Crystal structure of the human RXR alpha ligand-binding domain bound to its natural ligand: 9-cis retinoic acid

The pleiotropic effects of active retinoids are transduced by their cognate nuclear receptors, retinoid X receptors (RXRs) and retinoic acid receptors (RARs), which act as transcriptional regulators activated by two stereoiso mers of retinoic acid (RA): 9-cis RA (9-cRA) and all-trans RA (a-tRA). Amon g nuclear receptors, RXR occupies a central position and plays a crucial ro le in many intracellular signalling pathways as a ubiquitous heterodimeriza tion partner with numerous other members of this superfamily, Whereas RARs bind both isomers, RXRs exclusively bind 9-cRA, The crystal structure of th e ligand-binding domain (LBD) of human RXR alpha bound to 9-cRA reveals the molecular basis of this ligand selectivity and allows a comparison of both apo and hole forms of the same nuclear receptor. In the crystal, the recep tor is monomeric and exhibits a canonical agonist conformation without dire ct contacts between the ligand and the transactivation helix H12. Compariso n with the unliganded RXR alpha LED structure reveals the molecular mechani sms of ligand-induced conformational changes and allows us to describe at t he atomic level how these changes generate the proper protein interface inv olved in nuclear receptor-coactivator interaction.