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- PDB-4twy: Structure of SARS-3CL protease complex with a phenylbenzoyl (S,R)... -

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Basic information

Entry
Database: PDB / ID: 4twy
TitleStructure of SARS-3CL protease complex with a phenylbenzoyl (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


Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / Transcription of SARS-CoV-1 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / K48-linked deubiquitinase activity / Replication of the SARS-CoV-1 genome / K63-linked deubiquitinase activity / host cell endoplasmic reticulum / viral transcription / SARS-CoV-1 modulates host translation machinery ...Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / Transcription of SARS-CoV-1 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / K48-linked deubiquitinase activity / Replication of the SARS-CoV-1 genome / K63-linked deubiquitinase activity / host cell endoplasmic reticulum / viral transcription / SARS-CoV-1 modulates host translation machinery / Transferases; Transferring one-carbon groups; Methyltransferases / SARS-CoV-1 activates/modulates innate immune responses / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / double membrane vesicle viral factory outer membrane / host cell endoplasmic reticulum-Golgi intermediate compartment / SARS coronavirus main proteinase / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / endonuclease activity / host cell endosome / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / host cell Golgi apparatus / symbiont-mediated suppression of host NF-kappaB cascade / symbiont-mediated perturbation of host ubiquitin-like protein modification / DNA helicase / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / regulation of autophagy / viral protein processing / lyase activity / host cell perinuclear region of cytoplasm / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / ATP hydrolysis activity / proteolysis / zinc ion binding / ATP binding / identical protein binding / membrane
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 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) 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 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus Nsp12 Interface domain profile. / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Nidovirus 2-O-methyltransferase / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerization / Nonstructural protein 15, middle domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / : / DNA2/NAM7 helicase-like, C-terminal / AAA domain / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Trypsin-like serine proteases / Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, N-terminal, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / NSP1 globular domain superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Betacoronavirus single-stranded poly(A) binding domain / Betacoronavirus Nsp3c-M domain profile. / NSP1, globular domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / NSP1, C-terminal domain, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / : / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Non-structural protein NSP3, nucleic acid-binding domain superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Papain-like viral protease, palm and finger domains, coronavirus / Papain-like protease, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP2, N-terminal / : / Coronavirus replicase NSP2, C-terminal / Coronavirus (CoV) Nsp2 middle domain profile. / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / Nonstructural protein 2, N-terminal domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Peptidase family C16 domain profile. / : / : / Coronavirus replicase NSP7
Similarity search - Domain/homology
Chem-3BL / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesHuman SARS coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 Å
AuthorsAkaji, K. / Teruya, K. / Shimamoto, Y. / Sanjho, A. / Yamashita, E. / Nakagawa, A.
CitationJournal: Bioorg.Med.Chem. / Year: 2015
Title: Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors
Authors: Shimamoto, Y. / Hattori, Y. / Kobayashi, K. / Teruya, K. / Sanjoh, A. / Nakagawa, A. / Yamashita, E. / Akaji, K.
History
DepositionJul 2, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Feb 18, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2020Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy
Category: citation / diffrn_source ...citation / diffrn_source / entity_src_gen / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _diffrn_source.pdbx_synchrotron_site ..._citation.journal_id_CSD / _diffrn_source.pdbx_synchrotron_site / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Nov 8, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3032
Polymers33,8331
Non-polymers4711
Water3,009167
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6064
Polymers67,6652
Non-polymers9412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area2530 Å2
ΔGint-8 kcal/mol
Surface area26330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.834, 82.128, 53.271
Angle α, β, γ (deg.)90.000, 104.980, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-537-

HOH

Details1

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Components

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


Mass: 33832.602 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Akaji K, Konno H, Mitsui H, Teruya K , Shimamoto Y, Hattori Y, Ozaki T, Kusunoki M, Sanjoh A.Structure-Based Design, Synthesis, and Evaluation of Peptide-mimetic SARS 3CL Protease Inhibitors. ...Details: Akaji K, Konno H, Mitsui H, Teruya K , Shimamoto Y, Hattori Y, Ozaki T, Kusunoki M, Sanjoh A.Structure-Based Design, Synthesis, and Evaluation of Peptide-mimetic SARS 3CL Protease Inhibitors.Journal of Medicinal Chemistry 54, 7962-7973, 2011.
Source: (gene. exp.) Human SARS coronavirus / Gene: rep, 1a-1b / Plasmid: pMAL-3CL-R188I / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0C6X7, SARS coronavirus main proteinase
#2: Chemical ChemComp-3BL / (2S)-2-({[(3S,4aR,8aS)-2-(biphenyl-4-ylcarbonyl)decahydroisoquinolin-3-yl]methyl}amino)-3-(1H-imidazol-5-yl)propanal


Mass: 470.606 Da / Num. of mol.: 1 / Fragment: aza-decaline type inhibitor / Source method: obtained synthetically / Formula: C29H34N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 167 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence detailsTHE SEQUENCE HAS BEEN DEPOSITED TO GENBANK WITH ACCESSION ID NP_828863, WHICH IS NOT AVAILABLE FROM ...THE SEQUENCE HAS BEEN DEPOSITED TO GENBANK WITH ACCESSION ID NP_828863, WHICH IS NOT AVAILABLE FROM UNIPROT AT PRESENT. RESIDUE 188 IS ARG ACCORDING TO THE DATABASE.

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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: 3.37 Å3/Da / Density % sol: 63.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 10%(w/v) of PEG20000, 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
ReflectionResolution: 1.6→50 Å / Num. obs: 57490 / % possible obs: 97 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.076 / Χ2: 1.32 / Net I/av σ(I): 21.878 / Net I/σ(I): 10.5 / Num. measured all: 239434
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Num. unique allΧ2% possible allRmerge(I) obs
1.6-1.633.628321.00196.4
1.63-1.663.828761.0196.50.841
1.66-1.693.928781.03597.90.663
1.69-1.72428721.04896.70.616
1.72-1.764.128471.04998.20.529
1.76-1.84.228961.03898.20.464
1.8-1.854.329011.09197.50.392
1.85-1.94.329101.08298.20.327
1.9-1.954.329091.12498.70.252
1.95-2.024.328881.17498.50.196
2.02-2.094.329361.14198.40.158
2.09-2.174.329181.16198.70.117
2.17-2.274.329231.20398.80.103
2.27-2.394.329281.26799.10.088
2.39-2.544.329451.35298.70.078
2.54-2.744.329281.54599.50.071
2.74-3.014.329461.76399.30.065
3.01-3.454.329761.96699.30.058
3.45-4.344.127832.18993.30.057
4.34-503.823982.2978.80.058

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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
Starting model: 3ATW

3atw


Resolution: 1.6→25.33 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.912 / SU ML: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.112 / ESU R Free: 0.123 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3187 2653 5 %RANDOM
Rwork0.2901 49902 --
obs0.2916 52555 88.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 115.63 Å2 / Biso mean: 40.804 Å2 / Biso min: 20 Å2
Baniso -1Baniso -2Baniso -3
1--0.88 Å2-0 Å2-0.06 Å2
2--1.1 Å2-0 Å2
3----0.17 Å2
Refinement stepCycle: final / Resolution: 1.6→25.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2367 0 35 167 2569
Biso mean--20 30 -
Num. residues----306
LS refinement shellResolution: 1.598→1.64 Å
Num. reflection% reflection
Rfree135 -
Rwork2855 -
obs-68.61 %

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