Deactivation of Mcl-1 by Dual-Function Small-Molecule Inhibitors Targeting the Bcl-2 Homology 3 Domain and Facilitating Mcl-1 Ubiquitination
Deactivation of Mcl-1 by Dual-Function Small-Molecule Inhibitors Targeting the Bcl-2 Homology 3 Domain and Facilitating Mcl-1 Ubiquitination
复制标题
通过靶向 Bcl-2 同源 3 结构域的双功能小分子抑制剂使 Mcl-1 失活并促进 Mcl-1 泛素化
DOI：
10.1002/anie.201606543
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Zhang Zhichao
中科院分区：
文献类型：
--
作者：
Song Ting;Wang Ziqian;Ji Fangling;Feng Yingang;Fan Yudan;Chai Gaobo;Li Xiangqian;Li Zhiqiang;Zhang Zhichao
通过有限的蛋白水解分析，三维NMR，X射线晶体学和丙氨酸突变，Mcl-1的Bcl-2同源性3（BH 3）结构域中的Q221 R222 N223基序的动态区域已被确定为控制Mcl-1泛素化的构象开关。NoxaBH 3结合使QRN基序偏向螺旋构象，从而导致Mcl-1的体外泛素化增强。与此相反，BimBH 3结合偏向QRN基序朝向非螺旋构象，从而导致抑制泛素化。描述了一种双功能Mcl-1抑制剂，其位于Mcl-1的BH 3结构域并与His 224形成氢键以驱动螺旋QRN构象，使得其不仅干扰促凋亡伴侣，而且促进活细胞中的Mcl-1泛素化。因此，该抑制剂在Mcl-1依赖性癌细胞中表现出比与其表现出类似结合亲和力的其他抑制剂更有效的凋亡诱导。
By means of limited proteolysis assay, three‐dimensional NMR, X‐ray crystallography and alanine mutations, a dynamic region at the Q221R222N223 motif in the Bcl‐2 homology 3 (BH3) domain of Mcl‐1 has been identified as a conformational switch which controls Mcl‐1 ubiquitination. NoxaBH3binding biases the QRN motif toward a helical conformation, thus leading to an enhanced in vitro ubiquitination of Mcl‐1. In contrast, BimBH3binding biases the QRN motif toward a nonhelical conformation, thus leading to the inhibition of ubiquitination. A dual function Mcl‐1 inhibitor, which locates at the BH3 domain of Mcl‐1 and forms hydrogen bond with His224 to drive a helical QRN conformation, so that it not only interferes with the pro‐apoptotic partners, but also facilitates Mcl‐1 ubiquitination in living cells, is described. As a result, this inhibitor manifests a more effective apoptosis induction in Mcl‐1‐dependent cancer cells than other inhibitors exhibiting a similar binding affinity with it.