Figure 6. Model for ligand-dependent activation of RORγ.

(A) Apo RORγ exhibits extensive conformational dynamics in the absence of compound. Ligand recognition through the BSR, H3 and H7 confer thermal stability and allows for H10-12 stability where H12 and H4 dynamics are the key structural determinants for coactivator affinity and receptor hyperactivation. (B) Based on mutagenesis studies, apo RORγ is presumed to be inactive. The observed high basal activity is likely due to activation of RORγ by endogenous agonists. Compounds that outcompete these endogenous ligands and activate RORγ to the observed levels should be considered silent agonists.