6T0J

Crystal structure of CYP124 in complex with SQ109

6T0J の概要

• エントリーDOI: 10.2210/pdb6t0j/pdb
• 分子名称: Methyl-branched lipid omega-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, N-[(2Z)-3,7-dimethylocta-2,6-dien-1-yl]-N'-[(1R,3S,5R,7R)-tricyclo[3.3.1.1~3,7~]dec-2-yl]ethane-1,2-diamine, ... (8 entities in total)
• 機能のキーワード: cytochrome, p450, cyp, oxidoreductase, sq109, sq, 109, mmpl3, tuberculosis, mycobacterium tuberculosis, antituberculosis, drug, substrate
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 50509.20

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

Bukhdruker, S.,Varaksa, T.,Grabovec, I.,Marin, E.,Shabunya, P.,Kadukova, M.,Grudinin, S.,Kavaleuski, A.,Gusach, A.,Gilep, A.,Borshchevskiy, V.,Strushkevich, N.
Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450.
Int J Mol Sci, 21:-, 2020

PubMed Abstract: Spreading of the multidrug-resistant (MDR) strains of the one of the most harmful pathogen (Mtb) generates the need for new effective drugs. SQ109 showed activity against resistant Mtb and already advanced to Phase II/III clinical trials. Fast SQ109 degradation is attributed to the human liver Cytochrome P450s (CYPs). However, no information is available about interactions of the drug with Mtb CYPs. Here, we show that Mtb CYP124, previously assigned as a methyl-branched lipid monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25 Å-resolution crystal structure of the CYP124-SQ109 complex unambiguously shows two conformations of the drug, both positioned for hydroxylation of the ω-methyl group in the trans position. The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs.

PubMed: 33081390
DOI: 10.3390/ijms21207683

実験手法

X-RAY DIFFRACTION (1.25 Å)