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Publication Abstract from PubMed

Retinoic X receptor (RXR) is a promising target for drug discovery against cancer and metabolic syndromes. Here, we identified a specific RXRalpha antagonist, danthron, from the traditional Chinese medicine rhubarb. Danthron repressed all tested RXRalpha-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 RXRalpha-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-RXRalpha 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 RXRalpha-LBD suggested a new mechanism for danthron antagonism to tetrameric RXRalpha. 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 RXRalpha antagonist for its further potential therapeutic application.

Danthron functions as a retinoic X receptor antagonist by stabilizing tetramers of the receptor.,Zhang H, Zhou R, Li L, Chen J, Chen L, Li C, Ding H, Yu L, Hu L, Jiang H, Shen X J Biol Chem. 2011 Jan 21;286(3):1868-75. Epub 2010 Nov 17. PMID:21084305^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.