7ZB9

Crystal structure of CYP124 in complex with inhibitor carbethoxyhexyl imidazole in the absence of glycerol (NoCryo)

7ZB9 の概要

• エントリーDOI: 10.2210/pdb7zb9/pdb
• 分子名称: CYP124 in complex with inhibitor carbethoxyhexyl imidazole, PROTOPORPHYRIN IX CONTAINING FE, ethyl 7-imidazol-1-ylheptanoate, ... (7 entities in total)
• 機能のキーワード: carbethoxyhexyl imidazole, cyp124, mtb, tuberculosis, inhibitor, glycerol, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis H37Rv
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 50099.58

構造登録者

Bukhdruker, S.,Varaksa, T.,Marin, E.,Gilep, A.,Strushkevich, N.,Borshchevskiy, V. (登録日: 2022-03-23, 公開日: 2023-01-11, 最終更新日: 2024-03-27)

主引用文献

Bukhdruker, S.,Varaksa, T.,Orekhov, P.,Grabovec, I.,Marin, E.,Kapranov, I.,Kovalev, K.,Astashkin, R.,Kaluzhskiy, L.,Ivanov, A.,Mishin, A.,Rogachev, A.,Gordeliy, V.,Gilep, A.,Strushkevich, N.,Borshchevskiy, V.
Structural insights into the effects of glycerol on ligand binding to cytochrome P450.
Acta Crystallogr D Struct Biol, 79:66-77, 2023

PubMed Abstract: New antitubercular drugs are vital due to the spread of resistant strains. Carbethoxyhexyl imidazole (CHImi) inhibits cytochrome P450 CYP124, which is a steroid-metabolizing enzyme that is important for the survival of Mycobacterium tuberculosis in macrophages. The available crystal structure of the CYP124-CHImi complex reveals two glycerol molecules in the active site. A 1.15 Å resolution crystal structure of the glycerol-free CYP124-CHimi complex reported here shows multiple conformations of CHImi and the CYP124 active site which were previously restricted by glycerol. Complementary molecular dynamics simulations show coherence of the ligand and enzyme conformations. Spectrophotometric titration confirmed the influence of glycerol on CHImi binding: the affinity decreases more than tenfold in glycerol-containing buffer. In addition, it also showed that glycerol has a similar effect on other azole and triazole CYP124 ligands. Together, these data show that glycerol may compromise structural-functional studies and impede rational drug-design campaigns.

PubMed: 36601808
DOI: 10.1107/S2059798322011019

実験手法

X-RAY DIFFRACTION (1.15 Å)