7ZSU

Crystal structure of CYP125 from Mycobacterium tuberculosis in complex with an inhibitor

7ZSU の概要

• エントリーDOI: 10.2210/pdb7zsu/pdb
• 関連するPDBエントリー: 7QKE 7QWN 7R1I 7R3U 7YXF
• 分子名称: Steroid C26-monooxygenase, methyl 3-pyridin-4-ylbenzoate, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total)
• 機能のキーワード: cyp, p450, cholesterol, monooxygenase, tuberculosis, inhibitor, mycobacterium, cytochrome, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis H37Rv
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 142980.73

構造登録者

Snee, M.,Katariya, M.,Levy, C.,Leys, D. (登録日: 2022-05-09, 公開日: 2023-04-05, 最終更新日: 2024-02-07)

主引用文献

Katariya, M.M.,Snee, M.,Tunnicliffe, R.B.,Kavanagh, M.E.,Boshoff, H.I.M.,Amadi, C.N.,Levy, C.W.,Munro, A.W.,Abell, C.,Leys, D.,Coyne, A.G.,McLean, K.J.
Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis.
Chemistry, 29:e202203868-e202203868, 2023

PubMed Abstract: Mycobacterium tuberculosis (Mtb) was responsible for approximately 1.6 million deaths in 2021. With the emergence of extensive drug resistance, novel therapeutic agents are urgently needed, and continued drug discovery efforts required. Host-derived lipids such as cholesterol not only support Mtb growth, but are also suspected to function in immunomodulation, with links to persistence and immune evasion. Mtb cytochrome P450 (CYP) enzymes facilitate key steps in lipid catabolism and thus present potential targets for inhibition. Here we present a series of compounds based on an ethyl 5-(pyridin-4-yl)-1H-indole-2-carboxylate pharmacophore which bind strongly to both Mtb cholesterol oxidases CYP125 and CYP142. Using a structure-guided approach, combined with biophysical characterization, compounds with micromolar range in-cell activity against clinically relevant drug-resistant isolates were obtained. These will incite further development of much-needed additional treatment options and provide routes to probe the role of CYP125 and CYP142 in Mtb pathogenesis.

PubMed: 36912255
DOI: 10.1002/chem.202203868

実験手法

X-RAY DIFFRACTION (2.2 Å)