Deactivation of Mcl-1 by Dual-Function Small-Molecule Inhibitors Targeting the Bcl-2 Homology 3 Domain and Facilitating Mcl-1 Ubiquitination

CORC > 海洋研究所 > 中国科学院海洋研究所 > 实验海洋生物学重点实验室

	Deactivation of Mcl-1 by Dual-Function Small-Molecule Inhibitors Targeting the Bcl-2 Homology 3 Domain and Facilitating Mcl-1 Ubiquitination
	Song, Ting 1; Wang, Ziqian 2; Ji, Fangling 3; Feng, Yingang 4; Fan, Yudan 3; Chai, Gaobo 2; Li, Xiangqian 5; Li, Zhiqiang 2; Zhang, Zhichao 2
刊名	ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
	2016-11-07
卷号	55 期号:46 页码:14248-14254
关键词	apoptosis conformation analysis drug design inhibitors structure elucidation
英文摘要	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.
收录类别	SCI
语种	英语
WOS记录号	WOS:000387028000006
内容类型	期刊论文
版本	出版稿
源URL	[http://ir.qdio.ac.cn/handle/337002/135943]
专题	海洋研究所_实验海洋生物学重点实验室
作者单位	1.Dalian Univ Technol, Zhang Dayu Sch Chem, State Key Lab Fine Chem, Dalian, Liaoning, Peoples R China 2.Dalian Univ Technol, Sch Chem, Dalian, Liaoning, Peoples R China 3.Dalian Univ Technol, Sch Life Sci & Technol, Dalian, Peoples R China 4.Chinese Acad Sci, Qingdao Inst Bioenergy & Bioproc Technol, Shandong Key Lab Synthet Biol, Key Lab Biofuels, Qingdao, Shandong, Peoples R China 5.Chinese Acad Sci, Inst Oceanol, Qingdao, Shandong, Peoples R China
推荐引用方式 GB/T 7714	Song, Ting,Wang, Ziqian,Ji, Fangling,et al. Deactivation of Mcl-1 by Dual-Function Small-Molecule Inhibitors Targeting the Bcl-2 Homology 3 Domain and Facilitating Mcl-1 Ubiquitination[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2016,55(46):14248-14254.
APA	Song, Ting.,Wang, Ziqian.,Ji, Fangling.,Feng, Yingang.,Fan, Yudan.,...&Zhang, Zhichao.(2016).Deactivation of Mcl-1 by Dual-Function Small-Molecule Inhibitors Targeting the Bcl-2 Homology 3 Domain and Facilitating Mcl-1 Ubiquitination.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,55(46),14248-14254.
MLA	Song, Ting,et al."Deactivation of Mcl-1 by Dual-Function Small-Molecule Inhibitors Targeting the Bcl-2 Homology 3 Domain and Facilitating Mcl-1 Ubiquitination".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 55.46(2016):14248-14254.