Deactivation of Mcl-1 by Dual-Function Small-Molecule Inhibitors Targeting the Bcl-2 Homology 3 Domain and Facilitating Mcl-1 Ubiquitination
发布时间：2019-03-12
点击次数：
- 论文类型：
- 期刊论文
- 发表时间：
- 2016-11-07
- 发表刊物：
- ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
- 收录刊物：
- PubMed、EI、SCIE
- 文献类型：
- J
- 卷号：
- 55
- 期号：
- 46
- 页面范围：
- 14248-14254
- ISSN号：
- 1433-7851
- 关键字：
- apoptosis; conformation analysis; drug design; inhibitors; structure elucidation
- 摘要：
- 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.
- 第一作者
- Song, Ting
- 合写作者
- Li, Zhiqiang,Zhang, Zhichao,Wang, Ziqian,Ji, Fangling,Feng, Yingang,Fan, Yudan,Chai, Gaobo,Li, Xiangqian
- 通讯作者
- Zhang, ZC (reprint author), Dalian Univ Technol, Sch Chem, Dalian, Liaoning, Peoples R China.