1. Division of Cellular and Molecular Medicine, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA
2. Division of Endocrinology and Metabolism, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA
3. Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA
4. Department of Structural Chemistry, GlaxoWellcome Inc., Research Triangle Park, North Carolina 27709, USA

Correspondence to: Christopher K. Glass^1,2 Correspondence and requests for materials should be addressed to C.K.G. (e-mail: Email: cglass@ucsd.edu).

Retinoic-acid receptor- (RAR-) and peroxisome proliferator-activated receptor- (PPAR-) are members of the nuclear-receptor superfamily that bind to DNA as heterodimers with retinoid-X receptors (RXRs)¹,². PPAR–RXR heterodimers can be activated by PPAR or RXR ligands³, whereas RAR–RXR heterodimers are selectively activated by RAR ligands only, because of allosteric inhibition of the binding of ligands to RXR by RAR⁴,⁵. However, RXR ligands can potentiate the transcriptional effects of RAR ligands in cells⁶. Transcriptional activation by nuclear receptors requires a carboxy-terminal helical region, termed activation function-2 (AF-2) (refs 7,8,9), that forms part of the ligand-binding pocket and undergoes a conformational change required for the recruitment of co-activator proteins, including NCoA-1/SRC-1 (refs 10,11,12,13,14,15,16,17). Here we show that allosteric inhibition of RXR results from a rotation of the RXR AF-2 helix that places it in contact with the RAR coactivator-binding site. Recruitment of an LXXLL motif of SRC-1 to RAR in response to ligand displaces the RXR AF-2 domain, allowing RXR ligands to bind and promote the binding of a second LXXLL motif from the same SRC-1 molecule. These results may partly explain the different responses of nuclear-receptor heterodimers to RXR-specific ligands.