All animals have evolved complex systems of gene regulation in response to environmental cues such as the 24hr light-dark cycle, which has influenced many aspects of animal behavior and physiology including feeding and metabolism. In mammals, the central clock, located in the Suprachiasmatic Nucleus (SCN) of the hypothalamus, is entrained by light. In turn, the SCN entrains peripheral clocks that are maintained, even in the absence of a light-dark cycle, by a web of interacting gene transcription feedback loops, tightly controlling gene expression with 24hr periodicity. Two transcription factors, CLOCK and BMAL1, activate gene expression of Per (Period) and Cry (Cryptochrome). The protein products of Per and Cry form a heterodimeric complex that translocates back into the nucleus and inhibits BMAL1 and CLOCK expression, forming a negative feedback loop. Superimposed upon this transcriptional loop are two nuclear hormone receptors, RORa and Rev-erba, which are ligand dependent transcription factors that have recently been deorphanized. The endogenous ligand for RAR-related orphan receptor alpha (RORa) has been identified as 7a-hydroxycholesterol while Rev-erba requires heme. Both receptors are constitutive, RORa as an activator and Rev-erba as a repressor, and they compete for the same binding elements near the transcription start sites of metabolically important genes. Here we describe synthetic ligands for RORa, co-crystal structures of these ligands bound to the ligand binding domain, and protein hydrogen deuterium exchange (HDX) studies of ligand binding. Using these compounds, we identified RORa target genes and demonstrated activity in vitro and in vivo.

Characterization of ligands targeting RAR-related orphan receptor alpha (RORa)

246th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.