R. Kurokawa et al., REGULATION OF RETINOID SIGNALING BY RECEPTOR POLARITY AND ALLOSTERIC CONTROL OF LIGAND-BINDING, Nature, 371(6497), 1994, pp. 528-531
RETINOIC acid receptors (RARs) and retinoid X receptors (RXRs) regulat
e transcription by binding to response elements in target genes that g
enerally consist of two direct repeat half-sites of consensus sequence
AGGTCA (ref. 1). RAR/RXR heterodimers activate transcription in respo
nse to all-irans or 9-cis retinoic acid by binding to direct repeats s
paced by five base pairs (DR5 elements)(2-8), such that RAR occupies t
he downstream half-site(9-12). RXR homodimers activate transcription i
n response to 9-cis retinoic acid by binding to direct repeats spaced
by one base pair (DR1 elements)(8,13,14). Although RXR/RAR heterodimer
s bind to DR1 elements with higher affinity than RXR homodimers, in mo
st contexts they are unable to activate transcription in response to e
ither 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 t
he 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.