Premium
Deactivation of Mcl‐1 by Dual‐Function Small‐Molecule Inhibitors Targeting the Bcl‐2 Homology 3 Domain and Facilitating Mcl‐1 Ubiquitination
Author(s) -
Song Ting,
Wang Ziqian,
Ji Fangling,
Feng Yingang,
Fan Yudan,
Chai Gaobo,
Li Xiangqian,
Li Zhiqiang,
Zhang Zhichao
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201606543
Subject(s) - ubiquitin , chemistry , microbiology and biotechnology , proteolysis , in vitro , small molecule , stereochemistry , biophysics , biochemistry , biology , enzyme , gene
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.