9N3M
SARS-CoV-2 Mpro L50F/E166A/L167F triple mutant bound to inhibitor
This is a non-PDB format compatible entry.
Summary for 9N3M
| Entry DOI | 10.2210/pdb9n3m/pdb |
| Descriptor | 3C-like proteinase, (1S,2S,4S)-2-{[3-cyclopropyl-N-(4-methoxy-1H-indole-2-carbonyl)-L-alanyl]amino}-1-hydroxy-4-methyl-5-(methylamino)-5-oxopentane-1-sulfonic acid (3 entities in total) |
| Functional Keywords | sars-cov-2, inhibitor, main protease, 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 | 34360.13 |
| Authors | Lu, J.,Chen, P.,Demmon, S.,Fischer, C.,Vederas, J.C.,Lemieux, M.J. (deposition date: 2025-01-31, release date: 2025-08-20, Last modification date: 2025-10-29) |
| Primary citation | Fischer, C.,Lu, J.,van Belkum, M.J.,Demmon, S.,Chen, P.,Wang, C.,Van Oers, T.J.,Lamer, T.,Lemieux, M.J.,Vederas, J.C. Structural insights into the nirmatrelvir-resistant SARS-CoV-2 M pro L50F/E166A/L167F triple mutant-inhibitor-complex reveal strategies for next generation coronaviral inhibitor design. Rsc Med Chem, 16:5032-5040, 2025 Cited by PubMed Abstract: Drug-resistance is an eminent threat in antiviral therapy, and is currently a concern in nirmatrelvir-based therapy of SARS-CoV-2. Nirmatrelvir (antiviral component in Paxlovid) binds covalently to the active site cysteine of the main protease of SARS-CoV-2 (M), thereby blocking enzyme activity and halting viral replication. passage experiments mimicking a multi-dosage nirmatrelvir treatment regime, identified M variants with mutations in the active site and near the C-terminal dimerization interface with variable levels of nirmatrelvir resistance. One such variant harbors a triple mutation in M, L50F/E166A/L167F, that displays decreased potency for nirmatrelvir (IC ∼ 850-1600 nM) and ibuzatrelvir while viral replication remained similar to that of the wildtype (WT) virus. We here confirm a previously developed short peptide aldehyde bisulfite compound 4 as potent inhibitor for SARS-CoV-2 M L50F/E166A/L167F and related variants. A co-crystal structure reveals tight inhibitor binding that is stabilized by a network of hydrogen bonds formed by the mutated residues A166 and F167. This study provides the groundwork for optimized M inhibitors against potential emerging variants of SARS-CoV-2, as well as strategies for broad-spectrum inhibitor design against variants of M. PubMed: 40823489DOI: 10.1039/d5md00356c PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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