Ting Song
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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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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

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.

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Associate Professor
Supervisor of Master's Candidates

Gender:Female

Alma Mater:Dalian University of Technology

Degree:Doctoral Degree

School/Department:School of Chemistry

Discipline:Organic Chemistry. Cell Biology

Business Address:Chemical complex building C508

Contact Information:Email: songting@dlut.edu.cn Tel: 18098885828

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Address: No.2 Linggong Road, Ganjingzi District, Dalian City, Liaoning Province, P.R.C., 116024

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