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- PDB-8h3g: Crystal Structure of SARS-CoV-2 Main Protease (Mpro) E166V Mutant... -

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Entry
Database: PDB / ID: 8h3g
TitleCrystal Structure of SARS-CoV-2 Main Protease (Mpro) E166V Mutant in Complex with Inhibitor Enstrelvir
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / SARS-CoV-2 / Mutant
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 / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / endonuclease activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / methylation / 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 / host cell endoplasmic reticulum membrane / 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 / lipid binding / host cell nucleus / 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 / 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 / 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
Similarity search - Domain/homology
Chem-7YY / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.46 Å
AuthorsWang, H. / Lin, M. / Duan, Y. / Zhang, X. / Zhou, H. / Bian, Q. / Liu, X. / Rao, Z. / Yang, H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)92169109 China
CitationJournal: Nature / Year: 2023
Title: Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir.
Authors: Duan, Y. / Zhou, H. / Liu, X. / Iketani, S. / Lin, M. / Zhang, X. / Bian, Q. / Wang, H. / Sun, H. / Hong, S.J. / Culbertson, B. / Mohri, H. / Luck, M.I. / Zhu, Y. / Liu, X. / Lu, Y. / Yang, ...Authors: Duan, Y. / Zhou, H. / Liu, X. / Iketani, S. / Lin, M. / Zhang, X. / Bian, Q. / Wang, H. / Sun, H. / Hong, S.J. / Culbertson, B. / Mohri, H. / Luck, M.I. / Zhu, Y. / Liu, X. / Lu, Y. / Yang, X. / Yang, K. / Sabo, Y. / Chavez, A. / Goff, S.P. / Rao, Z. / Ho, D.D. / Yang, H.
History
DepositionOct 8, 2022Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3C-like proteinase nsp5
B: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,0238
Polymers67,5912
Non-polymers1,4326
Water10,395577
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3420 Å2
ΔGint-10 kcal/mol
Surface area24740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.785, 99.291, 58.933
Angle α, β, γ (deg.)90.000, 108.280, 90.000
Int Tables number4
Space group name H-MP1211

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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: 33795.562 Da / Num. of mol.: 2 / Mutation: E166V
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-7YY / 6-[(6-chloranyl-2-methyl-indazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[[2,4,5-tris(fluoranyl)phenyl]methyl]-1,3,5-triazine-2,4-dione


Mass: 531.878 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H17ClF3N9O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antivirus, protease inhibitor*YM
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 577 / 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: 2.33 Å3/Da / Density % sol: 47.16 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop
Details: 0.2M Sodium formate, 0.1M BICINE pH 8.5, 20% w/v PEG monomethyl ether 5000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.978642 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Aug 17, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978642 Å / Relative weight: 1
ReflectionResolution: 1.46→26.93 Å / Num. obs: 101380 / % possible obs: 96 % / Redundancy: 7.02 % / Biso Wilson estimate: 19.91 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.052 / Rrim(I) all: 0.056 / Χ2: 0.834 / Net I/σ(I): 18.94 / Num. measured all: 711723
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.46-1.556.7820.6562.8610794817018159180.870.70993.5
1.55-1.657.3020.3975.0611037015969151150.9530.42794.7
1.65-1.797.2280.2268.6610283314927142270.9830.24495.3
1.79-1.966.8080.11914.638959613720131600.9940.12995.9
1.96-2.1970.07223.728410412431120140.9970.07896.6
2.19-2.537.2570.05431.777776410986107160.9980.05997.5
2.53-3.096.970.04338.4763795932591530.9980.04798.2
3.09-4.366.5510.03843.9946461718070920.9980.04198.8
4.36-26.937.240.03948.3528852405839850.9980.04298.2

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Processing

Software
NameVersionClassification
PHENIX1.20.1-4487refinement
XDS2020-12-02data scaling
PHENIX1.20.1_4487phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7VU6

7vu6


Resolution: 1.46→26.93 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.09 / Phase error: 16.48 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1622 2011 1.98 %
Rwork0.1413 99348 -
obs0.1417 101359 96.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 181.39 Å2 / Biso mean: 29.2165 Å2 / Biso min: 13.34 Å2
Refinement stepCycle: final / Resolution: 1.46→26.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4618 0 98 577 5293
Biso mean--31.68 41.85 -
Num. residues----603
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.46-1.50.23811400.21846807694793
1.5-1.540.22211410.17546920706194
1.54-1.580.19631430.1566966710995
1.58-1.630.211310.15086985711695
1.63-1.690.1811440.14797050719495
1.69-1.760.19961400.1516981712195
1.76-1.840.21171490.14977099724896
1.84-1.940.15971420.14337056719896
1.94-2.060.18761310.1387116724796
2.06-2.220.15261530.13937164731797
2.22-2.440.17351450.14287218736398
2.44-2.790.18291490.14857299744898
2.79-3.520.14611540.14017276743099
3.52-26.930.1351490.12857411756099

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