Nature 371, 528 - 531 (06 October 1994); doi:10.1038/371528a0

Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding

Riki Kurokawa^*, James DiRenzo^*, Marcus Boehm^†, Jeffrey Sugarman^*, Berndt Gloss, Michael G. Rosenfeld^§, Richard A. Heyman^¶ & Christopher K. Glass^*§£

^* Division of Cellular and Molecular Medicine,^§ Division of Endocrinology and Metabolism, Howard Hughes Medical Institute, University of California, San Diego, 9500 Oilman Drive, La Jolla, California 92093-0656, USA
^† Department of Medicinal Chemistry,^¶ Department of Cell Biology, Ligand Pharmaceuticals,9393 Towne Center Drive, San Diego, California 92121, USA
^£ To whom correspondence should be addressed

RETINOIC acid receptors (RARs) and retinoid X receptors (RXRs) regulate transcription by binding to response elements in target genes that generally consist of two direct repeat half-sites of consensus sequence AGGTCA (ref. 1). RAR/RXR heterodimers activate transcription in response to all-trans or 9-cis retinoic acid by binding to direct repeats spaced by five base pairs (DR5 elements)2–8, such that RAR occupies the downstream naif-site^9–12. RXR homodimers activate transcription in response to 9-cis retinoic acid by binding to direct repeats spaced by one base pair (DR1 elements)^8,13,14. Although RXR/RAR heterodimers bind to DR1 elements with higher affinity than RXR homodimers, in most contexts they are unable to activate transcription in response to either all-trans or 9-cis retinoic acid^3–5. As a result, RARs inhibit RXR-dependent transcription from these sites^13,15. We report that the switching of the RAR from an activator to an inhibitor of retinoid-dependent transcription requires that it be bound to the upstream half-site of DR1 elements and that it allosterically block the binding of ligand to the RXR.

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