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- PDB-8h5f: Crystal Structure of SARS-CoV-2 Main Protease (Mpro) L167F Mutant... -

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Entry
Database: PDB / ID: 8h5f
TitleCrystal Structure of SARS-CoV-2 Main Protease (Mpro) L167F Mutant in Complex with Inhibitor Nirmatrelvir
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 / 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 / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / methylation / omega peptidase activity / SARS-CoV-2 modulates host translation machinery / 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 / 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-4WI / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 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 13, 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
Revision 1.2Oct 9, 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:
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Assembly

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


Theoretical massNumber of molelcules
Total (without water)34,3612
Polymers33,8601
Non-polymers5021
Water3,855214
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,7224
Polymers67,7192
Non-polymers1,0032
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_565-x,-y+1,z1
Buried area3230 Å2
ΔGint-13 kcal/mol
Surface area24530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.373, 63.825, 105.839
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-668-

HOH

21A-710-

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: 33859.562 Da / Num. of mol.: 1 / Mutation: L167F
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-4WI / (1R,2S,5S)-N-{(1E,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide / PF-07321332, bound form / nirmatrelvir, bound form / Paxlovid, bound form


Mass: 501.542 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H34F3N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 214 / 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: 2.26 Å3/Da / Density % sol: 45.65 %
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 3 pH 8.5 (Tris ...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 3 pH 8.5 (Tris base, BICINE), 20% v/v ethylene glycol, 10% w/v PEG 8,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.95374 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Aug 10, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95374 Å / Relative weight: 1
ReflectionResolution: 1.79→27.33 Å / Num. obs: 29844 / % possible obs: 99.9 % / Redundancy: 13.3 % / CC1/2: 1 / Rmerge(I) obs: 0.08 / Rrim(I) all: 0.083 / Net I/σ(I): 21.05
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.79-1.90.65847290.9190.6841
1.9-2.030.444470.9720.4171
2.03-2.190.26441530.9830.2751
2.19-2.40.18538500.9920.1911
2.4-2.680.13135000.9970.1361
2.68-3.080.08630950.9980.091
3.08-3.770.04926800.9990.0511
3.77-5.280.033210210.0341
5.28-27.330.03312880.9990.0351

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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: 7vh8

7vh8


Resolution: 1.79→27.33 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 22.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2273 1999 6.71 %
Rwork0.184 --
obs0.1869 29813 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.79→27.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2357 0 35 214 2606
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082459
X-RAY DIFFRACTIONf_angle_d1.0463355
X-RAY DIFFRACTIONf_dihedral_angle_d10.386351
X-RAY DIFFRACTIONf_chiral_restr0.068379
X-RAY DIFFRACTIONf_plane_restr0.008434
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.79-1.830.31121400.23551954X-RAY DIFFRACTION100
1.83-1.880.27651410.22371958X-RAY DIFFRACTION100
1.88-1.940.27691400.20831938X-RAY DIFFRACTION100
1.94-20.26321400.19761957X-RAY DIFFRACTION100
2-2.070.28021410.19941961X-RAY DIFFRACTION100
2.07-2.150.23791420.19071964X-RAY DIFFRACTION100
2.16-2.250.24671410.19581969X-RAY DIFFRACTION100
2.25-2.370.25081410.18961969X-RAY DIFFRACTION100
2.37-2.520.23981440.20121992X-RAY DIFFRACTION100
2.52-2.710.26471410.19561958X-RAY DIFFRACTION100
2.71-2.990.21491430.19821991X-RAY DIFFRACTION100
2.99-3.420.22291450.1782019X-RAY DIFFRACTION100
3.42-4.310.20771470.16192032X-RAY DIFFRACTION100
4.31-27.330.18441530.16762152X-RAY DIFFRACTION100

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