Molecular basis for the inhibition of β-hydroxyacyI-ACP dehydratase HadAB complex from Mycobacterium tuberculosis by flavonoid inhibitors
Molecular basis for the inhibition of β-hydroxyacyI-ACP dehydratase HadAB complex from Mycobacterium tuberculosis by flavonoid inhibitors作者机构：National Laboratory of Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China University of Chinese Academy of Sciences Beijing 100049China Structure Biology Laboratory Tsinghua University Beijing 100084 China Tianjin Key Laboratory of Protein Science College of'Life Sciences Nankai University Tianjin 300071 China
出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)
年 卷 期：2015年第6卷第7期
页 面：504-517页
核心收录：
学科分类：090603[农学-临床兽医学] 0710[理学-生物学] 071001[理学-植物学] 07[理学] 09[农学] 0906[农学-兽医学]
基 金：国家自然科学基金 国家973计划 supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences
主 题：Mycobacterium tuberculosis hotdog fold,mycolic acid dehydratase flavonoid thiacetazone isoxyl
摘 要：Dehydration is one of the key steps in the biosynthesis of mycolic acids and is vital to the growth of Mycobac- terium tuberculosis （Mtb）. Consequently, stalling dehy-dration cures tuberculosis （TB）. Clinically used anti-TB drugs like thiacetazone （TAC） and isoxyl （ISO） as well as flavonoids inhibit the enzyme activity of the β-hydroxy- acyI-ACP dehydratase HadAB complex. How this inhi- bition is exerted, has remained an enigma for years. Here, we describe the first crystal structures of the MtbHadAB complex bound with flavonoid inhibitor butein, 2＇,4,4＇-trihydroxychalcone or fisetin. Despite sharing no sequence identity from Blast, HadA and HadB adopt a very similar hotdog fold. HadA forms a tight dimer with HadB in which the proteins are sitting side-by-side, but are oriented anti-parallel. While HadB contributes the catalytically critical His-Asp dyad, HadA binds the fatty acid substrate in a long channel. The atypical double hotdog fold with a single active site formed by MtbHadAB gives rise to a long, narrow cavity that vertically traverses the fatty acid binding channel. At the base of this cavity lies Cys61, which upon muta- tion to Ser confers drug-resistance in TB patients. We show that inhibitors bind in this cavity and protrude into the substrate binding channel. Thus, inhibitors of MtbHadAB exert their effect by occluding substrate from the active site, The unveiling of this mechanism of inhibition paves the way for accelerating development of next generation of anti-TB drugs,
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