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

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Abstract

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-site9–12. 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 acid3–5. As a result, RARs inhibit RXR-dependent transcription from these sites13,15. 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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Author notes

  1. Christopher K. Glass: To whom correspondence should be addressed

Authors and Affiliations

  1. Division of Cellular and Molecular Medicine, University of California, San Diego, 9500 Oilman Drive, La Jolla, California, 92093-0656, USA

    Riki Kurokawa, James DiRenzo, Jeffrey Sugarman & Christopher K. Glass

  2. Division of Endocrinology and Metabolism, University of California, San Diego, 9500 Oilman Drive, La Jolla, California, 92093-0656, USA

    Michael G. Rosenfeld & Christopher K. Glass

  3. Howard Hughes Medical Institute, University of California, San Diego, 9500 Oilman Drive, La Jolla, California, 92093-0656, USA

    Berndt Gloss & Michael G. Rosenfeld

  4. Department of Medicinal Chemistry, Ligand Pharmaceuticals, 9393 Towne Center Drive, San Diego, California, 92121, USA

    Marcus Boehm

  5. Department of Cell Biology, Ligand Pharmaceuticals, 9393 Towne Center Drive, San Diego, California, 92121, USA

    Richard A. Heyman

Authors
  1. Riki Kurokawa
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  2. James DiRenzo
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  3. Marcus Boehm
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  4. Jeffrey Sugarman
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  5. Berndt Gloss
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  6. Michael G. Rosenfeld
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  7. Richard A. Heyman
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  8. Christopher K. Glass
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Kurokawa, R., DiRenzo, J., Boehm, M. et al. Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding. Nature 371, 528–531 (1994). https://doi.org/10.1038/371528a0

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  • DOI: https://doi.org/10.1038/371528a0

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