宋婷

个人信息Personal Information

副教授

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:化学学院

学科:有机化学. 细胞生物学

办公地点:大连理工大学西部新校区化学综合楼C508

联系方式:Email: songting@dlut.edu.cn Tel: 18098885828

电子邮箱:songting@dlut.edu.cn

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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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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.