本月出版的《自然—化學(xué)生物學(xué)》Nature Chemical Biology報(bào)道了一種通過新機(jī)制激活細(xì)胞凋亡通路的化合物,。
由BcL-2蛋白家族所構(gòu)成的復(fù)雜蛋白間互作網(wǎng)絡(luò)既能抑制也能促使細(xì)胞凋亡的發(fā)生——這取決于其中各種不同蛋白的激活狀態(tài)。在癌細(xì)胞群中，各種蛋白構(gòu)成的激活平衡被打破,，從而促使癌細(xì)胞存活。因而針對(duì)該蛋白家族的一些抗癌研究很大程度上著眼于抑制其中那些會(huì)促進(jìn)細(xì)胞存活的蛋白活動(dòng)。研究發(fā)現(xiàn)，其中一種被稱為Bax的蛋白就足夠具有激活細(xì)胞凋亡通路的能力,。
Loren Walensky等人發(fā)現(xiàn)，一種名為BAM7的小分子可以通過觸發(fā)Bax蛋白中的構(gòu)象變化,，有選擇地激活細(xì)胞,，促使細(xì)胞凋亡。因?yàn)檎＜?xì)胞和癌細(xì)胞都能表達(dá)Bax,，所以該發(fā)現(xiàn)能否有效應(yīng)用于抗癌治療,，還需要進(jìn)一步的研究，但BAM7的發(fā)現(xiàn)以及其作為Bax的選擇性激活物這一特點(diǎn),，意味著一種殺死癌細(xì)胞的新方法的誕生,。
（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.
