Modulators of the structural dynamics of the retinoid X receptor to reveal receptor function

Institut National de la Santé et de la Recherche Médicale, U554, 34090 Montpellier, France.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2007; 104(44):17323-8. DOI: 10.1073/pnas.0705356104
Source: PubMed


Retinoid X receptors (RXRalpha, -beta, and -gamma) occupy a central position in the nuclear receptor superfamily, because they form heterodimers with many other family members and hence are involved in the control of a variety of (patho)physiologic processes. Selective RXR ligands, referred to as rexinoids, are already used or are being developed for cancer therapy and have promise for the treatment of metabolic diseases. However, important side effects remain associated with existing rexinoids. Here we describe the rational design and functional characterization of a spectrum of RXR modulators ranging from partial to pure antagonists and demonstrate their utility as tools to probe the implication of RXRs in cell biological phenomena. One of these ligands renders RXR activity particularly sensitive to coactivator levels and has the potential to act as a cell-specific RXR modulator. A combination of crystallographic and fluorescence anisotropy studies reveals the molecular details accounting for the agonist-to-antagonist transition and provides direct experimental evidence for a correlation between the pharmacological activity of a ligand and its impact on the structural dynamics of the activation helix H12. Using RXR and its cognate ligands as a model system, our correlative analysis of 3D structures and dynamic data provides an original view on ligand actions and enables the establishment of mechanistic concepts, which will aid in the development of selective nuclear receptor modulators.

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    • "The present study used a synthetic RXR antagonist, UVI3003 (Fig. 1), which has been proven a high-affinity RXR selective full antagonist and a tool to reveal RXR function (Nahoum et al., 2007). The UVI3003-induced teratogenic effects and related typical anomalies of zebrafish embryos, an attractive in vivo model for toxicological study, were analyzed. "
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    ABSTRACT: Retinoid X receptor (RXR) interfering activity has been detected in different water resources. To study RXR disruptor-induced toxicological effects on vertebrates, embryos of zebrafish (Danio rerio) were exposed to a representative RXR antagonist UVI3003. Results showed that the teratogenic index (LC50/EC50) of UVI3003 was as high as 5.4. UVI3003 induced multiple malformations of embryos, including deformed fins, reduced brains, small jaws, bent tails and edema in hearts, the degree of which became more severe with increasing exposure concentration. Although no significant difference was observed in the hatching rates between the exposure group and control, the whole body length was significantly reduced by 6.5% and 8.9% when exposed to 200 and 300 µg l−1 of UVI3003, respectively. The heart rate also significantly decreased by 8.8–50.2% during exposure. Further experiments revealed that the pharyngula stage was the most sensitive development phase in terms of embryo response to UVI3003. The results demonstrated severe teratogenicity of RXR antagonist in zebrafish embryos and provided important data for ecotoxicological evaluation of RXR antagonists. Copyright © 2014 John Wiley & Sons, Ltd.
    Full-text · Article · Sep 2014 · Journal of Applied Toxicology
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    • "Nevertheless , RXRs can form different heterodimers with other nuclear receptors, suggesting that some nuclear receptors other than RAR might be responsible for the developmental malformations in Xenopus embryos. UVI3003 is a highly selective antagonist of RXR and has been suggested to be a valid tool to study the function of RXR (Nahoum et al., 2007). Amphibian embryos have been used as the model to test the developmental toxicity of man-made chemicals and natural compounds (Moreno et al., 2012; Güngördü, 2013). "
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    ABSTRACT: We exposed Xenopus tropicalis embryos to a selective antagonist of retinoid X receptor (UVI3003). UVI3003 induced multiple malformations at the concentrations of 200-1000μg/L after 48h exposure. The most prominent malformations affected brains, eyes, cement gland and fins. UVI3003 also induced variable and divergent malformations at 250-1500μg/L after 0-24 and 24-48h exposure. Microarray analysis showed that seven genes (rps15, serp2, fmr1, cyp2e1, lrrc9, ugtla6 and LOC100490188) were differentially regulated in all three treatment groups after 0-24h exposure. The most significantly affected pathway was galactose metabolism. In 24-48h exposure groups, 18 genes were differentially regulated, mainly comprising components of the PPAR signaling pathway. These results suggested that UVI3003 is teratogenic in amphibian embryos. Differential gene expression suggests that galactose metabolism and PPAR signaling pathways may provide underlying mechanistic detail accounting for the observed malformations.
    Full-text · Article · May 2014 · Environmental Toxicology and Pharmacology
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    • "In crystal structures, each receptor was bound to a coactivator peptide. Quite probably this could be to increase the symmetry and to obtain better crystal packing (Greschik et al., 2004; Nahoum et al., 2007; Nettles et al., 2007). Based on the use of larger fragments of coactivators, such as the functional domains of Med1 and SRC1, and on mutating residues in AF2 of both receptor partners that are indispensible for coactivator binding, solution structures suggest that only 1 coactivator binds to the heterodimeric complex, more precisely to the binding partner of RXR (Rochel et al., 2011). "
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    ABSTRACT: While the structures of the DNA- and ligand-binding domains of many nuclear receptors have been determined in great detail; the mechanisms by which these domains interact and possibly 'communicate' is still under debate. The first crystal structures of receptor dimers bound to ligand, DNA and coactivator peptides provided new insights in this matter. The observed binding modes revealed exciting new interaction surfaces between the different nuclear receptor domains. Such interfaces are proposed to be the route through which allosteric signals from the DNA are passed on to the ligand-binding domain and the activating functions of the receptor. The structural determinations of DNA-bound receptor dimers in solution, however, revealed an extended structure of the receptors. Here, we discuss these apparent contradictory structural data and their possible implications for the functioning of nuclear receptors.
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