BCL-2家族的成员是调节细胞凋亡信号通路的重要因子，其中包括能够促进凋亡的Bax、BH3-only和能够抑制凋亡的BCL-2三个蛋白亚家族。BAX在正常状态下以单体形式存在，细胞凋亡时转化为有活性的大分子量复合体。促凋亡蛋白的BH3结构域能够与抗凋亡蛋白BH结构域的疏水沟结合，形成二聚体，BCL-2家族成员之间的二聚体反应是调节细胞凋亡或存活的关键。抗凋亡蛋白往往通过隔离凋亡前蛋白，如BAX的BH3结构域来使细胞对凋亡信号不敏感，从而得以存活。
在肿瘤细胞内，抗凋亡的BH3疏水结合沟能够起到让凋亡的细胞重新存活的作用。本文中，研究者鉴定出了一个能够直接调节BAX活性的BH3结合沟。这也就意味着，可以通过使BAX基因处于活化状态，从而特异性的诱导肿瘤细胞的凋亡。研究者通过计算设计出了一个能够选择性直接激活BAX的分子，并诱导BAX途径依赖的细胞凋亡。通过磁共振分析和生化手段分析，这个小分子确实能够激活BAX并促进BAX的寡聚化。并且该小分子不与抗凋亡蛋白的BH3结合域以及其它促凋亡蛋白反应。研究者称：这是第一个能够调节BCL-2家族成员的功能性小分子，这一研究为药物诱导的凋亡途径提供了新的例证。（生物谷 Bioon.com ）
doi:10.1038/nchembio.995
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Direct and selective small-molecule activation of proapoptotic BAX
Evripidis Gavathiotis, Denis E Reyna, Joseph A Bellairs, Elizaveta S Leshchiner & Loren D Walensky
BCL-2 family proteins are key regulators of the apoptotic pathway. Antiapoptotic members sequester the BCL-2 homology 3 (BH3) death domains of proapoptotic members such as BAX to maintain cell survival. The antiapoptotic BH3-binding groove has been successfully targeted to reactivate apoptosis in cancer. We recently identified a geographically distinct BH3-binding groove that mediates direct BAX activation, suggesting a new strategy for inducing apoptosis by flipping BAX's 'on switch'. Here we applied computational screening to identify a BAX activator molecule that directly and selectively activates BAX. We demonstrate by NMR and biochemical analyses that the molecule engages the BAX trigger site and promotes the functional oligomerization of BAX. The molecule does not interact with the BH3-binding pocket of antiapoptotic proteins or proapoptotic BAK and induces cell death in a BAX-dependent fashion. To our knowledge, we report the first gain-of-function molecular modulator of a BCL-2 family protein and demonstrate a new paradigm for pharmacologic induction of apoptosis.
