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- PDB-7end: Crystal structure of SARS-CoV 3CLpro in complex with the non-cova... -

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Database: PDB / ID: 7end
TitleCrystal structure of SARS-CoV 3CLpro in complex with the non-covalent inhibitor WU-04
ComponentsReplicase polyprotein 1a
KeywordsVIRAL PROTEIN / Non-covalent / Inhibitor / 3CLpro / Coronavirus
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 / host cell endoplasmic reticulum / K63-linked deubiquitinase activity / SARS-CoV-1 modulates host translation machinery / viral genome replication ...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 / host cell endoplasmic reticulum / K63-linked deubiquitinase activity / SARS-CoV-1 modulates host translation machinery / viral genome replication / methyltransferase activity / SARS-CoV-1 activates/modulates innate immune responses / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / 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 / methylation / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / regulation of autophagy / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / 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 / cysteine-type endopeptidase activity / RNA-directed RNA polymerase activity / proteolysis / zinc ion 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 / 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 ...Non-structural protein 3, SUD-N macrodomain, SARS-CoV / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / 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 / Trypsin-like serine proteases / 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 / Betacoronavirus replicase NSP1 / Betacoronavirus single-stranded poly(A) binding domain / NSP1, C-terminal domain, betacoronavirus / : / 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 / Coronavirus 3Ecto domain profile. / 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. / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Coronavirus main protease (M-pro) domain profile. / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP7, coronavirus / Non-structural protein NSP8, coronavirus / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Papain-like protease, thumb domain superfamily, coronavirus / Peptidase C30, domain 3, coronavirus / Non-structural protein 6, coronavirus / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus endopeptidase C30 / Coronavirus papain-like peptidase / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus replicase NSP9 / Thrombin, subunit H / Non-structural protein 3, X-domain-like / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-J7R / Replicase polyprotein 1a
Similarity search - Component
Biological speciesHuman SARS coronavirus
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsHou, N. / Peng, C. / Hu, Q.
CitationJournal: Acs Cent.Sci. / Year: 2023
Title: Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro.
Authors: Hou, N. / Shuai, L. / Zhang, L. / Xie, X. / Tang, K. / Zhu, Y. / Yu, Y. / Zhang, W. / Tan, Q. / Zhong, G. / Wen, Z. / Wang, C. / He, X. / Huo, H. / Gao, H. / Xu, Y. / Xue, J. / Peng, C. / ...Authors: Hou, N. / Shuai, L. / Zhang, L. / Xie, X. / Tang, K. / Zhu, Y. / Yu, Y. / Zhang, W. / Tan, Q. / Zhong, G. / Wen, Z. / Wang, C. / He, X. / Huo, H. / Gao, H. / Xu, Y. / Xue, J. / Peng, C. / Zou, J. / Schindewolf, C. / Menachery, V. / Su, W. / Yuan, Y. / Shen, Z. / Zhang, R. / Yuan, S. / Yu, H. / Shi, P.Y. / Bu, Z. / Huang, J. / Hu, Q.
History
DepositionApr 16, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 20, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 8, 2023Group: 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.title / _citation.year
Revision 1.2Mar 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID
Revision 1.3Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Replicase polyprotein 1a
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4032
Polymers33,8771
Non-polymers5261
Water4,702261
1
A: Replicase polyprotein 1a
hetero molecules

A: Replicase polyprotein 1a
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,8064
Polymers67,7532
Non-polymers1,0532
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area2470 Å2
ΔGint-9 kcal/mol
Surface area26450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.496, 82.677, 107.454
Angle α, β, γ (deg.)90.000, 103.640, 90.000
Int Tables number5
Space group name H-MI121
Space group name HallC2y(x,y,-x+z)
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z+1/2
#4: -x+1/2,y+1/2,-z+1/2
Components on special symmetry positions
IDModelComponents
11A-727-

HOH

21A-754-

HOH

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Components

#1: Protein Replicase polyprotein 1a / pp1a / ORF1a polyprotein


Mass: 33876.637 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human SARS coronavirus / Gene: 1a / Production host: Escherichia coli (E. coli)
References: UniProt: P0C6U8, ubiquitinyl hydrolase 1, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases, SARS coronavirus main proteinase
#2: Chemical ChemComp-J7R / ~{N}-[(1~{S},2~{R})-2-[[4-bromanyl-2-(methylcarbamoyl)-6-nitro-phenyl]amino]cyclohexyl]isoquinoline-4-carboxamide


Mass: 526.382 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H24BrN5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 261 / 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: 3.41 Å3/Da / Density % sol: 63.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.4
Details: 10% 2-propanal, 0.1 M sodium citrate pH 5.4, 10% PEG 10,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.541 Å
DetectorType: RIGAKU HyPix-6000HE / Detector: PIXEL / Date: Nov 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.541 Å / Relative weight: 1
ReflectionResolution: 1.99→30.76 Å / Num. obs: 31238 / % possible obs: 99.46 % / Redundancy: 11 % / Biso Wilson estimate: 21.85 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.1236 / Rpim(I) all: 0.03849 / Rrim(I) all: 0.1295 / Net I/σ(I): 33.16
Reflection shellResolution: 1.99→2.061 Å / Redundancy: 8.4 % / Rmerge(I) obs: 0.4076 / Mean I/σ(I) obs: 5.12 / Num. unique obs: 3133 / CC1/2: 0.864 / Rpim(I) all: 0.149 / Rrim(I) all: 0.4344 / % possible all: 99.62

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Processing

Software
NameVersionClassification
CrysalisPro1.171.40.73adata collection
PHENIX1.17.1_3660refinement
CrysalisPro1.171.40.73adata reduction
CrysalisPro1.171.40.73adata scaling
PHENIX1.17.1_3660phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1uj1

1uj1


Resolution: 1.99→30.76 Å / SU ML: 0.2244 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.2464
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.237 1477 4.75 %
Rwork0.1974 29610 -
obs0.1993 31087 99.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.99 Å2
Refinement stepCycle: LAST / Resolution: 1.99→30.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2371 0 34 261 2666
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00342461
X-RAY DIFFRACTIONf_angle_d0.63863346
X-RAY DIFFRACTIONf_chiral_restr0.0434374
X-RAY DIFFRACTIONf_plane_restr0.0049433
X-RAY DIFFRACTIONf_dihedral_angle_d15.4767874
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.99-2.050.26251350.22462703X-RAY DIFFRACTION99.79
2.05-2.130.27841340.21962673X-RAY DIFFRACTION99.93
2.13-2.210.38071310.29212641X-RAY DIFFRACTION98.02
2.21-2.310.41091320.33662628X-RAY DIFFRACTION98.05
2.31-2.440.28051350.24672708X-RAY DIFFRACTION99.44
2.44-2.590.27421340.21592669X-RAY DIFFRACTION99.79
2.59-2.790.22581330.20542698X-RAY DIFFRACTION99.89
2.79-3.070.24211350.20192709X-RAY DIFFRACTION99.89
3.07-3.510.2291340.1842695X-RAY DIFFRACTION99.89
3.51-4.420.17451360.15182714X-RAY DIFFRACTION99.96
4.42-30.760.16741380.14412772X-RAY DIFFRACTION99.9

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