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- PDB-23mh: Crystal structure of SARS-CoV-2 main protease T21I/E166V mutant i... -

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Basic information

Entry
Database: PDB / ID: 23mh
TitleCrystal structure of SARS-CoV-2 main protease T21I/E166V mutant in complex with leritrelvir
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / SARS-CoV-2 / NSP5 / main protease / coronavirus / protease inhibitor / alpha-ketoamide inhibitor / peptidomimetic inhibitor
Function / homology
Function and homology information


viral genome replication / methyltransferase activity / endonuclease 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 / methylation / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome ...viral genome replication / methyltransferase activity / endonuclease 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 / methylation / 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 / mRNA guanylyltransferase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / SARS-CoV-2 modulates host translation machinery / symbiont-mediated perturbation of host ubiquitin-like protein modification / host cell Golgi apparatus / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / ubiquitinyl hydrolase 1 / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / cysteine-type deubiquitinase activity / single-stranded RNA binding / viral protein processing / host cell perinuclear region of cytoplasm / 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
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 / Coronavirus Nsp6 transmembrane protein 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 / Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / Betacoronavirus single-stranded poly(A) binding domain / 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 / 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 / Carbamoyl-phosphate synthase subdomain signature 2. / Coronavirus replicase NSP2, N-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 Nsp3 ectodomain (3Ecto) 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 replicase NSP7 / 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-7ON / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsHuang, X. / Li, Q. / Yang, Z. / Zhong, N. / Xiong, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82341085 China
CitationJournal: Biorxiv / Year: 2026
Title: Enhanced Target Binding by Leritrelvir Restores Dimerization of Mpro Mutants and Mitigates Drug Resistance
Authors: Huang, X. / Kuzmic, P. / Zhang, S. / Ramos-Guzman, C.A. / Chen, X. / Gui, J. / Li, Q. / Yan, S. / Zou, B. / Niu, C. / Zhao, Y. / Lin, H. / Wang, N. / Chen, J. / Chen, X. / Spencer, J. / ...Authors: Huang, X. / Kuzmic, P. / Zhang, S. / Ramos-Guzman, C.A. / Chen, X. / Gui, J. / Li, Q. / Yan, S. / Zou, B. / Niu, C. / Zhao, Y. / Lin, H. / Wang, N. / Chen, J. / Chen, X. / Spencer, J. / Mulholland, A.J. / Chen, J. / Zhong, N. / Yang, Z. / Xiong, X.
History
DepositionFeb 11, 2026Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 3, 2026Provider: repository / Type: Initial release
Revision 1.1Jun 24, 2026Group: 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.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: 3C-like proteinase nsp5
B: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,3599
Polymers67,6152
Non-polymers1,7447
Water5,170287
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4360 Å2
ΔGint-13 kcal/mol
Surface area24390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.340, 105.787, 54.208
Angle α, β, γ (deg.)90.000, 102.922, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: GLN / End label comp-ID: GLN / Auth seq-ID: 1 - 306 / Label seq-ID: 1 - 306

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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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: 33807.617 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0DTC1, SARS coronavirus main proteinase
#2: Chemical ChemComp-7ON / Leritrelvir bound form


