6T0L

Crystal structure of CYP124 in complex with inhibitor compound 5'

6T0L の概要

• エントリーDOI: 10.2210/pdb6t0l/pdb
• 分子名称: CYP124 in complex with inhibitor compound 5', PROTOPORPHYRIN IX CONTAINING FE, ~{N}-[[[2-methyl-4-(3-methylbutyl)phenyl]amino]methyl]hydroxylamine, ... (8 entities in total)
• 機能のキーワード: cytochrome, p450, cyp, cyp124, 124, oxidoreductase, inhibition, inhibitor, drug, antituberculosis, tuberculosis, mycobacterium tuberculosis, compound, 5'
• 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: 50329.89

構造登録者

Bukhdruker, S.,Marin, E.,Varaksa, T.,Gilep, A.,Strushkevich, N.,Borshchevskiy, V. (登録日: 2019-10-03, 公開日: 2020-10-14, 最終更新日: 2024-01-24)

主引用文献

Varaksa, T.,Bukhdruker, S.,Grabovec, I.,Marin, E.,Kavaleuski, A.,Gusach, A.,Kovalev, K.,Maslov, I.,Luginina, A.,Zabelskii, D.,Astashkin, R.,Shevtsov, M.,Smolskaya, S.,Kavaleuskaya, A.,Shabunya, P.,Baranovsky, A.,Dolgopalets, V.,Charnou, Y.,Savachka, A.,Litvinovskaya, R.,Hurski, A.,Shevchenko, E.,Rogachev, A.,Mishin, A.,Gordeliy, V.,Gabrielian, A.,Hurt, D.E.,Nikonenko, B.,Majorov, K.,Apt, A.,Rosenthal, A.,Gilep, A.,Borshchevskiy, V.,Strushkevich, N.
Metabolic Fate of Human Immunoactive Sterols in Mycobacterium tuberculosis.
J.Mol.Biol., 433:166763-166763, 2021

PubMed Abstract: Mycobacterium tuberculosis (Mtb) infection is among top ten causes of death worldwide, and the number of drug-resistant strains is increasing. The direct interception of human immune signaling molecules by Mtb remains elusive, limiting drug discovery. Oxysterols and secosteroids regulate both innate and adaptive immune responses. Here we report a functional, structural, and bioinformatics study of Mtb enzymes initiating cholesterol catabolism and demonstrated their interrelation with human immunity. We show that these enzymes metabolize human immune oxysterol messengers. Rv2266 - the most potent among them - can also metabolize vitamin D3 (VD3) derivatives. High-resolution structures show common patterns of sterols binding and reveal a site for oxidative attack during catalysis. Finally, we designed a compound that binds and inhibits three studied proteins. The compound shows activity against Mtb H37Rv residing in macrophages. Our findings contribute to molecular understanding of suppression of immunity and suggest that Mtb has its own transformation system resembling the human phase I drug-metabolizing system.

PubMed: 33359098
DOI: 10.1016/j.jmb.2020.166763

実験手法

X-RAY DIFFRACTION (1.8 Å)