Danthron Functions as a Retinoic X Receptor Antagonist by Stabilizing Tetramers of the Receptor
Danthron Functions as a Retinoic X Receptor Antagonist by Stabilizing Tetramers of the Receptor
复制标题
Danthron 通过稳定受体的四聚体发挥视黄酸 X 受体拮抗剂的作用
DOI：
10.1074/jbc.m110.166215
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发表时间：
2011-01-21
影响因子：
4.8
通讯作者：
Shen, Xu
中科院分区：
文献类型：
--
作者：
Zhang, Haitao;Zhou, Rong;Shen, Xu
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.
