3OF2

Crystal structure of InhA_T266D:NADH complex

3OF2 の概要

• エントリーDOI: 10.2210/pdb3of2/pdb
• 関連するPDBエントリー: 3OEW 3OEY
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (4 entities in total)
• 機能のキーワード: enoyl-reductase, 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: 29350.36

構造登録者

Molle, V.,Gulten, G.,Vilcheze, C.,Veyron-Churlet, R.,Zanella-Cleon, I.,Sacchettini, J.C.,Jacobs Jr, W.R.,Kremer, L. (登録日: 2010-08-13, 公開日: 2010-12-01, 最終更新日: 2024-02-21)

主引用文献

Molle, V.,Gulten, G.,Vilcheze, C.,Veyron-Churlet, R.,Zanella-Cleon, I.,Sacchettini, J.C.,Jacobs Jr, W.R.,Kremer, L.
Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis.
Mol.Microbiol., 78:1591-1605, 2010

PubMed Abstract: The remarkable survival ability of Mycobacterium tuberculosis in infected hosts is related to the presence of cell wall-associated mycolic acids. Despite their importance, the mechanisms that modulate expression of these lipids in response to environmental changes are unknown. Here we demonstrate that the enoyl-ACP reductase activity of InhA, an essential enzyme of the mycolic acid biosynthetic pathway and the primary target of the anti-tubercular drug isoniazid, is controlled via phosphorylation. Thr-266 is the unique kinase phosphoacceptor, both in vitro and in vivo. The physiological relevance of Thr-266 phosphorylation was demonstrated using inhA phosphoablative (T266A) or phosphomimetic (T266D/E) mutants. Enoyl reductase activity was severely impaired in the mimetic mutants in vitro, as a consequence of a reduced binding affinity to NADH. Importantly, introduction of inhA_T266D/E failed to complement growth and mycolic acid defects of an inhA-thermosensitive Mycobacterium smegmatis strain, in a similar manner to what is observed following isoniazid treatment. This study suggests that phosphorylation of InhA may represent an unusual mechanism that allows M. tuberculosis to regulate its mycolic acid content, thus offering a new approach to future anti-tuberculosis drug development.

PubMed: 21143326
DOI: 10.1111/j.1365-2958.2010.07446.x

実験手法

X-RAY DIFFRACTION (2 Å)