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- PDB-8cae: Crystal structure of SARS-CoV-2 Mpro-H172Y mutant in complex with... -

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Basic information

Entry
Database: PDB / ID: 8cae
TitleCrystal structure of SARS-CoV-2 Mpro-H172Y mutant in complex with nirmatrelvir
ComponentsNon-structural protein 11
KeywordsANTIVIRAL PROTEIN / Mpro mutation
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: 2.65 Å
AuthorsEl Kilani, H. / Hilgenfeld, R.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European CommissionEuropean Union
CitationJournal: Crystals / Year: 2025
Title: 13b-K and Nirmatrelvir Resistance Mutations of SARS-CoV-2 Main Protease: Structural, Biochemical, and Biophysical Characterization of Free Enzymes and Inhibitor Complexes
Authors: El Kilani, H. / Sun, X. / Ibrahim, M.F. / Curth, U. / Hilgenfeld, R.
History
DepositionJan 24, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 6, 2025Provider: repository / Type: Initial release
Revision 1.1Sep 3, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Non-structural protein 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9762
Polymers33,4741
Non-polymers5021
Water45025
1
A: Non-structural protein 11
hetero molecules

A: Non-structural protein 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,9514
Polymers66,9482
Non-polymers1,0032
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area2750 Å2
ΔGint-10 kcal/mol
Surface area25110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.208, 53.761, 45.551
Angle α, β, γ (deg.)90.000, 101.585, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-510-

HOH

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Components

#1: Protein Non-structural protein 11 / nsp11


Mass: 33474.172 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 (bacteria) / References: UniProt: P0DTC1
#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.: 25 / 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 Å3/Da / Density % sol: 38.59 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 0.1M MMT pH8.0, 25% w/vPEG 1500

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.033 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 22, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 2.65→48.583 Å / Num. obs: 7973 / % possible obs: 98.7 % / Redundancy: 3.9 % / CC1/2: 0.986 / Net I/σ(I): 6
Reflection shellResolution: 2.72→2.86 Å / Num. unique obs: 942 / CC1/2: 0.327

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.65→48.583 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.935 / SU B: 20.918 / SU ML: 0.399 / Cross valid method: NONE / ESU R Free: 0.393
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.258 398 4.992 %
Rwork0.1765 7575 -
all0.181 --
obs-7973 98.884 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 79.122 Å2
Baniso -1Baniso -2Baniso -3
1-4.402 Å2-0 Å23.017 Å2
2---2.435 Å20 Å2
3----2.956 Å2
Refinement stepCycle: LAST / Resolution: 2.65→48.583 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2342 0 35 25 2402
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0122432
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162257
X-RAY DIFFRACTIONr_angle_refined_deg1.3731.8043313
X-RAY DIFFRACTIONr_angle_other_deg0.491.7335183
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.7455302
X-RAY DIFFRACTIONr_dihedral_angle_2_deg16.0966.33315
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.81810384
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg12.615101
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.25310108
X-RAY DIFFRACTIONr_chiral_restr0.0660.2376
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022880
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02574
X-RAY DIFFRACTIONr_nbd_refined0.2420.2580
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2140.22322
X-RAY DIFFRACTIONr_nbtor_refined0.1930.21226
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0850.21275
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1910.278
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0850.24
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1570.234
X-RAY DIFFRACTIONr_nbd_other0.2110.2119
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1670.28
X-RAY DIFFRACTIONr_mcbond_it6.2987.7251211
X-RAY DIFFRACTIONr_mcbond_other6.2867.7241211
X-RAY DIFFRACTIONr_mcangle_it9.61913.8411512
X-RAY DIFFRACTIONr_mcangle_other9.61613.8461513
X-RAY DIFFRACTIONr_scbond_it6.4238.3441221
X-RAY DIFFRACTIONr_scbond_other6.428.3451222
X-RAY DIFFRACTIONr_scangle_it10.23615.0691798
X-RAY DIFFRACTIONr_scangle_other10.23415.0691799
X-RAY DIFFRACTIONr_lrange_it14.58580.5622764
X-RAY DIFFRACTIONr_lrange_other14.58380.562765
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.65-2.7190.283180.3695630.3655870.9360.88698.97790.351
2.719-2.7930.339300.355340.355650.9240.89499.8230.331
2.793-2.8740.341250.3245350.3255620.9160.91399.64410.296
2.874-2.9620.342300.2815100.2855450.9120.9499.08260.252
2.962-3.0580.306280.255020.2535330.9310.95499.43710.214
3.058-3.1650.366290.2134730.2215140.9240.96497.66540.184
3.165-3.2840.308180.214290.2144730.9550.96994.50320.182
3.284-3.4180.363230.1764550.1834820.9220.97999.17010.153
3.418-3.5690.295200.1794470.1844670.9410.981000.159
3.569-3.7420.299240.1794090.1854330.9350.9821000.164
3.742-3.9430.226270.1673810.1714080.9630.9831000.156
3.943-4.1810.268150.1573840.1614020.9510.98599.25370.145
4.181-4.4670.184290.1343410.1393720.980.98899.46240.127
4.467-4.8220.253160.1373160.1423350.9630.98999.10450.13
4.822-5.2770.243210.1353000.1423280.9690.98997.86590.128
5.277-5.8910.20370.1812780.1812900.9790.98598.27590.169
5.891-6.7850.61680.1642380.1722550.9370.98596.47060.156
6.785-8.270.299140.1352080.1452220.9620.9891000.14
8.27-11.530.09280.1021760.1011840.9960.9941000.109
11.53-48.5830.26180.185960.191050.9840.98399.04760.192

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