Structural basis for diosgenin as an inverse agonist of retinoic acid receptor-related orphan receptor γ

Retinoic acid receptor-related orphan receptor γ (RORγ) is a member of the nuclear receptor superfamily involved in many physiological activities such as metabolic and autoimmune diseases, and therefore a potential therapeutic drug target. Here we report that the steroidal sapogenin, diosgenin, a novel ligand for RORγ, inhibits the transcriptional activity of the RORγ with distinctive properties in coregulator recruitment. Biochemical and cell-based studies indicated that diosgenin functions as a selective RORγ inverse agonist by inducing both coactivator and corepressor binding to RORγ, thereby uncovering a molecular mechanism for the actions of this natural compound. Further, the crystal structure of diosgenin complexed with the ligand-binding domain of RORγ reveals a unique binding mode including the active conformation of AF-2 helix and the conformational shift of Helix 11. Structural and functional studies suggest the plasticity of RORγ pockets in recognizing ligands and the vital roles of the backbone of diosgenin in recognizing RORγ. Our results provide a unique inverse agonist template of RORγ with high selectivity and efficacy, which contributes to further drug design and optimization targeting RORγ.