9CMN

Room-temperature X-ray structure of SARS-CoV-2 main protease drug resistant mutant (E166A, L167F)

9CMN の概要

• エントリーDOI: 10.2210/pdb9cmn/pdb
• 関連するPDBエントリー: 9CMJ
• 分子名称: 3C-like proteinase nsp5 (2 entities in total)
• 機能のキーワード: cysteine protease, drug resistant mutant, homodimer, hydrolase
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33801.53

構造登録者

Kovalevsky, A.,Coates, L.,Gerlits, O. (登録日: 2024-07-15, 公開日: 2024-10-16, 最終更新日: 2024-11-06)

主引用文献

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

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: 39370853
DOI: 10.1021/acs.jmedchem.4c01781

実験手法

X-RAY DIFFRACTION (2 Å)