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- PDB-5c5o: Structure of SARS-3CL protease complex with a phenyl-beta-alanyl ... -

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Entry
Database: PDB / ID: 5c5o
TitleStructure of SARS-3CL protease complex with a phenyl-beta-alanyl (S,R)-N-decalin type inhibitor
Components3C-like proteinase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / hydrase proteinase converting / designed inhibitor / hydrase-inhibitor complex / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of ubiquitin-specific protease activity / Maturation of replicase proteins / Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-1 sgRNAs / Lys48-specific deubiquitinase activity / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-1 genome / 7-methylguanosine mRNA capping / mRNA (guanine-N7-)-methyltransferase activity / Transferases; Transferring one-carbon groups; Methyltransferases ...positive regulation of ubiquitin-specific protease activity / Maturation of replicase proteins / Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-1 sgRNAs / Lys48-specific deubiquitinase activity / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-1 genome / 7-methylguanosine mRNA capping / mRNA (guanine-N7-)-methyltransferase activity / Transferases; Transferring one-carbon groups; Methyltransferases / 5'-3' RNA helicase activity / RNA phosphodiester bond hydrolysis, exonucleolytic / Lyases; Phosphorus-oxygen lyases / mRNA methylation / double membrane vesicle viral factory outer membrane / suppression by virus of host translation / ISG15-specific protease activity / suppression by virus of host type I interferon production / 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 / mRNA (nucleoside-2'-O-)-methyltransferase activity / suppression by virus of host TRAF activity / helicase activity / ubiquitinyl hydrolase 1 / double-stranded RNA binding / 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 / : / endoplasmic reticulum membrane / zinc ion binding / integral component of membrane / ATP binding / identical protein binding / cytosol
Similarity search - Function
Non-structural protein 3, SUD-N macrodomain, SARS-CoV / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nonstructural protein 14, betacoronavirus / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. ...Non-structural protein 3, SUD-N macrodomain, SARS-CoV / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nonstructural protein 14, betacoronavirus / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / 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 / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerisation / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Coronavirus 2'-O-methyltransferase / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, middle domain / Coronavirus RNA-dependent RNA polymerase, N-terminal / Coronavirus proofreading exoribonuclease / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Polyprotein cleavage domain PL2pro superfamily, coronavirus / Non-structural protein NSP1 superfamily, betacoronavirus / Non-structural protein NSP3, N-terminal, betacoronavirus / Betacoronavirus replicase NSP3, N-terminal / Betacoronavirus SUD-C domain / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / Endoribonuclease EndoU-like / 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 NSP1, betacoronavirus / Betacoronavirus single-stranded poly(A) binding domain / Betacoronavirus replicase NSP1 / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Coronavirus (CoV) Nsp1 globular domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / 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 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 / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, N-terminal / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / Non-structural protein 2, C-terminal domain, coronavirus / NSP3, first ubiquitin-like (Ubl) 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 / Non-structural protein NSP7, coronavirus / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Coronavirus replicase NSP3, C-terminal / Non-structural protein 6, coronavirus / Coronavirus replicase NSP4, N-terminal / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP8 / Coronavirus papain-like peptidase / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Coronavirus replicase NSP4, C-terminal / RNA synthesis protein NSP10 superfamily, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP8, coronavirus-like / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / Coronavirus endopeptidase C30 / Peptidase C30, domain 3, coronavirus / Coronavirus main protease (M-pro) domain profile. / Non-structural protein NSP8 superfamily, coronavirus
Similarity search - Domain/homology
Chem-SDJ / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesHuman SARS coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.5 Å
AuthorsAkaji, K. / Teruya, K. / Shimamoto, Y. / Sanjho, A. / Yamashita, E. / Nakagawa, A.
CitationJournal: to be published
Title: Fused-ring structure of N-decalin as a novel scaffold for SARS 3CL protease inhibitors
Authors: Shimamoto, Y. / Hattori, H. / Kobayashi, K. / Teruya, K. / Sanjho, A. / Nakagawa, A. / Yamashita, E. / Akaji, K.
History
DepositionJun 21, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 22, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2020Group: Data collection / Derived calculations / Category: diffrn_source / pdbx_struct_oper_list
Item: _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_oper_list.symmetry_operation

