| Structural highlights
Function
RXRA_MOUSE 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]
Evolutionary Conservation
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Publication Abstract from PubMed
Retinoic acid receptors (RARs) and Retinoid X nuclear receptors (RXRs) are ligand-dependent transcriptional modulators that execute their biological action through the generation of functional heterodimers. RXR acts as an obligate dimer partner in many signalling pathways, gene regulation by rexinoids depending on the liganded state of the specific heterodimeric partner. To address the question of the effect of rexinoid antagonists on RAR/RXR function, we solved the crystal structure of the heterodimer formed by the ligand binding domain (LBD) of the RARalpha bound to its natural agonist ligand (all-trans retinoic acid, atRA) and RXRalpha bound to a rexinoid antagonist (LG100754). We observed that RARalpha exhibits the canonical agonist conformation and RXRalpha an antagonist one with the C-terminal H12 flipping out to the solvent. Examination of the protein-LG100754 interactions reveals that its propoxy group sterically prevents the H12 associating with the LBD, without affecting the dimerization or the active conformation of RAR. Although LG100754 has been reported to act as a 'phantom ligand' activating RAR in a cellular context, our structural data and biochemical assays demonstrate that LG100754 mediates its effect as a full RXR antagonist. Finally we show that the 'phantom ligand effect' of the LG100754 is due to a direct binding of the ligand to RAR that stabilizes coactivator interactions thus accounting for the observed transcriptional activation of RAR/RXR.
The "Phantom Effect" of the Rexinoid LG100754: structural and functional insights.,Sato Y, Ramalanjaona N, Huet T, Potier N, Osz J, Antony P, Peluso-Iltis C, Poussin-Courmontagne P, Ennifar E, Mely Y, Dejaegere A, Moras D, Rochel N PLoS One. 2010 Nov 30;5(11):e15119. doi: 10.1371/journal.pone.0015119. PMID:21152046[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub A, Garnier JM, Mader S, et al.. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell. 1992 Jan 24;68(2):377-95. PMID:1310259
- ↑ Adam-Stitah S, Penna L, Chambon P, Rochette-Egly C. Hyperphosphorylation of the retinoid X receptor alpha by activated c-Jun NH2-terminal kinases. J Biol Chem. 1999 Jul 2;274(27):18932-41. PMID:10383391
- ↑ Bastien J, Adam-Stitah S, Plassat JL, Chambon P, Rochette-Egly C. The phosphorylation site located in the A region of retinoic X receptor alpha is required for the antiproliferative effect of retinoic acid (RA) and the activation of RA target genes in F9 cells. J Biol Chem. 2002 Aug 9;277(32):28683-9. Epub 2002 May 24. PMID:12032153 doi:10.1074/jbc.M203623200
- ↑ Sato Y, Ramalanjaona N, Huet T, Potier N, Osz J, Antony P, Peluso-Iltis C, Poussin-Courmontagne P, Ennifar E, Mely Y, Dejaegere A, Moras D, Rochel N. The "Phantom Effect" of the Rexinoid LG100754: structural and functional insights. PLoS One. 2010 Nov 30;5(11):e15119. doi: 10.1371/journal.pone.0015119. PMID:21152046 doi:http://dx.doi.org/10.1371/journal.pone.0015119
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