ACTIVATION OF SPECIFIC RXR HETERODIMERS BY AN ANTAGONIST OF RXR HOMODIMERS

RETINOID X receptor (RXR) plays a central role in the regulation a of many intracellular receptor signalling pathways(1) and can mediate lig and-dependent transcription, acting as a homodimer or as a heterodimer (1-6). Here we identify an antagonist towards RXR homodimers which als o functions as an agonist when RXR is paired as a heterodimer to speci fic partners, including peroxisome proliferator-activated receptor and retinoic acid receptor. This dimer-selective ligand confers different ial interactions on the transcription machinery: the antagonist promot es association with TAF110) (TATA-binding protein (TBP)-associated fac tor 110) and the co-repressor SMRT(7), but not with TBP, and these pro perties are distinct from pure RXR agonists. This unique class of RXR ligands will provide a means to control distinct target genes at the l evel of transcription and allow the development of retinoids with a ne w pharmacological action.