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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)68,5404
Polymers67,6652
Non-polymers8752
Water8,125451
1
A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2702
Polymers33,8331
Non-polymers4381
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2702
Polymers33,8331
Non-polymers4381
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2620 Å2
ΔGint-7 kcal/mol
Surface area25680 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)54.663, 58.662, 68.098
Angle α, β, γ (deg.)93.730, 103.400, 106.510
Int Tables number1
Space group name H-MP1
Details1

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Components

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


Mass: 33832.602 Da / Num. of mol.: 2 / Mutation: R188I
Source method: isolated from a genetically manipulated source
Details: beta-site amyloid precursor protein-converting enzyme
Source: (gene. exp.) Human SARS coronavirus / Plasmid: pMAL-3CL-R188I / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P0C6X7, SARS coronavirus main proteinase
#2: Chemical ChemComp-SDJ / (2S)-3-(1H-imidazol-5-yl)-2-({[(3S,4aR,8aS)-2-(N-phenyl-beta-alanyl)decahydroisoquinolin-3-yl]methyl}amino)propanal


Mass: 437.578 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H35N5O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 451 / Source method: isolated from a natural source / Formula: H2O

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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: 3.04 Å3/Da / Density % sol: 59.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 10% (w/v) PEG 20000, 100mM MES, 5mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 0.9 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Dec 17, 2013 / Details: horizontal focusing mirror
RadiationMonochromator: double-crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionRedundancy: 2.2 % / Number: 262674 / Rmerge(I) obs: 0.058 / Χ2: 1.69 / D res high: 1.5 Å / D res low: 50 Å / Num. obs: 119208 / % possible obs: 95.5
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsChi squaredRedundancy
4.075010.042.9752.1
3.234.0710.0433.0352.1
2.823.2310.0462.7412.2
2.562.8210.0512.4132.2
2.382.5610.0562.2372.2
2.242.3810.0682.2762.2
2.132.2410.0742.1262.2
2.042.1310.0741.7292.2
1.962.0410.0841.5622.2
1.891.9610.1452.3872.2
1.831.8910.1271.3072.2
1.781.8310.1451.1612.2
1.731.7810.1791.1232.2
1.691.7310.21.0882.2
1.651.6910.2491.0432.2
1.621.6510.3031.0332.2
1.581.6210.3541.0112.2
1.551.5810.42212.2
1.531.5510.4790.9342.2
1.51.5310.5240.9682.2
ReflectionResolution: 1.5→50 Å / Num. obs: 119208 / % possible obs: 95.5 % / Redundancy: 2.2 % / Rmerge(I) obs: 0.058 / Χ2: 1.686 / Net I/av σ(I): 21.429 / Net I/σ(I): 10.8 / Num. measured all: 262674
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.5-1.532.20.52459350.96895.4
1.53-1.552.20.47959440.93495.5
1.55-1.582.20.4226011195.7
1.58-1.622.20.35459911.01195.9
1.62-1.652.20.30359391.03396.1
1.65-1.692.20.24960331.04396.3
1.69-1.732.20.259961.08896.4
1.73-1.782.20.17960951.12396.6
1.78-1.832.20.14560231.16196.8
1.83-1.892.20.12761101.30796.9
1.89-1.962.20.14556612.38792.3
1.96-2.042.20.08460881.56297.2
2.04-2.132.20.07460761.72997.5
2.13-2.242.20.07459792.12695.9
2.24-2.382.20.06859782.27695.8
2.38-2.562.20.05661142.23797.9
2.56-2.822.20.05161232.41397.9
2.82-3.232.20.04660902.74197.4
3.23-4.072.10.04357473.03592.6
4.07-502.10.0452752.97584.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
DENZOdata collection
SCALEPACKdata reduction
REFMAC5.8.0049refinement
PDB_EXTRACT3.14data extraction
MOLREPmodel building
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→30.17 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.932 / SU B: 0.007 / SU ML: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.082 / ESU R Free: 0.09 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2714 5934 5 %RANDOM
Rwork0.2467 112777 --
obs0.248 118711 94.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 85.31 Å2 / Biso mean: 28.972 Å2 / Biso min: 13.65 Å2
Baniso -1Baniso -2Baniso -3
1--0.14 Å2-0.02 Å20.08 Å2
2--0.17 Å20.06 Å2
3----0.1 Å2
Refinement stepCycle: final / Resolution: 1.5→30.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4646 0 64 451 5161
Biso mean--20 30 -
Num. residues----600
LS refinement shellResolution: 1.501→1.539 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.33 459 -
Rwork0.309 7812 -
all-8271 -
obs--89.42 %

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