2VKU

4,4'-Dihydroxybenzophenone Mimics Sterol Substrate in the Binding Site of Sterol 14alpha-Demethylase (CYP51) in the X-ray Structure of the Complex

2VKU の概要

• エントリーDOI: 10.2210/pdb2vku/pdb
• 関連するPDBエントリー: 1E9X 1EA1 1H5Z 1U13 1X8V 2BZ9 2CI0 2CIB
• 分子名称: CYTOCHROME P450 51, bis(4-hydroxyphenyl)methanone, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total)
• 機能のキーワード: steroid biosynthesis, cyp51-4, cytoplasm, alpha-beta, heme co-factor, lipid synthesis, sterol biosynthesis, 4'-dihydroxybenzophenone complex, nadp, iron, heme, monooxygenase, metal-binding, oxidoreductase
• 由来する生物種: MYCOBACTERIUM TUBERCULOSIS
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 53527.02

構造登録者

Eddine, A.N.,von Kries, J.P.,Podust, M.V.,Podust, L.M. (登録日: 2007-12-29, 公開日: 2008-03-25, 最終更新日: 2023-12-13)

主引用文献

Eddine, A.N.,P Von Kries, J.,Podust, M.V.,Warrier, T.,Kaufmann, S.H.E.,Podust, L.M.
X-Ray Structure of 4,4'-Dihydroxybenzophenone Mimicking Sterol Substrate in the Active Site of Sterol 14Alpha-Demethylase (Cyp51)
J.Biol.Chem., 283:15152-, 2008

PubMed Abstract: A universal step in the biosynthesis of membrane sterols and steroid hormones is the oxidative removal of the 14alpha-methyl group from sterol precursors by sterol 14alpha-demethylase (CYP51). This enzyme is a primary target in treatment of fungal infections in organisms ranging from humans to plants, and development of more potent and selective CYP51 inhibitors is an important biological objective. Our continuing interest in structural aspects of substrate and inhibitor recognition in CYP51 led us to determine (to a resolution of 1.95A) the structure of CYP51 from Mycobacterium tuberculosis (CYP51(Mt)) co-crystallized with 4,4'-dihydroxybenzophenone (DHBP), a small organic molecule previously identified among top type I binding hits in a library screened against CYP51(Mt). The newly determined CYP51(Mt)-DHBP structure is the most complete to date and is an improved template for three-dimensional modeling of CYP51 enzymes from fungal and prokaryotic pathogens. The structure demonstrates the induction of conformational fit of the flexible protein regions and the interactions of conserved Phe-89 essential for both fungal drug resistance and catalytic function, which were obscure in the previously characterized CYP51(Mt)-estriol complex. DHBP represents a benzophenone scaffold binding in the CYP51 active site via a type I mechanism, suggesting (i) a possible new class of CYP51 inhibitors targeting flexible regions, (ii) an alternative catalytic function for bacterial CYP51 enzymes, and (iii) a potential for hydroxybenzophenones, widely distributed in the environment, to interfere with sterol biosynthesis. Finally, we show the inhibition of M. tuberculosis growth by DHBP in a mouse macrophage model.

PubMed: 18367444
DOI: 10.1074/JBC.M801145200

実験手法

X-RAY DIFFRACTION (1.95 Å)