文献类型：期刊文献

英文题名：Danthron Functions as a Retinoic X Receptor Antagonist by Stabilizing Tetramers of the Receptor

作者：Zhang, Haitao;Zhou, Rong[2];Li, Li[2];Chen, Jing;Chen, Lili;Li, Chenjing;Ding, Hong;Yu, Liang;Hu, Lihong;Jiang, Hualiang[1];Shen, Xu[1,2,3]

机构：[1]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;[2]E China Univ Sci & Technol, Shanghai 200237, Peoples R China;[3]Shanghai Jiao Tong Univ, Sch Med, E Inst Shanghai Municipal Educ Commiss, Shanghai 200025, Peoples R China

年份：2011

卷号：286

期号：3

起止页码：1868

外文期刊名：JOURNAL OF BIOLOGICAL CHEMISTRY

收录：;EI(收录号：20110413616972);WOS:【SCI-EXPANDED(收录号:WOS:000286191500027)】；

基金：This work was supported by the State Key Program of Basic Research of China (Grants 2010CB912501, 2007CB914304, and 2009CB918502), the National Natural Science Foundation of China (Grants 30925040, 30890044, and 10979072), Key New Drug Creation and Manufacturing Program (2009ZX09301-001), the Science Foundation of Shanghai (Grant 08431902900), the E-Institutes of Shanghai Municipal Education Commission (Grant E09013), and the Foundation of Chinese Academy of Sciences (Grants KSCX2-YW-R-168 and SCX1-YW-02-2).

语种：英文

外文关键词：Ligands - Oligomers - Medicine

摘要：Retinoic X receptor (RXR) is a promising target for drug discovery against cancer and metabolic syndromes. Here, we identified a specific RXR alpha antagonist, danthron, from the traditional Chinese medicine rhubarb. Danthron repressed all tested RXR alpha-involved response element transcription, including the RXRE, PPRE, FXRE, and LXRE. Results from native PAGE and isothermal titration calorimetry (ITC)-based assays indicated that danthron bound to the tetrameric RXR alpha-LBD in a specific stoichimetric ratio, and such a binding could influence the corepressor SMRT affinity to the receptor. Additionally, a unique tetrameric structure of the apo-RXR alpha ligand-binding domain (LBD) was determined, which exhibited a larger tetramer interface and different ligand-binding pocket size compared with the one previously reported. Together with the biochemical and biophysical results, the determined crystal structure of danthron-soaked RXR alpha-LBD suggested a new mechanism for danthron antagonism to tetrameric RXR alpha. Moreover, the in vivo efficient improvement of insulin sensitivity by danthron was observed in diet-induced obese (DIO) mice. Thus, our findings were expected to supply new insights into the structural basis of RXR alpha antagonist for its further potential therapeutic application.