3IVY

Crystal structure of Mycobacterium tuberculosis cytochrome P450 CYP125, p212121 crystal form

3IVY の概要

• エントリーDOI: 10.2210/pdb3ivy/pdb
• 関連するPDBエントリー: 3IW0 3IW1 3IW2
• 分子名称: Cytochrome P450 CYP125, PROTOPORPHYRIN IX CONTAINING FE (3 entities in total)
• 機能のキーワード: cholesterol, cytochrome p450, tuberculosis, monooxygenase, heme, iron, 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: 49107.98

構造登録者

McLean, K.J.,Levy, C.,Munro, A.W.,Leys, D. (登録日: 2009-09-02, 公開日: 2009-11-03, 最終更新日: 2023-09-06)

主引用文献

McLean, K.J.,Lafite, P.,Levy, C.,Cheesman, M.R.,Mast, N.,Pikuleva, I.A.,Leys, D.,Munro, A.W.
The Structure of Mycobacterium tuberculosis CYP125: molecular basis for cholesterol binding in a P450 needed for host infection.
J.Biol.Chem., 284:35524-35533, 2009

PubMed Abstract: We report characterization and the crystal structure of the Mycobacterium tuberculosis cytochrome P450 CYP125, a P450 implicated in metabolism of host cholesterol and essential for establishing infection in mice. CYP125 is purified in a high spin form and undergoes both type I and II spectral shifts with various azole drugs. The 1.4-A structure of ligand-free CYP125 reveals a "letterbox" active site cavity of dimensions appropriate for entry of a polycyclic sterol. A mixture of hexa-coordinate and penta-coordinate states could be discerned, with water binding as the 6th heme-ligand linked to conformation of the I-helix Val(267) residue. Structures in complex with androstenedione and the antitubercular drug econazole reveal that binding of hydrophobic ligands occurs within the active site cavity. Due to the funnel shape of the active site near the heme, neither approaches the heme iron. A model of the cholesterol CYP125 complex shows that the alkyl side chain extends toward the heme iron, predicting hydroxylation of cholesterol C27. The alkyl chain is in close contact to Val(267), suggesting a substrate binding-induced low- to high-spin transition coupled to reorientation of the latter residue. Reconstitution of CYP125 activity with a redox partner system revealed exclusively cholesterol 27-hydroxylation, consistent with structure and modeling. This activity may enable catabolism of host cholesterol or generation of immunomodulatory compounds that enable persistence in the host. This study reveals structural and catalytic properties of a potential M. tuberculosis drug target enzyme, and the likely mode by which the host-derived substrate is bound and hydroxylated.

PubMed: 19846552
DOI: 10.1074/jbc.M109.032706

実験手法

X-RAY DIFFRACTION (1.352 Å)