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- PDB-8hhu: Crystal structure of the SARS-CoV-2 main protease in complex with... -

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Entry
Database: PDB / ID: 8hhu
TitleCrystal structure of the SARS-CoV-2 main protease in complex with SY110
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / Severe acute respiratory syndrome coronavirus 2 / main protease
Function / homology
Function and homology information


viral genome replication / methyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase ...viral genome replication / methyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / 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 / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / endonuclease activity / ubiquitinyl hydrolase 1 / methylation / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / host cell perinuclear region of cytoplasm / single-stranded RNA binding / host cell endoplasmic reticulum membrane / viral protein processing / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / viral translational frameshifting / cysteine-type endopeptidase activity / virus-mediated perturbation of host defense response / lipid binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / proteolysis / zinc ion binding / membrane
Similarity search - Function
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 / Carbamoyl-phosphate synthase subdomain signature 2. ...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 / Carbamoyl-phosphate synthase subdomain signature 2. / 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 / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp2 middle domain profile. / 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 / : / Coronavirus 3Ecto domain profile. / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / : / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus replicase NSP7 / Peptidase family C16 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 Nsp4 C-terminal (Nsp4C) 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 main protease (M-pro) domain profile. / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Macro domain / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-LVX / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.258 Å
AuthorsZeng, R. / Xie, L.W. / Huang, C. / Wang, K. / Liu, Y.Z. / Yang, S.Y. / Lei, J.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)2021YFF0702004 China
CitationJournal: Signal Transduct Target Ther / Year: 2023
Title: A new generation M pro inhibitor with potent activity against SARS-CoV-2 Omicron variants.
Authors: Huang, C. / Shuai, H. / Qiao, J. / Hou, Y. / Zeng, R. / Xia, A. / Xie, L. / Fang, Z. / Li, Y. / Yoon, C. / Huang, Q. / Hu, B. / You, J. / Quan, B. / Zhao, X. / Guo, N. / Zhang, S. / Ma, R. / ...Authors: Huang, C. / Shuai, H. / Qiao, J. / Hou, Y. / Zeng, R. / Xia, A. / Xie, L. / Fang, Z. / Li, Y. / Yoon, C. / Huang, Q. / Hu, B. / You, J. / Quan, B. / Zhao, X. / Guo, N. / Zhang, S. / Ma, R. / Zhang, J. / Wang, Y. / Yang, R. / Zhang, S. / Nan, J. / Xu, H. / Wang, F. / Lei, J. / Chu, H. / Yang, S.
History
DepositionNov 17, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 30, 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 nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4052
Polymers33,8671
Non-polymers5391
Water3,909217
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,8104
Polymers67,7332
Non-polymers1,0772
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area2640 Å2
ΔGint-12 kcal/mol
Surface area25960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.704, 82.411, 51.946
Angle α, β, γ (deg.)90.000, 114.690, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 33866.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: Escherichia coli (E. coli)
References: UniProt: P0DTC1, SARS coronavirus main proteinase
#2: Chemical ChemComp-LVX / (1~{R})-3,3-bis(fluoranyl)-~{N}-[(2~{R})-3-methoxy-1-oxidanylidene-1-[[(2~{R},3~{S})-3-oxidanyl-4-oxidanylidene-1-phenyl-4-(1,3-thiazol-2-ylmethylamino)butan-2-yl]amino]propan-2-yl]cyclohexane-1-carboxamide


Type: peptide-like / Mass: 538.607 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H32F2N4O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 217 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.83 Å3/Da / Density % sol: 56.25 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 0.2 M BIS-TRIS pH 5.5, 25% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.976246 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 8, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976246 Å / Relative weight: 1
ReflectionResolution: 2.258→60.68 Å / Num. obs: 17608 / % possible obs: 98.8 % / Redundancy: 6.8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.028 / Rrim(I) all: 0.072 / Net I/σ(I): 14
Reflection shellResolution: 2.258→2.33 Å / Rmerge(I) obs: 0.619 / Mean I/σ(I) obs: 3 / Num. unique obs: 1599 / CC1/2: 0.968 / Rpim(I) all: 0.258 / Rrim(I) all: 0.672

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (16-JUL-2021)refinement
MOLREPphasing
Aimlessdata scaling
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7C7P

7c7p


Resolution: 2.258→44.84 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.924 / SU R Cruickshank DPI: 0.253 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.27 / SU Rfree Blow DPI: 0.2 / SU Rfree Cruickshank DPI: 0.198
RfactorNum. reflection% reflectionSelection details
Rfree0.2268 809 4.62 %RANDOM
Rwork0.1854 ---
obs0.1873 17517 98.3 %-
Displacement parametersBiso max: 127.78 Å2 / Biso mean: 64.21 Å2 / Biso min: 39.66 Å2
Baniso -1Baniso -2Baniso -3
1--17.9823 Å20 Å27.8136 Å2
2---8.932 Å20 Å2
3---26.9143 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: final / Resolution: 2.258→44.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2343 0 37 217 2597
Biso mean--79.51 77.41 -
Num. residues----303
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d820SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes418HARMONIC5
X-RAY DIFFRACTIONt_it2440HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion316SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2094SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2440HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3316HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion3.3
X-RAY DIFFRACTIONt_other_torsion16.56
LS refinement shellResolution: 2.26→2.28 Å / Rfactor Rfree error: 0 / Total num. of bins used: 41
RfactorNum. reflection% reflection
Rfree0.4084 23 5.25 %
Rwork0.4041 415 -
all0.4043 438 -
obs--86.6 %

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