Indexed by:
期刊论文
First Author:
Song, Ting
Correspondence Author:
Zhang, ZC (reprint author), Dalian Univ Technol, Sch Chem, Dalian, Liaoning, Peoples R China.
Co-author:
Wang, Ziqian,Ji, Fangling,Feng, Yingang,Fan, Yudan,Chai, Gaobo,Li, Xiangqian,Li, Zhiqiang,Zhang, Zhichao
Date of Publication:
2016-11-07
Journal:
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Included Journals:
SCIE、EI、PubMed
Document Type:
J
Volume:
55
Issue:
46
Page Number:
14248-14254
ISSN No.:
1433-7851
Key Words:
apoptosis; conformation analysis; drug design; inhibitors; structure
elucidation
Abstract:
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.
Translation or Not:
no
