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- PDB-8i4s: the complex structure of SARS-CoV-2 Mpro with D8 -

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Basic information

Entry
Database: PDB / ID: 8i4s
Titlethe complex structure of SARS-CoV-2 Mpro with D8
ComponentsORF1a polyprotein
KeywordsHYDROLASE / inhibitor / complex
Function / homology
Function and homology information


host cell membrane / viral genome replication / methyltransferase activity / symbiont-mediated degradation of host mRNA / 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 / symbiont-mediated perturbation of host ubiquitin-like protein modification / methylation ...host cell membrane / viral genome replication / methyltransferase activity / symbiont-mediated degradation of host mRNA / 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 / symbiont-mediated perturbation of host ubiquitin-like protein modification / methylation / single-stranded RNA binding / host cell perinuclear region of cytoplasm / 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 / 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 / Betacoronavirus Nsp3c-M domain profile. ...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 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 / 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 replicase NSP7 / Peptidase family C16 domain profile. / 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. / 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-OU3 / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsLu, M.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 M pro ).
Authors: Zhang, K. / Wang, T. / Li, M. / Liu, M. / Tang, H. / Wang, L. / Ye, K. / Yang, J. / Jiang, S. / Xiao, Y. / Xie, Y. / Lu, M. / Zhang, X.
History
DepositionJan 21, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 29, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ORF1a polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4612
Polymers37,1031
Non-polymers3581
Water2,738152
1
A: ORF1a polyprotein
hetero molecules

A: ORF1a polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,9234
Polymers74,2062
Non-polymers7172
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_557-x,y,-z+21
Buried area2590 Å2
ΔGint-6 kcal/mol
Surface area24960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.364, 81.332, 51.675
Angle α, β, γ (deg.)90.000, 114.743, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Components on special symmetry positions
IDModelComponents
11A-530-

HOH

21A-584-

HOH

31A-621-

HOH

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Components

#1: Protein ORF1a polyprotein


Mass: 37103.090 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: ORF1ab
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: A0A8B1JQ63
#2: Chemical ChemComp-OU3 / 3-(4-fluoranyl-3-methyl-phenyl)-2-(2-methylpropyl)-5,6,7-tris(oxidanyl)quinazolin-4-one


Mass: 358.364 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C19H19FN2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 152 / 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: 2.53 Å3/Da / Density % sol: 56.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 12% PEG 20,000, 0.1 M MES monohydrate (pH 6.5)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 2, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.2→42.41 Å / Num. obs: 35746 / % possible obs: 99.69 % / Redundancy: 3.7 % / Biso Wilson estimate: 29.4 Å2 / CC1/2: 0.986 / Net I/σ(I): 6.82
Reflection shellResolution: 2.2→2.279 Å / Num. unique obs: 6681 / CC1/2: 0.89

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→42.41 Å / SU ML: 0.2358 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 23.8931
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2238 2081 5.82 %
Rwork0.1855 33665 -
obs0.1878 35746 96.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.83 Å2
Refinement stepCycle: LAST / Resolution: 2.2→42.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2323 0 26 152 2501
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00782403
X-RAY DIFFRACTIONf_angle_d1.02233270
X-RAY DIFFRACTIONf_chiral_restr0.0519364
X-RAY DIFFRACTIONf_plane_restr0.0064422
X-RAY DIFFRACTIONf_dihedral_angle_d19.75853
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.250.28961390.24742217X-RAY DIFFRACTION95.85
2.25-2.310.26871390.24132214X-RAY DIFFRACTION96.59
2.31-2.370.28861410.22482282X-RAY DIFFRACTION97.47
2.37-2.440.29321430.22312275X-RAY DIFFRACTION97.86
2.44-2.520.29511340.22532250X-RAY DIFFRACTION97.39
2.52-2.610.2551360.21142273X-RAY DIFFRACTION97.61
2.61-2.710.25631390.21912228X-RAY DIFFRACTION96.69
2.71-2.840.26851450.20752253X-RAY DIFFRACTION97.05
2.84-2.990.25051390.20532227X-RAY DIFFRACTION96.85
2.99-3.170.24531380.19472280X-RAY DIFFRACTION97.97
3.17-3.420.20141410.1922261X-RAY DIFFRACTION96.97
3.42-3.760.19321340.16882235X-RAY DIFFRACTION95.91
3.76-4.30.20861370.15182238X-RAY DIFFRACTION96.58
4.31-5.420.1661360.14752200X-RAY DIFFRACTION95.86
5.42-42.410.19221400.16322232X-RAY DIFFRACTION95.68

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