2WGY

Crystal structure of the G243A mutant of CYP130 from M. tuberculosis

2WGY の概要

• エントリーDOI: 10.2210/pdb2wgy/pdb
• 関連するPDBエントリー: 2UUQ 2UVN 2WH8 2WHF
• 分子名称: CYTOCHROME P450 130, PROTOPORPHYRIN IX CONTAINING FE, ISOPROPYL ALCOHOL, ... (5 entities in total)
• 機能のキーワード: heme, hypothetical protein, iron, metal-binding, monooxygenase, 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: 47020.81

構造登録者

Podust, L.M.,Ouellet, H.,von Kries, J.P.,Ortiz de Montellano, P.R. (登録日: 2009-04-28, 公開日: 2009-05-12, 最終更新日: 2023-12-13)

主引用文献

Podust, L.M.,Ouellet, H.,von Kries, J.P.,de Montellano, P.R.
Interaction of Mycobacterium tuberculosis CYP130 with heterocyclic arylamines.
J. Biol. Chem., 284:25211-25219, 2009

PubMed Abstract: The Mycobacterium tuberculosis P450 enzymes are of interest for their pharmacological development potential, as evidenced by their susceptibility to inhibition by antifungal azole drugs that normally target sterol 14alpha-demethylase (CYP51). Although antifungal azoles show promise, direct screening of compounds against M. tuberculosis P450 enzymes may identify novel, more potent, and selective inhibitory scaffolds. Here we report that CYP130 from M. tuberculosis has a natural propensity to bind primary arylamines with particular chemical architectures. These compounds were identified via a high throughput screen of CYP130 with a library of synthetic organic molecules. As revealed by subsequent x-ray structure analysis, selected compounds bind in the active site by Fe-coordination and hydrogen bonding of the arylamine group to the carbonyl oxygen of Gly(243). As evidenced by the binding of structural analogs, the primary arylamine group is indispensable, but synergism due to hydrophobic contacts between the rest of the molecule and protein amino acid residues is responsible for a binding affinity comparable with that of the antifungal azole drugs. The topology of the CYP130 active site favors angular coordination of the arylamine group over the orthogonal coordination of azoles. Upon substitution of Gly(243) by an alanine, the binding mode of azoles and some arylamines reverted from type II to type I because of hydrophobic and steric interactions with the alanine side chain. We suggest a role for the conserved Ala(Gly)(243)-Gly(244) motif in the I-helix in modulating both the binding affinity of the axial water ligand and the ligand selectivity of cytochrome P450 enzymes.

PubMed: 19605350
DOI: 10.1074/jbc.M109.017632

実験手法

X-RAY DIFFRACTION (1.5 Å)