Neurosteroids Inhibit RORγ and Induce Major Rearrangement of Its Activation Motif.

A subset of endogenous steroids can be formed in the brain and exhibit brain-specific activities linked to neuronal health and disease. Despite the biological relevance of these so-called neurosteroids, molecular profiling of their effects is incomplete and their signature in the nuclear hormone receptor family that mediates signals of classical steroid hormones is elusive. Here, we present a comprehensive characterization of neurosteroids for nuclear receptor modulation and reveal pronounced inverse RORγ agonism as a relevant molecular mechanism of several abundant neurosteroids, with an impact on circadian rhythms and transcriptomic profiles in cellular settings. Structural analysis of the DHEA-RORγ interaction demonstrated orthosteric binding and pronounced rearrangements in the RORγ ligand binding domain to a fully repressed state, rationalizing the strong inverse agonist efficacy.