Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design
Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design
复制标题
DOI：
10.1016/j.molcel.2017.11.001
复制
发表时间：
2017-11-16
期刊：
影响因子：
16
通讯作者：
Czabotar, Peter E.
中科院分区：
文献类型：
--
作者：
Brouwer, Jason M.;Lan, Ping;Czabotar, Peter E.
某些仅BH3蛋白瞬时结合并激活巴克和Bax，引发它们的寡聚化和线粒体外膜的透化，这是线粒体凋亡途径中的关键步骤。在这里，我们描述的第一个晶体结构的激活剂BH 3肽结合到巴克，并说明其使用的BH 3衍生物的设计能够抑制人巴克对线粒体。这些BH 3衍生物竞争典型沟处的活化位点，是巴克活化的第一个工程化抑制剂，并且支持与巴克活化相关的关键构象转变的作用。
Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating their oligomerization and the permeabilization of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak and illustrate their use in the design of BH3 derivatives capable of inhibiting human Bak on mitochondria. These BH3 derivatives compete for the activation site at the canonical groove, are the first engineered inhibitors of Bak activation, and support the role of key conformational transitions associated with Bak activation.