Ligand-induced fit in mycobacterial MabA: The sequence-specific C-terminus locks the conformational change
Ligand-induced fit in mycobacterial MabA: The sequence-specific C-terminus locks the conformational change
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DOI：
10.1002/prot.20494
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发表时间：
2005-08-15
影响因子：
2.9
通讯作者：
Labesse, G
中科院分区：
文献类型：
--
作者：
Cohen-Gonsaud, M;Ducasse-Cabanot, S;Labesse, G
结核分枝杆菌的蛋白质MabA是β-酮酰基还原酶（KAR），催化脂肪酸延伸系统FAS-II的四个步骤之一。不同的KAR的晶体结构揭示了一个显着的重排的活性位点之间的“封闭”的非活性构象和“开放”和活性形式的辅因子的存在。MabA是一个潜在的治疗靶点。然而，仅获得了69个封闭形式的结构，并且合理的药物设计需要活性形式的结构。在此，我们描述了稳定MabA“开放形式”的KAR的序列和结构分析。突变的MabA蛋白的晶体结构然后以无活性和活性形式被解析。在NADP存在下的野生型MabA的晶体结构也被解决，并显示出两种相互排斥的构象的混合物。鉴于其独特的酶和结构特性以及相关酶的特性，对MabA的这种新结构进行了分析。
The protein MabA of Mycobacterium tuberculosis is a beta-ketoacyl reductase (KAR) and catalyses one of the four steps of the fatty acid elongation system FAS-II. The crystal structures of different KARs revealed a significant rearrangements of the active site between a "closed" inactive conformation and an "open" and active form in presence of the cofactor. MabA is a potential therapeutic target. However, only the structure of the 69 closed" form was obtained and rational drug design requires the structure of the active form. Here we described the sequences and structures analysis of the KARs to stabilize the "open form" in MabA. The crystal structure of a mutated MabA protein was then solved in both inactive and active form. The crystal structure of the wild-type MabA in the presence of NADP was also solved and showing a mixture of the two mutually exclusive conformations. This new structure of MabA is analyzed in view of its distinctive enzymatic and structural properties and those of related enzymes.