Structures of ClpP in complex with acyldepsipeptide antibiotics reveal its activation mechanism
Structures of ClpP in complex with acyldepsipeptide antibiotics reveal its activation mechanism
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DOI：
10.1038/nsmb.1787
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发表时间：
2010-04-01
影响因子：
16.8
通讯作者：
Song, Hyun Kyu
中科院分区：
文献类型：
--
作者：
Lee, Byung-Gil;Park, Eun Young;Song, Hyun Kyu
Clp家族蛋白是研究ATP依赖性蛋白酶机制的原型，因为ClpP核心的蛋白水解活性受到激活Clp-ATP酶的严格调节。尽管如此，蛋白水解激活机制仍然难以捉摸，因为缺乏一个复杂的结构。酰基缩酚肽（ADEP）是最近发现的一类抗生素，其激活和失调ClpP。在这里，我们阐明了结构变化的ClpP激活过程中的ADEP。我们提出了枯草芽孢杆菌ClpP单独和与ADEP 1和ADEP 2复合的结构。结构显示ClpP N-末端片段在活化时的闭-开-门转变以及限制于ClpP上部的构象变化。构象运动的方向和稳定封闭结构的疏水性聚集与其他ATP依赖性蛋白酶的方向明显不同，为ClpP的激活提供了前所未有的见解。
Clp-family proteins are prototypes for studying the mechanism of ATP-dependent proteases because the proteolytic activity of the ClpP core is tightly regulated by activating Clp-ATPases. Nonetheless, the proteolytic activation mechanism has remained elusive because of the lack of a complex structure. Acyldepsipeptides (ADEPs), a recently discovered class of antibiotics, activate and disregulate ClpP. Here we have elucidated the structural changes underlying the ClpP activation process by ADEPs. We present the structures of Bacillus subtilis ClpP alone and in complex with ADEP1 and ADEP2. The structures show the closed-to-open-gate transition of the ClpP N-terminal segments upon activation as well as conformational changes restricted to the upper portion of ClpP. The direction of the conformational movement and the hydrophobic clustering that stabilizes the closed structure are markedly different from those of other ATP-dependent proteases, providing unprecedented insights into the activation of ClpP.