3nsq
Crystal structure of tetrameric RXRalpha-LBD complexed with antagonist danthron
Structural highlights
FunctionRXRA_HUMAN Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.[1] [2] [3] [4] Publication Abstract from PubMedRetinoic 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[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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