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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, Ting1; Wang, Ziqian2; Ji, Fangling3; Feng, Yingang4; Fan, Yudan3; Chai, Gaobo2; Li, Xiangqian5; Li, Zhiqiang2; Zhang, Zhichao2
2016-11-07
Source PublicationANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume55Issue:46Pages:14248-14254
SubtypeArticle
AbstractBy 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.
KeywordApoptosis Conformation Analysis Drug Design Inhibitors Structure Elucidation
DOI10.1002/anie.201606543
Indexed BySCI
Language英语
WOS IDWOS:000387028000006
Citation statistics
Document Type期刊论文
Version出版稿
Identifierhttp://ir.qdio.ac.cn/handle/337002/135943
Collection实验海洋生物学重点实验室
Affiliation1.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
Recommended Citation
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.
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