Mass: 641.722 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H46F3N5O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 287 / 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: 38.44 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Sodium acetate trihydrate pH 4.6, 2.0 M Sodium formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97923 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 8, 2024
RadiationMonochromator: double mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97923 Å / Relative weight: 1
ReflectionResolution: 1.95→47.27 Å / Num. obs: 35017 / % possible obs: 90.5 % / Redundancy: 6.2 % / CC1/2: 0.998 / Rmerge(I) obs: 0.093 / Net I/σ(I): 14.5
Reflection shellResolution: 1.95→2 Å / Rmerge(I) obs: 0.701 / Mean I/σ(I) obs: 2.7 / Num. unique obs: 2299 / CC1/2: 0.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0430refinement
XDSBUILT 20240630data reduction
Aimless0.7.7data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→47.16 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.929 / WRfactor Rfree: 0.211 / WRfactor Rwork: 0.161 / SU B: 4.494 / SU ML: 0.127 / Average fsc free: 0.9639 / Average fsc work: 0.9785 / Cross valid method: FREE R-VALUE / ESU R: 0.228 / ESU R Free: 0.184
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2286 1780 5.093 %
Rwork0.175 33171 -
all0.178 --
obs-34951 90.373 %
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: 31.044 Å2
Baniso -1Baniso -2Baniso -3
1--0.082 Å2-0 Å20.869 Å2
2---0.748 Å2-0 Å2
3---0.39 Å2
Refinement stepCycle: LAST / Resolution: 1.95→47.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4708 0 120 287 5115
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0124939
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164576
X-RAY DIFFRACTIONr_angle_refined_deg1.6741.7916717
X-RAY DIFFRACTIONr_angle_other_deg0.5951.72610522
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3495610
X-RAY DIFFRACTIONr_dihedral_angle_2_deg16.8836.87532
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.89710756
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg2.019102
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.16510216
X-RAY DIFFRACTIONr_chiral_restr0.0870.2767
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.025810
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021154
X-RAY DIFFRACTIONr_nbd_refined0.220.21021
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2030.24631
X-RAY DIFFRACTIONr_nbtor_refined0.1840.22500
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0890.22636
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1540.2284
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0570.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.30.233
X-RAY DIFFRACTIONr_nbd_other0.2230.298
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1350.222
X-RAY DIFFRACTIONr_mcbond_it3.2933.0912446
X-RAY DIFFRACTIONr_mcbond_other3.2913.0912446
X-RAY DIFFRACTIONr_mcangle_it4.725.5273054
X-RAY DIFFRACTIONr_mcangle_other4.7215.5293055
X-RAY DIFFRACTIONr_scbond_it4.0343.4582493
X-RAY DIFFRACTIONr_scbond_other4.0343.4582494
X-RAY DIFFRACTIONr_scangle_it6.0456.1843663
X-RAY DIFFRACTIONr_scangle_other6.0456.1843664
X-RAY DIFFRACTIONr_lrange_it8.72737.0325593
X-RAY DIFFRACTIONr_lrange_other8.73336.2295550
X-RAY DIFFRACTIONr_ncsr_local_group_10.0880.059851
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.087730.05008
12BX-RAY DIFFRACTIONLocal ncs0.087730.05008
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
1.95-2.0010.2711090.25823030.25928420.9570.95884.86980.235
2.001-2.0550.2941220.25222170.25427490.9420.96185.08550.227
2.055-2.1150.249650.20611840.20827310.9580.97745.73420.178
2.115-2.180.2441460.224500.20325960.9610.9761000.173
2.18-2.2510.227810.18916550.19125480.960.97668.13190.159
2.251-2.330.277980.19118690.19524740.9560.97879.50690.154
2.33-2.4180.2341300.19522300.19723700.9710.9899.57810.157
2.418-2.5160.2441320.19421570.19722940.9660.98299.7820.158
2.516-2.6280.2321220.1920450.19221680.970.98399.95390.155
2.628-2.7550.2941060.18119930.18721060.9550.98399.66760.148
2.755-2.9040.261020.16518970.16920090.9620.98399.50220.145
2.904-3.0790.203870.15917940.16118840.9720.98499.84080.143
3.079-3.2910.208770.16616880.16817660.9730.98299.94340.154
3.291-3.5530.22730.16915950.17116680.9680.9821000.162
3.553-3.890.221700.1614550.16315310.9710.98599.60810.158
3.89-4.3460.208820.14112960.14513880.9740.98799.27950.145
4.346-5.0110.175600.13611550.13812240.980.98999.26470.143
5.011-6.120.23520.1779880.1810420.9750.98499.80810.187
6.12-8.5820.244490.1687460.1728000.960.98399.3750.183
8.582-47.160.159170.1884540.1874810.9790.9897.9210.204

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