Deactivation of Mcl-1 by Dual-Function Small-Molecule Inhibitors Targeting the Bcl-2 Homology 3 Domain and Facilitating Mcl-1 Ubiquitination

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• 作者：Dr. Ting Song ; Ziqian Wang ; Dr. Fangling Ji ; Dr. Yingang Feng ; Yudan Fan ; Gaobo Chai ; Dr. Xiangqian Li ; Zhiqiang Li and Dr. Zhichao Zhang
• 刊名：Angewandte Chemie
• 出版年：2016
• 出版时间：November 7, 2016
• 年：2016
• 卷：128
• 期：46
• 页码：14462-14468
• 全文大小：5861K
• ISSN：1521-3757

文摘

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. Noxa^BH3 binding biases the QRN motif toward a helical conformation, thus leading to an enhanced in vitro ubiquitination of Mcl-1. In contrast, Bim^BH3 binding 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.