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.(2011) J Biol Chem 286: 1868-1875
- PubMed: 21084305 
- DOI: https://doi.org/10.1074/jbc.M110.166215
- Primary Citation of Related Structures:  
3NSP, 3NSQ - PubMed Abstract: 
Retinoic X receptor (RXR) is a promising target for drug discovery against cancer and metabolic syndromes. Here, we identified a specific RXRα antagonist, danthron, from the traditional Chinese medicine rhubarb. Danthron repressed all tested RXRα-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 RXRα-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-RXRα 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 RXRα-LBD suggested a new mechanism for danthron antagonism to tetrameric RXRα. 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 RXRα antagonist for its further potential therapeutic application.
Organizational Affiliation: 
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.