2WM5

X-ray structure of the substrate-free Mycobacterium tuberculosis cytochrome P450 CYP124

2WM5 の概要

• エントリーDOI: 10.2210/pdb2wm5/pdb
• 関連するPDBエントリー: 2WM4
• 分子名称: PUTATIVE CYTOCHROME P450 124, PROTOPORPHYRIN IX CONTAINING FE (3 entities in total)
• 機能のキーワード: metal-binding, oxidoreductase, omega-hydroxylation, p450, iron, heme, fatty acid, monooxygenase
• 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: 49455.42

構造登録者

Johnston, J.B.,Kells, P.M.,Podust, L.M.,Ortiz de Montellano, P.R. (登録日: 2009-06-30, 公開日: 2009-10-06, 最終更新日: 2024-05-01)

主引用文献

Johnston, J.B.,Kells, P.M.,Podust, L.M.,Ortiz de Montellano, P.R.
Biochemical and structural characterization of CYP124: a methyl-branched lipid omega-hydroxylase from Mycobacterium tuberculosis.
Proc. Natl. Acad. Sci. U.S.A., 106:20687-20692, 2009

PubMed Abstract: Mycobacterium tuberculosis (Mtb) produces a variety of methyl-branched lipids that serve important functions, including modulating the immune response during pathogenesis and contributing to a robust cell wall that is impermeable to many chemical agents. Here, we report characterization of Mtb CYP124 (Rv2266) that includes demonstration of preferential oxidation of methyl-branched lipids. Spectrophotometric titrations and analysis of reaction products indicate that CYP124 tightly binds and hydroxylates these substrates at the chemically disfavored omega-position. We also report X-ray crystal structures of the ligand-free and phytanic acid-bound protein at a resolution of 1.5 A and 2.1 A, respectively, which provide structural insights into a cytochrome P450 with predominant omega-hydroxylase activity. The structures of ligand-free and substrate-bound CYP124 reveal several differences induced by substrate binding, including reorganization of the I helix and closure of the active site by elements of the F, G, and D helices that bind the substrate and exclude solvent from the hydrophobic active site cavity. The observed regiospecific catalytic activity suggests roles of CYP124 in the physiological oxidation of relevant Mtb methyl-branched lipids. The enzymatic specificity and structures reported here provide a scaffold for the design and testing of specific inhibitors of CYP124.

PubMed: 19933331
DOI: 10.1073/pnas.0907398106

実験手法

X-RAY DIFFRACTION (1.5 Å)