BCL-2家族的成員是調(diào)節(jié)細(xì)胞凋亡信號(hào)通路的重要因子,，其中包括能夠促進(jìn)凋亡的Bax,、BH3-only和能夠抑制凋亡的BCL-2三個(gè)蛋白亞家族,。BAX在正常狀態(tài)下以單體形式存在,，細(xì)胞凋亡時(shí)轉(zhuǎn)化為有活性的大分子量復(fù)合體,。促凋亡蛋白的BH3結(jié)構(gòu)域能夠與抗凋亡蛋白BH結(jié)構(gòu)域的疏水溝結(jié)合，形成二聚體,，BCL-2家族成員之間的二聚體反應(yīng)是調(diào)節(jié)細(xì)胞凋亡或存活的關(guān)鍵,。抗凋亡蛋白往往通過隔離凋亡前蛋白,，如BAX的BH3結(jié)構(gòu)域來使細(xì)胞對(duì)凋亡信號(hào)不敏感,，從而得以存活。
在腫瘤細(xì)胞內(nèi),，抗凋亡的BH3疏水結(jié)合溝能夠起到讓凋亡的細(xì)胞重新存活的作用,。本文中，研究者鑒定出了一個(gè)能夠直接調(diào)節(jié)BAX活性的BH3結(jié)合溝,。這也就意味著,，可以通過使BAX基因處于活化狀態(tài)，從而特異性的誘導(dǎo)腫瘤細(xì)胞的凋亡,。研究者通過計(jì)算設(shè)計(jì)出了一個(gè)能夠選擇性直接激活BAX的分子,，并誘導(dǎo)BAX途徑依賴的細(xì)胞凋亡。通過磁共振分析和生化手段分析,，這個(gè)小分子確實(shí)能夠激活BAX并促進(jìn)BAX的寡聚化,。并且該小分子不與抗凋亡蛋白的BH3結(jié)合域以及其它促凋亡蛋白反應(yīng)。研究者稱：這是第一個(gè)能夠調(diào)節(jié)BCL-2家族成員的功能性小分子,，這一研究為藥物誘導(dǎo)的凋亡途徑提供了新的例證。（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.
