Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex
Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex
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DOI：
10.7554/elife.10222
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发表时间：
2015-12-10
期刊：
影响因子：
7.7
通讯作者：
Taunton, Jack
中科院分区：
文献类型：
--
作者：
Carelli, Jordan D.;Sethofer, Steven G.;Taunton, Jack
环肽天然产物已经进化到利用不同的蛋白质靶点，其中许多控制着基本的细胞过程。受一系列具有部分阐明结构的环肽的启发，我们设计了半胱氨酸的合成变异体，半胱氨酸是一种具有细胞毒性和抗成脂作用的天然产物，其分子作用机制未知。新的半胱氨酸变异体对癌细胞具有细胞毒性，其效力是半胱氨酸本身的500倍。利用半胱氨酸光亲和探针，我们将翻译延伸因子-1A三元复合体(eEF1A.GTP)确定为特异性靶标，并证明了与之无关的天然产物--敌草素和细胞三烯蛋白的竞争性结合。EEF1A结构域III的突变阻止了半胱氨酸的结合，并对其细胞毒作用产生了抵抗，表明邻近的疏水表面是eEF1A调控的功能热点。我们的结论是，真核延长因子-1A及其与GTP和氨基酰-tRNA的三元复合体是细胞毒天然产物进化的共同靶点。
Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A.GTP.aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products.