9XYX
Crystal Structure of SARS-CoV-2 Main Protease (Mpro) T169S Mutant
Summary for 9XYX
| Entry DOI | 10.2210/pdb9xyx/pdb |
| Descriptor | 3C-like proteinase nsp5 (2 entities in total) |
| Functional Keywords | protease, sars-cov-2, mpro, covid-19, viral protein, hydrolase |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 1 |
| Total formula weight | 33811.52 |
| Authors | Kohaal, N.,Wang, J.,Chen, Y. (deposition date: 2025-08-26, release date: 2026-01-21, Last modification date: 2026-02-11) |
| Primary citation | Cai, Z.,Kohaal, N.,Georgiou, K.,Liang, X.,Chi, X.,Tan, H.,Tan, B.,Li, K.,Fan, G.,Lambrinidis, G.,Kolocouris, A.,Deng, X.,Chen, Y.,Wang, J. Structure-Based Design of Covalent SARS-CoV‐2 Main Protease Inhibitors Targeting the Nirmatrelvir-Resistant E166 Mutants. Jacs Au, 6:233-244, 2026 Cited by PubMed Abstract: The COVID-19 pandemic spurred the rapid development of nirmatrelvir, a main protease (M) inhibitor now widely prescribed as part of Paxlovid (nirmatrelvir plus ritonavir). However, increasing use has raised concerns about drug resistance. Resistance selection studies have identified multiple M mutations, with E166V emerging as a particularly resistant variant. Sequencing data from COVID-19 patients confirms E166V as a clinically relevant mutation, and importantly, this substitution also confers cross-resistance to several next-generation M inhibitors under development. In response, this study reports the rational design of inhibitors active against nirmatrelvir-resistant E166V/A mutants. The lead candidate, , shows potent inhibition of both wild-type M and the E166V/A mutants. Structural studies and molecular dynamics simulations reveal that forms stable complexes with wild-type and mutant proteases, consistent with its potent enzymatic and antiviral activity. Together, these findings position as a promising next-generation M inhibitor capable of overcoming clinically relevant nirmatrelvir resistance. PubMed: 41614164DOI: 10.1021/jacsau.5c01178 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.67 Å) |
Structure validation
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