9M9R
Crystal Structure of SARS-CoV-2 Main Protease (Mpro) Mutant del23 in Complex with Nirmatrelvir
Summary for 9M9R
| Entry DOI | 10.2210/pdb9m9r/pdb |
| Descriptor | 3C-like proteinase nsp5, (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 (3 entities in total) |
| Functional Keywords | complex, inhibitor, viral protein, viral protein-inhibitor complex, viral protein/inhibitor |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 1 |
| Total formula weight | 33737.45 |
| Authors | |
| Primary citation | Min, S.C.,Seo, J.J.,Jeong, J.H.,Kim, B.K.,Park, J.H.,Lee, J.R.,Lee, D.G.,Lee, G.C.,An, S.H.,Baek, Y.H.,Choi, Y.K.,Choo, H.,Park, H.Y.,Kim, G.,Jeon, B.,Shin, S.C.,Song, M.S. A SARS-CoV-2 M pro mutation conferring ensitrelvir resistance paradoxically increases nirmatrelvir susceptibility. Nat Commun, 16:10737-10737, 2025 Cited by PubMed Abstract: SARS-CoV-2 variants resistant to current antivirals remain a significant threat, particularly in high-risk patients. Although nirmatrelvir and ensitrelvir both target the viral 3CL protease (M), their distinct susceptibility profiles may allow alternative therapeutic approaches. Here, we identify a deletion mutation at glycine 23 (Δ23G) in M that conferred high-level resistance to ensitrelvir ( ~ 35-fold) while paradoxically increasing susceptibility to nirmatrelvir ( ~ 8-fold). This opposite susceptibility pattern is confirmed both in vitro and in a male hamster infection model. Recombinant viruses carrying M-Δ23G exhibit impaired replication, pathogenicity, and transmissibility compared to wild-type, though the co-occurring mutation T45I partially restore viral fitness. Structural analyses reveal critical conformational changes in the catalytic loop (Ile136-Val148) and β-hairpin loop (Cys22-Thr26), directly influencing inhibitor binding selectivity. These results highlight differential resistance profiles of M inhibitors, supporting potential sequential or alternative use of nirmatrelvir and ensitrelvir in patients requiring prolonged antiviral treatment. PubMed: 41274896DOI: 10.1038/s41467-025-65767-z PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.11 Å) |
Structure validation
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