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- PDB-8h7k: SARS-CoV-2 Mpro Double Mutant (H41A and T21I) in complex with nsp... -

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Basic information

Entry
Database: PDB / ID: 8h7k
TitleSARS-CoV-2 Mpro Double Mutant (H41A and T21I) in complex with nsp4/5 peptidyl substrate
Components
  • 3C-like proteinase nsp5
  • nsp4/5 peptidyl substrate
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 / methylation / double membrane vesicle viral factory outer membrane ...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 / methylation / 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 / SARS-CoV-2 modulates host translation machinery / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / endonuclease activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / viral protein processing / induction by virus of host autophagy / symbiont-mediated suppression of host gene expression / cysteine-type endopeptidase activity / lipid binding / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / 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. / Coronavirus 3Ecto domain profile. / : / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / NSP1, C-terminal domain, betacoronavirus / 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 / Betacoronavirus (BetaCoV) Nsp1 C-terminal 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 superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / : / Coronavirus (CoV) Nsp2 middle domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / NSP1, globular domain, alpha/betacoronavirus / : / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl 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. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Papain-like protease, thumb domain superfamily, coronavirus / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Non-structural protein NSP7, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, 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 / 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
Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 Å
AuthorsLin, M. / Liu, X.
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 20, 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

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase nsp5
B: nsp4/5 peptidyl substrate


Theoretical massNumber of molelcules
Total (without water)34,8372
Polymers34,8372
Non-polymers00
Water4,143230
1
A: 3C-like proteinase nsp5
B: nsp4/5 peptidyl substrate

A: 3C-like proteinase nsp5
B: nsp4/5 peptidyl substrate


Theoretical massNumber of molelcules
Total (without water)69,6734
Polymers69,6734
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area5670 Å2
ΔGint-30 kcal/mol
Surface area25320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.668, 80.884, 51.647
Angle α, β, γ (deg.)90.000, 114.520, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-437-

HOH

21A-551-

HOH

31A-555-

HOH

41A-562-

HOH

51A-614-

HOH

61A-621-

HOH

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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: 33770.531 Da / Num. of mol.: 1 / Mutation: H41A/T21I
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: Protein/peptide nsp4/5 peptidyl substrate


Mass: 1066.189 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: chemical production metagenome (others)
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 230 / Source method: isolated from a natural source / Formula: H2O

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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: 2.66 Å3/Da / Density % sol: 53.83 %
Crystal growTemperature: 293 K / Method: evaporation
Details: 0.2% w/v Lidocaine hydrochloride monohydrate, 0.2% w/v Procaine hydrochloride, 0.2% w/v Proparacaine hydrochloride, 0.2% w/v tetracaine hydrochloride, 0.1 M Buffer System 2 pH 7.5 (sodium ...Details: 0.2% w/v Lidocaine hydrochloride monohydrate, 0.2% w/v Procaine hydrochloride, 0.2% w/v Proparacaine hydrochloride, 0.2% w/v tetracaine hydrochloride, 0.1 M Buffer System 2 pH 7.5 (sodium HEPES, MOPS acid), 20% v/v Glycerol, 10% w/v PEG 4,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.97853 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 23, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 1.45→19.94 Å / Num. obs: 64519 / % possible obs: 99.7 % / Redundancy: 6.692 % / Biso Wilson estimate: 21.58 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.034 / Rrim(I) all: 0.037 / Χ2: 0.858 / Net I/σ(I): 24.02 / Num. measured all: 431767
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
1.45-1.546.5940.7492.386817810371103390.9040.81399.7
1.54-1.646.7560.4364.1165863976597490.9560.47399.8
1.64-1.776.5860.2357.3659804909690810.9850.25599.8
1.77-1.946.8830.12313.8957607838283690.9950.13499.8
1.94-2.176.5920.06325.6449948759375770.9980.06899.8
2.17-2.56.980.04140.0446827672967090.9990.04499.7
2.5-3.056.5550.02954.9537294571056890.9990.03299.6
3.05-4.266.6570.02272.79296034473444710.02499.4
4.26-19.946.5040.0279.1916643261725590.9990.02297.8

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
autoPROCdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7dvp

7dvp


Resolution: 1.45→19.94 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 20.33 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1838 1996 3.1 %
Rwork0.1681 62467 -
obs0.1686 64463 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 101.27 Å2 / Biso mean: 32.9251 Å2 / Biso min: 15.38 Å2
Refinement stepCycle: final / Resolution: 1.45→19.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2393 0 0 230 2623
Biso mean---41.05 -
Num. residues----312
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 (%)
1.45-1.490.31181420.28634431457399
1.49-1.530.30191420.24644414583100
1.53-1.570.23931430.224344394582100
1.57-1.620.23851430.193244644607100
1.62-1.680.2041410.184744404581100
1.68-1.750.17461420.177444514593100
1.75-1.830.1871420.177644524594100
1.83-1.920.2041420.171744734615100
1.92-2.040.19231420.169344484590100
2.04-2.20.19771420.168244514593100
2.2-2.420.22321440.172244814625100
2.42-2.770.19871430.179344704613100
2.77-3.490.16761430.170344884631100
3.49-19.940.14871450.143245384683100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.04680.79640.72991.39950.82013.34310.0604-0.00990.0511-0.03410.0018-0.1783-0.21870.1562-0.06580.2052-0.02860.02590.189-0.01470.22142.089410.647812.1815
22.53130.50290.54384.2288-0.35664.92290.0492-0.12560.18460.1978-0.0302-0.4648-0.4030.55660.00630.262-0.0825-0.03650.268-0.07820.27357.183615.285726.6595
30.9530.1224-0.32223.3889-0.30891.9635-0.02490.06320.0588-0.14410.07340.0027-0.1357-0.0118-0.0420.1718-0.01970.00430.17-0.01170.1424-2.42475.185711.1121
40.94610.48010.28881.10210.52962.21820.0438-0.0428-0.12350.09780.0333-0.1210.14620.1004-0.08690.1521-0.01060.00470.1845-0.00240.1988-3.8824-4.485815.8176
53.5319-0.12061.36832.58780.85422.87390.0072-0.3008-0.33120.18880.090.29070.4782-0.5853-0.08870.2621-0.11010.02740.28950.00270.2829-19.5614-18.37194.3714
65.6015-0.31070.08874.88670.35844.7952-0.01050.2138-0.4152-0.08320.0106-0.14890.3375-0.064-0.01470.1984-0.07060.00990.2155-0.04620.1608-11.9599-16.25770.4229
77.34813.7618-1.05497.1797-2.66818.2340.0877-0.37470.03390.37-0.0277-1.2134-0.21720.79310.03330.2077-0.0208-0.0210.37-0.03830.412813.43211.723621.0696
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 43 )A1 - 43
2X-RAY DIFFRACTION2chain 'A' and (resid 44 through 91 )A44 - 91
3X-RAY DIFFRACTION3chain 'A' and (resid 92 through 155 )A92 - 155
4X-RAY DIFFRACTION4chain 'A' and (resid 156 through 213 )A156 - 213
5X-RAY DIFFRACTION5chain 'A' and (resid 214 through 260 )A214 - 260
6X-RAY DIFFRACTION6chain 'A' and (resid 261 through 302 )A261 - 302
7X-RAY DIFFRACTION7chain 'B' and (resid 1 through 10 )B1 - 10

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