Allosteric Regulation of Hsp90 alpha's Activity by Small Molecules Targeting the Middle Domain of the Chaperone

doi:10.1016/j.isci.2020.100857

	Allosteric Regulation of Hsp90 alpha's Activity by Small Molecules Targeting the Middle Domain of the Chaperone
	Zhou, Chen 1; Zhang, Chi 2; Zhu, Hongwen 1,2; Liu, Zhijun 3; Su, Haixia 2,4; Zhang, Xianglei 2,4; Chen, Tingting 2,4; Zhong, Yan 1,4; Hu, Huifang 1,4; Xiong, Muya 2,4
刊名	ISCIENCE
	2020-02-21
卷号	23 期号:2 页码:46
DOI	10.1016/j.isci.2020.100857
通讯作者	Xu, Yechun(ycxu@simm.ac.cn) ; Zhang, Ao(aozhang@simm.ac.cn) ; Zhang, Naixia(nxzhang@simmn.ac.cn)
英文摘要	Hsp90 is a target for anti-cancer drug development. Both the conformational events tuned by ATP/ADP and co-chaperones and the chaperoning cycle timing are required for Hsp90's fully functional display. Interfering with either one of the conformational events or the cycle timing will down-regulate Hsp90's function. In this manuscript, non-covalent allosteric modulators (SOMCL-16-171 and SOMCL-16-175) targeting Hsp90 alpha's middle domain (Hsp90M) were developed for the first time. Multiple techniques were then applied to characterize the interactions between two active compounds and lisp90 alpha. Two loops and one alpha-helix (F349-N360, K443-E451, and D372-G387) in Hsp90M were identified responsible for the recognition of SOMCL-16-171 and SOMCL-16-175. Meanwhile, the binding of SOMCL-16-171 and SOMCL-16-175 to Hsp90M was demonstrated to allosterically modulate the structure and function of Hsp90's N-terminal domain. Finally, cellular assays were conducted to evaluate the cellular activity of SOMCL-16-175, and the results indicate that SOMCL-16-175 destabilizes Hsp90's client proteins and reduces cell viability.
资助项目	National Natural Science Foundation of China[21778061] ; National Natural Science Foundation of China[81430080] ; National Natural Science Foundation of China[21977105] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002]
WOS关键词	N-TERMINAL DOMAIN ; CLIENT PROTEIN ; ATPASE ACTIVITY ; HSP90 ; ACTIVATION ; CYCLE ; DEGRADATION ; INHIBITION ; ASSIGNMENT ; MECHANISM
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	CELL PRESS
WOS记录号	WOS:000518637100004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281023]
专题	中国科学院上海药物研究所
通讯作者	Xu, Yechun; Zhang, Ao; Zhang, Naixia
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Natl Facil Prot Sci Shanghai, Shanghai Adv Res Inst, ZhangJiang Lab, Shanghai 201210, Peoples R China 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Chen,Zhang, Chi,Zhu, Hongwen,et al. Allosteric Regulation of Hsp90 alpha's Activity by Small Molecules Targeting the Middle Domain of the Chaperone[J]. ISCIENCE,2020,23(2):46.
APA	Zhou, Chen.,Zhang, Chi.,Zhu, Hongwen.,Liu, Zhijun.,Su, Haixia.,...&Zhang, Naixia.(2020).Allosteric Regulation of Hsp90 alpha's Activity by Small Molecules Targeting the Middle Domain of the Chaperone.ISCIENCE,23(2),46.
MLA	Zhou, Chen,et al."Allosteric Regulation of Hsp90 alpha's Activity by Small Molecules Targeting the Middle Domain of the Chaperone".ISCIENCE 23.2(2020):46.