9CMU
Room-temperature X-ray structure of SARS-CoV-2 main protease drug resistant mutant (L50F, E166V) in complex with ensitrelvir (ESV)
Summary for 9CMU
| Entry DOI | 10.2210/pdb9cmu/pdb |
| Related | 9CMJ 9CMN 9CMS |
| Descriptor | 3C-like proteinase nsp5, 6-[(6-chloranyl-2-methyl-indazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[[2,4,5-tris(fluoranyl)phenyl]methyl]-1,3,5-triazine-2,4-dione (3 entities in total) |
| Functional Keywords | cysteine protease, drug resistant mutant, homodimer, enzyme-inhibitor complex, hydrolase |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 1 |
| Total formula weight | 34361.46 |
| Authors | Kovalevsky, A.,Coates, L.,Gerlits, O. (deposition date: 2024-07-15, release date: 2024-10-16, Last modification date: 2024-11-06) |
| Primary citation | Kovalevsky, A.,Aniana, A.,Ghirlando, R.,Coates, L.,Drago, V.N.,Wear, L.,Gerlits, O.,Nashed, N.T.,Louis, J.M. Effects of SARS-CoV-2 Main Protease Mutations at Positions L50, E166, and L167 Rendering Resistance to Covalent and Noncovalent Inhibitors. J.Med.Chem., 67:18478-18490, 2024 Cited by PubMed Abstract: SARS-CoV-2 propagation under nirmatrelvir and ensitrelvir pressure selects for main protease (MPro) drug-resistant mutations E166V (DRM2), L50F/E166V (DRM3), E166A/L167F (DRM4), and L50F/E166A/L167F (DRM5). DRM2-DRM5 undergoes N-terminal autoprocessing to produce mature MPro with dimer dissociation constants () 2-3 times larger than that of the wildtype. Co-selection of L50F restores catalytic activity of DRM2 and DRM4 from ∼10 to 30%, relative to that of the wild-type enzyme, without altering . Binding affinities and thermodynamic profiles that parallel the drug selection pressure, exhibiting significant decreases in affinity through entropy/enthalpy compensation, were compared with GC373. Reorganization of the active sites due to mutations observed in the inhibitor-free DRM3 and DRM4 structures as compared to MPro may account for the reduced binding affinities, although DRM2 and DRM3 complexes with ensitrelvir are almost identical to MPro-ensitrelvir. Chemical reactivity changes of the mutant active sites due to differences in electrostatic and protein dynamics effects likely contribute to losses in binding affinities. PubMed: 39370853DOI: 10.1021/acs.jmedchem.4c01781 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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