Abstract
The nuclear retinoid receptors RARs and RXRs are transcriptional regulators whose activity is mediated by their ligand-binding domain. The crystal structures of the unliganded human (apo) hRXRa ligand-binding domain and of the all-trans retinoic acid-liganded (holo) hRARγ ligand-binding domain have been described. We report the crystal structures of the hRARγ ligand-binding domain bound to either its other natural ligand 9-cis retinoic acid, or an RARγ-selective synthetic 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 combination of those of the natural ligands and an additional RARγ-specific 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 RARγ and can be extended to the other members of the retinoid family.
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Klaholz, B., Renaud, JP., Mitschler, A. et al. Conformational adaptation of agonists to the human nuclear receptor RARγ. Nat Struct Mol Biol 5, 199–202 (1998). https://doi.org/10.1038/nsb0398-199
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DOI: https://doi.org/10.1038/nsb0398-199
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