9EET
Crystal structure of the SARS-CoV-2 nsp5 main protease (Mpro) E166V mutant in complex with inhibitor GC376
Summary for 9EET
| Entry DOI | 10.2210/pdb9eet/pdb |
| Related | 9EEI |
| Related PRD ID | PRD_002495 |
| Descriptor | 3C-like proteinase nsp5, N~2~-[(benzyloxy)carbonyl]-N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-L-leucinamide (3 entities in total) |
| Functional Keywords | viral protein, nsp5, sars-cov-2, gc376, drug resistance, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 1 |
| Total formula weight | 34201.05 |
| Authors | |
| Primary citation | Neilsen, G.,Lan, S.,Slack, R.L.,Lorson, Z.C.,Emanuelli Castaner, A.,Lee, R.,Edwards, K.G.,Zhang, H.,Lee, J.,Cantara, W.A.,Cilento, M.E.,Zhang, H.,De, R.,Amblard, F.,Tedbury, P.R.,Kirby, K.A.,Schinazi, R.F.,Sarafianos, S.G. Strategy to overcome a nirmatrelvir resistance mechanism in the SARS-CoV-2 nsp5 protease. Sci Adv, 11:eadv8875-eadv8875, 2025 Cited by PubMed Abstract: E166V in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nsp5 protease confers strong resistance to the antiviral component of Paxlovid, nirmatrelvir (NIR), in passaging and clinical samples. In SARS-CoV-2 replicons, E166V drastically decreased Washington (WA1) but not Omicron (BA.1) fitness (20- versus 2-fold), suggesting a lower barrier to resistance in the BA.1 strain and consistent with observed differences in respective nsp5 dimerization affinities. Crystal structures reveal a steric clash between the rigid, bulky NIR -butyl group and the β-branched Val, disrupting the covalent binding of NIR to the catalytic Cys and leading to high resistance in BA.1 and WA1 replicons. NIR-resistant replicons remained susceptible to GC376, which can still covalently bind Cys by avoiding a steric clash with Val through "wiggling and jiggling." Hence, strategic flexibility is a strategy that will help design second-generation antivirals against NIR-resistant viruses. PubMed: 40479048DOI: 10.1126/sciadv.adv8875 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.39 Å) |
Structure validation
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