6T0F

Crystal structure of CYP124 in complex with cholest-4-en-3-one

Summary for 6T0F

• Entry DOI: 10.2210/pdb6t0f/pdb
• Descriptor: Methyl-branched lipid omega-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, (8ALPHA,9BETA)-CHOLEST-4-EN-3-ONE, ... (7 entities in total)
• Functional Keywords: cytochrome, p450, cyp, oxidoreductase, cyp124, 124, cholestenone, cholest-4-en-3-one, tuberculosis, mycobacterium tuberculosis
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 4
• Total formula weight: 202323.55

Authors

Bukhdruker, S.,Marin, E.,Varaksa, T.,Gilep, A.,Strushkevich, N.,Borshchevskiy, V. (deposition date: 2019-10-03, release date: 2020-10-14, Last modification date: 2024-01-24)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.65 Å)