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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 | |
| 发表期刊 | ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
 |
| 卷号 | 55期号:46页码:14248-14254 |
| 文章类型 | Article |
| 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. |
| 关键词 | Apoptosis Conformation Analysis Drug Design Inhibitors Structure Elucidation |
| DOI | 10.1002/anie.201606543 |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000387028000006 |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 版本 | 出版稿 |
| 条目标识符 | http://ir.qdio.ac.cn/handle/337002/135943 |
| 专题 | 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. |
| 条目包含的文件 | ||||||
| 文件名称/大小 | 文献类型 | 版本类型 | 开放类型 | 使用许可 | ||
| Deactivation of Mcl-（5903KB） | 期刊论文 | 出版稿 | 限制开放 | CC BY-NC-SA | 浏览 | |
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