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

doi:10.1002/anie.201606543

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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
	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
	2016-11-07
发表期刊	ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷号	55 期号:46 页码:14248-14254
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.
文章类型	Article
关键词	Apoptosis Conformation Analysis Drug Design Inhibitors Structure Elucidation
WOS标题词	Science & Technology ; Physical Sciences
DOI	10.1002/anie.201606543
关键词[WOS]	DEGRADATION ; RESISTANCE ; DISCOVERY ; APOPTOSIS ; MECHANISM ; PROTEINS ; THERAPY ; FAMILY
收录类别	SCI
语种	英语
WOS研究方向	Chemistry
项目资助者	Natural Science Foundation of China(21402022 ; 21372036 ; 81570129 ; 21502015 ; 81430083)
WOS类目	Chemistry, Multidisciplinary
WOS记录号	WOS:000387028000006
引用统计
文献类型	期刊论文
条目标识符	http://ir.qibebt.ac.cn/handle/337004/9073
专题	代谢物组学研究组
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.