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- PDB-23ml: Crystal structure of SARS-CoV-2 main protease Q189K mutant in com... -

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Basic information

Entry
Database: PDB / ID: 23ml
TitleCrystal structure of SARS-CoV-2 main protease Q189K 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


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / snRNP Assembly / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / host cell endoplasmic reticulum-Golgi intermediate compartment / host cell endosome / 3'-5'-RNA exonuclease activity / symbiont-mediated degradation of host mRNA / 5'-3' DNA helicase activity / mRNA guanylyltransferase / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / mRNA guanylyltransferase activity / DNA helicase / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / symbiont-mediated suppression of host NF-kappaB cascade / 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 / methyltransferase cap1 activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / ubiquitinyl hydrolase 1 / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / lyase activity / cysteine-type deubiquitinase activity / single-stranded RNA binding / viral protein processing / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / copper ion binding / viral translational frameshifting / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / proteolysis / DNA-templated transcription / RNA binding / zinc ion binding / ATP binding
Similarity search - Function
RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus Nsp12 Interface domain profile. / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Nidovirus 2-O-methyltransferase / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerization / Nonstructural protein 15, middle domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / : / Lipocalin signature. / DNA2/NAM7 helicase-like, C-terminal / AAA domain / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain 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.
Similarity search - Domain/homology
Chem-7ON / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.16 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)68,9374
Polymers67,6532
Non-polymers1,2832
Water4,035224
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3130 Å2
ΔGint-15 kcal/mol
Surface area24770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.613, 105.889, 54.291
Angle α, β, γ (deg.)90.000, 103.243, 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: Global NCS restraints 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: 33826.598 Da / Num. of mol.: 2 / Mutation: Q189K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: rep, 1a-1b / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-7ON / Leritrelvir bound form


Mass: 641.722 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C31H46F3N5O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 224 / 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: 2.06 Å3/Da / Density % sol: 40.35 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop
Details: 1.0 M Ammonium sulfate, 0.1 M HEPES pH 7.0, 0.5% w/v Polyethylene glycol 8,000

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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: 2.16→52.945 Å / Num. obs: 26951 / % possible obs: 93.8 % / Redundancy: 6.2 % / CC1/2: 0.994 / Rmerge(I) obs: 0.156 / Net I/σ(I): 12
Reflection shellResolution: 2.16→2.23 Å / Rmerge(I) obs: 1.737 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2489 / CC1/2: 0.764

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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: 2.16→52.945 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.9 / SU B: 7.797 / SU ML: 0.194 / Cross valid method: FREE R-VALUE / ESU R: 0.421 / ESU R Free: 0.254
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2533 1310 4.905 %
Rwork0.1918 25400 -
all0.195 --
obs-26710 93.024 %
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: 28.751 Å2
Baniso -1Baniso -2Baniso -3
1--0.445 Å2-0 Å21.001 Å2
2---0.338 Å2-0 Å2
3---0.281 Å2
Refinement stepCycle: LAST / Resolution: 2.16→52.945 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4713 0 90 224 5027
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0124919
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164546
X-RAY DIFFRACTIONr_angle_refined_deg1.7081.7976695
X-RAY DIFFRACTIONr_angle_other_deg0.591.7310461
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3965610
X-RAY DIFFRACTIONr_dihedral_angle_2_deg20.4246.87532
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.31310763
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg3.203102
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.41610216
X-RAY DIFFRACTIONr_chiral_restr0.0790.2760
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.025806
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021150
X-RAY DIFFRACTIONr_nbd_refined0.2130.2952
X-RAY DIFFRACTIONr_symmetry_nbd_other0.20.24406
X-RAY DIFFRACTIONr_nbtor_refined0.1840.22457
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0880.22509
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1540.2233
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0230.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2230.229
X-RAY DIFFRACTIONr_nbd_other0.2030.288
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2060.211
X-RAY DIFFRACTIONr_mcbond_it2.7572.8762446
X-RAY DIFFRACTIONr_mcbond_other2.7542.8762446
X-RAY DIFFRACTIONr_mcangle_it4.1695.1553054
X-RAY DIFFRACTIONr_mcangle_other4.1685.1573055
X-RAY DIFFRACTIONr_scbond_it3.393.1542473
X-RAY DIFFRACTIONr_scbond_other3.393.1542474
X-RAY DIFFRACTIONr_scangle_it5.1385.6613641
X-RAY DIFFRACTIONr_scangle_other5.1385.6613642
X-RAY DIFFRACTIONr_lrange_it7.86235.23120802
X-RAY DIFFRACTIONr_lrange_other7.85435.12120721
Refine LS restraints NCS

Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION / Type: tight positional; tight thermal / Rms dev Biso : 4.89825 Å2 / Rms dev position: 0.12581 Å / Weight Biso : 0.5 / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
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
2.16-2.2160.346890.27119610.27421290.9250.9596.28930.235
2.216-2.2770.359460.2998220.30220420.8940.93942.50730.259
2.277-2.3430.304930.24118930.24420060.940.96299.0030.2
2.343-2.4140.275830.23617840.23719390.9470.96496.28670.187
2.414-2.4930.291880.22917860.23218820.9470.96699.57490.184
2.493-2.5810.298820.2117690.21318580.950.97299.62330.164
2.581-2.6780.286640.21313960.21617440.9550.97183.71560.17
2.678-2.7870.281830.214520.20416950.9570.97490.56050.16
2.787-2.9110.338790.19315510.216330.9350.97699.81630.159
2.911-3.0520.219940.19114660.19315650.9710.97799.68050.161
3.052-3.2170.291700.17714010.18314770.9510.9899.59380.151
3.217-3.4110.199740.18612900.18713930.9730.97897.91820.163
3.411-3.6450.272520.18412550.18713210.9530.97998.94020.167
3.645-3.9360.326580.19510420.20112210.9330.97590.09010.183
3.936-4.3090.202730.16910510.17111330.9760.98199.20570.17
4.309-4.8140.173590.1419750.14210370.9780.98899.71070.145
4.814-5.5510.244400.1648740.1689150.9760.98499.89070.172
5.551-6.780.262370.1967310.1997710.9580.97999.61090.201
6.78-9.5110.161230.1365770.1376040.9820.98999.33780.156
9.511-52.9450.16230.1653230.1653470.9840.98399.71180.196

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