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Published on: June 21, 2016
Neurosteroids Inhibit RORγ and Induce Major Rearrangement of Its Activation Motif
Úrsula López-García1, Minh Sai1, Xiu Ge1
1Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich81377, Germany.
Abstract:
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.
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