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.

中文翻译：

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通过基于结构的设计将Bim-BH3从Bak的活化剂转化为抑制剂

某些仅BH3的蛋白质会瞬时结合并激活Bak和Bax，从而启动它们的寡聚和线粒体外膜的透化作用，这是线粒体凋亡的关键步骤。在这里，我们描述了与Bak结合的激活剂BH3肽的第一个晶体结构，并说明了它们在设计中能够抑制线粒体上人Bak的BH3衍生物的用途。这些BH3衍生物竞争规范凹槽中的激活位点，是第一个工程化的Bak激活抑制剂，并支持与Bak激活相关的关键构象转变的作用。