5SYJ

Crystal structure of the D141A variant of B. pseudomallei KatGin complex with isoniazid

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5SYJ の概要

• エントリーDOI: 10.2210/pdb5syj/pdb
• 分子名称: Catalase-peroxidase, PROTOPORPHYRIN IX CONTAINING FE, SODIUM ION, ... (8 entities in total)
• 機能のキーワード: katg, catalase-peroxidase, oxidoreductase, isoniazid
• 由来する生物種: Burkholderia pseudomallei (strain 1710b)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 162019.70

構造登録者

Loewen, P.C. (登録日: 2016-08-11, 公開日: 2016-09-21, 最終更新日: 2024-11-20)

主引用文献

Vidossich, P.,Loewen, P.C.,Carpena, X.,Fiorin, G.,Fita, I.,Rovira, C.
Binding of the antitubercular pro-drug isoniazid in the heme access channel of catalase-peroxidase (KatG). A combined structural and metadynamics investigation.
J Phys Chem B, 118:2924-2931, 2014

PubMed Abstract: Isonicotinic acid hydrazide (isoniazid or INH) is a front line antitubercular pro-drug that is converted to its active form, isonicotinyl-NAD, by the bacterial catalase-peroxidase KatG. Understanding the role of KatG in the INH activation process has been hampered by a lack of knowledge of the actual drug binding site. In this work, we have investigated the binding of INH in the main access channel of KatG with a combination of molecular dynamics, using an enhanced-sampling technique (metadynamics), X-ray crystallography, and site-directed mutagenesis. The metadynamics simulations show that there are several weak drug binding sites along the access channel. Moreover, the simulations evidence that complete entrance to the heme active site is impeded by an aspartate residue (D141) located above the heme. This has been confirmed by structural and functional analysis of the D141A mutant, leading to the first X-ray crystallography evidence of INH at the heme access channel.

PubMed: 24568093
DOI: 10.1021/jp4123425

実験手法

X-RAY DIFFRACTION (1.88 Å)