Allosteric inhibition of antiapoptotic MCL-1.
Allosteric inhibition of antiapoptotic MCL-1.
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DOI：
10.1038/nsmb.3223
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发表时间：
2016-06
影响因子：
16.8
通讯作者：
Walensky LD
中科院分区：
文献类型：
--
作者：
Lee S;Wales TE;Escudero S;Cohen DT;Luccarelli J;Gallagher CG;Cohen NA;Huhn AJ;Bird GH;Engen JR;Walensky LD
MCL-1是一种抗凋亡BCL-2家族蛋白，已成为人类癌症的主要致病因子。与BCL-2一样，MCL-1具有表面凹槽，其功能是隔离促凋亡BCL-2家族成员的BH 3杀伤结构域，这是癌细胞利用的一种机制来建立强大的细胞凋亡阻断。尽管已经实现了BCL-2的BH 3结合沟的药物化，但将这种方法转化为MCL-1一直具有挑战性。在这里，我们报告了一种替代机制MCL-1抑制小分子共价修饰C286在一个新的相互作用位点远离BH 3结合沟。我们的结构-功能分析表明，BH 3-结合能力的MCL-1和其抑制BAX受损的分子参与，C286 W诱变模拟在体外和细胞中重演的现象。因此，我们表征了用于破坏MCL-1的抗细胞凋亡、BH 3结合活性的变构机制，为解除MCL-1在癌症中的武装提供了新的策略。
MCL-1 is an anti-apoptotic BCL-2 family protein that has emerged as a major pathogenic factor in human cancer. Like BCL-2, MCL-1 bears a surface groove whose function is to sequester the BH3 killer domains of pro-apoptotic BCL-2 family members, a mechanism harnessed by cancer cells to establish formidable apoptotic blockades. Whereas drugging the BH3-binding groove has been achieved for BCL-2, translating this approach to MCL-1 has been challenging. Here, we report an alternative mechanism for MCL-1 inhibition by small molecule covalent modification of C286 at a novel interaction site distant from the BH3-binding groove. Our structure-function analyses revealed that the BH3-binding capacity of MCL-1 and its suppression of BAX are impaired by molecular engagement, a phenomenon recapitulated by C286W mutagenic mimicry in vitro and in cells. Thus, we characterize an allosteric mechanism for disrupting the anti-apoptotic, BH3-binding activity of MCL-1, informing a new strategy for disarming MCL-1 in cancer.