Alternative retinoid X receptor (RXR) ligands

Retinoid X receptors (RXRs) control a wide variety of functions by virtue of their dimerization with other nuclear hormone receptors (NRs), contributing thereby to activities of different signaling pathways. We review known RXR ligands as transcriptional modulators of specific RXR-dimers and the associated biological processes. We also discuss the physiological relevance of such ligands, which remains frequently a matter of debate and which at present is best met by member(s) of a novel family of retinoids, postulated as Vitamin A5. Through comparison with other natural, but also with synthetic ligands, we discuss high diversity in the modes of ligand binding to RXRs resulting in agonistic or antagonistic profiles and selectivity towards specific subtypes of permissive heterodimers. Despite such diversity, direct ligand binding to the ligand binding pocket resulting in agonistic activity was preferentially preserved in the course of animal evolution pointing to its functional relevance, and potential for existence of other, species-specific endogenous RXR ligands sharing the same mode of function.