个人信息Personal Information
教授
博士生导师
硕士生导师
性别:女
毕业院校:大连理工大学
学位:博士
所在单位:医学部
学科:化学生物学. 药理学. 细胞生物学
办公地点:Chemical complex building,D513
联系方式:zczhang@dlut.edu.cn 13942696903
电子邮箱:zczhang@dlut.edu.cn
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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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:SCIE、EI、PubMed
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.