CONFORMATIONAL ADAPTATION OF AGONISTS TO THE HUMAN NUCLEAR RECEPTOR RAR-GAMMA

The nuclear retinoid receptors RARs and RXRs are transcriptional regul ators whose activity is mediated by their ligand-binding domain. The c rystal structures of the unliganded human (ape) hRXRa ligand-binding d omain and of the all-trans retinoic acid-liganded (hole) hRAR gamma li gand-binding domain have been described. We report the crystal structu res of the hRAR gamma ligand-binding domain bound to either its other natural ligand 9-cis retinoic acid, or an RAR gamma-selective syntheti c agonist (BMS961). The two bound RA stereoisomers exhibit a striking structural resemblance, as their intrinsic flexibility allows them to fit into a unique ligand-binding pocket. The shape of BMS961 is a comb ination of those of the natural ligands and an additional RAR gamma-sp ecific hydrogen bond is responsible for the RARg isotype selectivity. All three agonist molecules fill almost entirely the ligand cavity and lead to an identical holo-ligand-binding domain protein conformation, thus accounting for their similar effect on RAR transactivation. The selectivity of different RAR ligands can now be explained using BMS961 as a template. The present conclusions are not limited to RAR gamma a nd can be extended to the other members of the retinoid family.