3NSQ

Crystal structure of tetrameric RXRalpha-LBD complexed with antagonist danthron

Summary for 3NSQ

• Entry DOI: 10.2210/pdb3nsq/pdb
• Related: 3NSP
• Descriptor: Retinoid X receptor, alpha, 1,8-dihydroxyanthracene-9,10-dione (3 entities in total)
• Functional Keywords: nuclear receptor retinoic x recepor alpha ligand binding domain antagonist danthron, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 53952.29

Authors

Zhang, H.,Hu, T.,Li, L.,Zhou, R.,Chen, L.,Hu, L.,Jiang, H.,Shen, X. (deposition date: 2010-07-02, release date: 2010-11-17, Last modification date: 2023-11-01)

Primary citation

Zhang, H.,Zhou, R.,Li, L.,Chen, J.,Chen, L.,Li, C.,Ding, H.,Yu, L.,Hu, L.,Jiang, H.,Shen, X.
Danthron functions as a retinoic X receptor antagonist by stabilizing tetramers of the receptor.
J.Biol.Chem., 286:1868-1875, 2011

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.

PubMed: 21084305
DOI: 10.1074/jbc.M110.166215

Experimental method

X-RAY DIFFRACTION (2.6 Å)