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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| Authors: | Dr. Ting Song Ziqian Wang Dr. Fangling Ji Dr. Yingang Feng Yudan Fan Gaobo Chai Dr. Xiangqian Li Zhiqiang Li Dr. Zhichao Zhang |
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| Affiliation: | 1. State Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China;2. School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China;3. School of Life Science and Technology, Dalian University of Technology, China;4. Shandong Key Laboratory of Synthetic Biology, CAS Key Laboratory of Biofuels, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, Shandong, China;5. Institute of Oceanology, Chinese Academy of Sciences, Qingdao, Shandong, China |
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| Abstract: | ![]()
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. NoxaBH3 binding biases the QRN motif toward a helical conformation, thus leading to an enhanced in vitro ubiquitination of Mcl‐1. In contrast, BimBH3 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. |
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| Keywords: | apoptosis conformation analysis drug design inhibitors structure elucidation |
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