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

Nature. 1994 Oct 6;371(6497):528-31. doi: 10.1038/371528a0.


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), such that RAR occupies the downstream half-site. RXR homodimers activate transcription in response to 9-cis retinoic acid by binding to direct repeats spaced by one base pair (DR1 elements). 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. As a result, RARs inhibit RXR-dependent transcription from these sites. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Allosteric Regulation
  • Base Sequence
  • Cell Line
  • DNA / metabolism
  • Escherichia coli
  • Humans
  • Ligands
  • Molecular Sequence Data
  • Protein Binding
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Retinoic Acid / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Repetitive Sequences, Nucleic Acid
  • Retinoid X Receptors
  • Signal Transduction*
  • Transcription Factors*
  • Transcription, Genetic*


  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Recombinant Fusion Proteins
  • Retinoid X Receptors
  • Transcription Factors
  • DNA