title: Deactivation of Mcl-1 by Dual-Function Small-Molecule Inhibitors Targeting the Bcl-2 Homology 3 Domain and Facilitating Mcl-1 Ubiquitination.
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. NoxaBH3binding biases the QRN motif toward a helical conformation, thus leading to an enhanced in vitro ubiquitination of Mcl-1. In contrast, BimBH3binding 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.
authors.affiliation: State Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.affiliation: School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Ziqian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Life Science and Technology, Dalian University of Technology, China.
authors.forename: Fangling
authors.initials: F
authors.lastname: Ji
authors.affiliation: 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.
authors.forename: Yingang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: School of Life Science and Technology, Dalian University of Technology, China.
authors.forename: Yudan
authors.initials: Y
authors.lastname: Fan
authors.affiliation: School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Gaobo
authors.initials: G
authors.lastname: Chai
authors.affiliation: Institute of Oceanology, Chinese Academy of Sciences, Qingdao, Shandong, China.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China. zczhang@dlut.edu.cn.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
keywords: apoptosis; conformation analysis; drug design; inhibitors; structure elucidation