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Activation of RXR-PPAR heterodimers by organotin environmental endocrine disruptors.

Abstract : The nuclear receptor retinoid X receptor-alpha (RXR-alpha)-peroxisome proliferator-activated receptor-gamma (PPAR-gamma) heterodimer was recently reported to have a crucial function in mediating the deleterious effects of organotin compounds, which are ubiquitous environmental contaminants. However, because organotins are unrelated to known RXR-alpha and PPAR-gamma ligands, the mechanism by which these compounds bind to and activate the RXR-alpha-PPAR-gamma heterodimer at nanomolar concentrations has remained elusive. Here, we show that tributyltin (TBT) activates all three RXR-PPAR-alpha, -gamma, -delta heterodimers, primarily through its interaction with RXR. In addition, the 1.9 A resolution structure of the RXR-alpha ligand-binding domain in complex with TBT shows a covalent bond between the tin atom and residue Cys 432 of helix H11. This interaction largely accounts for the high binding affinity of TBT, which only partly occupies the RXR-alpha ligand-binding pocket. Our data allow an understanding of the binding and activation properties of the various organotins and suggest a mechanism by which these tin compounds could affect other nuclear receptor signalling pathways.
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Submitted on : Monday, September 7, 2009 - 1:54:45 PM
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Albane Le Maire, Marina Grimaldi, Dominique Roecklin, Sonia Dagnino, Valérie Vivat-Hannah, et al.. Activation of RXR-PPAR heterodimers by organotin environmental endocrine disruptors.. EMBO Reports, EMBO Press, 2009, 10 (4), pp.367-73. ⟨10.1038/embor.2009.8⟩. ⟨inserm-00375675⟩



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