
Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsSacco, M. / Ma, C. / Wang, J. / Chen, Y.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI147325 United States
CitationJournal: Sci Adv / Year: 2020
Title: Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M pro and cathepsin L.
Authors: Sacco, M.D. / Ma, C. / Lagarias, P. / Gao, A. / Townsend, J.A. / Meng, X. / Dube, P. / Zhang, X. / Hu, Y. / Kitamura, N. / Hurst, B. / Tarbet, B. / Marty, M.T. / Kolocouris, A. / Xiang, Y. / Chen, Y. / Wang, J.
History
DepositionJun 15, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 24, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 18, 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 23, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Jan 27, 2021Group: Structure summary / Category: entity / entity_name_com / Item: _entity.pdbx_description / _entity_name_com.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase
B: UAW243
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6583
Polymers34,5652
Non-polymers921
Water3,027168
1
A: 3C-like proteinase
B: UAW243
hetero molecules

A: 3C-like proteinase
B: UAW243
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,3156
Polymers69,1314
Non-polymers1842
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area4910 Å2
ΔGint-13 kcal/mol
Surface area25530 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)114.566, 54.317, 44.492
Angle α, β, γ (deg.)90.000, 100.860, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-730-

HOH

21A-734-

HOH

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Components

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


Mass: 34094.887 Da / Num. of mol.: 1 / Fragment: UNP residues 3264-3569
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 (E. coli)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Protein/peptide UAW243


Mass: 470.561 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 168 / 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: 1.97 Å3/Da / Density % sol: 37.43 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.6 / Details: 20% PEG3000, 0.1 M sodium citrate, pH 5.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 28, 2020
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 29333 / % possible obs: 98.9 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.036 / Rrim(I) all: 0.074 / Χ2: 1.457 / Net I/σ(I): 8.7 / Num. measured all: 120459
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.7-1.734.20.70114450.6920.3870.8030.53199.8
1.73-1.764.20.59214850.7790.3210.6760.55899.5
1.76-1.794.20.50714480.8040.2770.580.63199.8
1.79-1.834.20.43814660.8670.2370.50.69399.8
1.83-1.874.10.36915000.8910.2020.4220.73499.3
1.87-1.914.10.30514510.9230.1690.350.80798.9
1.91-1.9640.24614330.9420.1380.2830.98297.5
1.96-2.023.80.21114170.9560.1180.2431.11695.6
2.02-2.074.30.18414500.9630.0990.2091.23199.5
2.07-2.144.20.16114840.9720.0870.1841.34599.7
2.14-2.224.20.13914880.9760.0760.1591.45399.8
2.22-2.314.20.1214510.9840.0650.1371.60899.2
2.31-2.414.10.11414720.9850.0620.131.81999.5
2.41-2.543.90.09514520.9870.0530.1091.82297
2.54-2.74.10.08514570.9880.0460.0972.07998.8
2.7-2.914.30.07514820.9930.0410.0862.23699.7
2.91-3.24.20.06414940.9940.0350.0742.37599
3.2-3.663.90.05714530.9930.0320.0652.58198.2
3.66-4.614.10.0514790.9950.0270.0572.6698.6
4.61-5040.0415260.9980.0220.0461.91198.3

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Processing

Software
NameVersionClassification
HKL-3000data scaling
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
HKL-3000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 6YB7
Resolution: 1.7→38.2 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.956 / SU B: 3.38 / SU ML: 0.108 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.129 / ESU R Free: 0.12 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2282 1490 5.1 %RANDOM
Rwork0.1954 ---
obs0.1972 27843 98.44 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 118.75 Å2 / Biso mean: 31.77 Å2 / Biso min: 16.51 Å2
Baniso -1Baniso -2Baniso -3
1-0.98 Å2-0 Å2-0.47 Å2
2---0.06 Å2-0 Å2
3----0.69 Å2
Refinement stepCycle: final / Resolution: 1.7→38.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2336 0 40 173 2549
Biso mean--43.73 39.22 -
Num. residues----304
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0132443
X-RAY DIFFRACTIONr_bond_other_d0.0010.0182189
X-RAY DIFFRACTIONr_angle_refined_deg1.7521.653319
X-RAY DIFFRACTIONr_angle_other_deg1.4031.5845082
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.8565307
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.7623.475118
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.70415382
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7881510
X-RAY DIFFRACTIONr_chiral_restr0.0880.2317
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022758
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02511
LS refinement shellResolution: 1.7→1.742 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.355 91 -
Rwork0.293 1957 -
obs--93.99 %

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