Activation of RXR-PPAR heterodimers by organotin environmental endocrine disruptors.
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.
le Maire
Albane
A
INSERM, U554, Universités Montpellier 1 & 2, 29 rue de Navacelles, 34090 Montpellier, France.
Grimaldi
Marina
M
Roecklin
Dominique
D
Dagnino
Sonia
S
Vivat-Hannah
Valérie
V
Balaguer
Patrick
P
Bourguet
William
W
D002460:Cell Line; D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D052244:Endocrine Disruptors / Q000737:chemistry / Q000494:pharmacology*; D005454:Fluorescence Polarization; D006801:Humans; D013058:Mass Spectrometry; D008954:Models, Biological; D015394:Molecular Structure; D047492:Peroxisome Proliferator-Activated Receptors / Q000737:chemistry / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects*; D017433:Protein Structure, Secondary; D047488:Retinoid X Receptors / Q000737:chemistry / Q000378:metabolism*; D014220:Trialkyltin Compounds / Q000737:chemistry / Q000494:pharmacology*
D052244:Endocrine Disruptors; D047492:Peroxisome Proliferator-Activated Receptors; D047488:Retinoid X Receptors; D014220:Trialkyltin Compounds; C011559:tributyltin