The orexin receptors (OX1R and OX2R) are targets in the brain for peptides (orexins) which are released by the hypothalamus. The binding of orexins to their receptor generates cellular signals that, depending on which subtype is bound, regulate sleep, eating, stress, and other factors that influence behavior. Disruption of these signaling pathways with selective inhibitors might reveal new insights and potential treatments for sleep disorders, obesity, and addiction.
Daniel Rosenbaum, Merck Research Laboratories, West Point, PA, USA, and colleagues have determined a set of crystal structures of OX1R bound to small-molecule ligands. A previous crystallographic study on OX2R had failed to reveal the basis for the selectivity between OX1R and OX2R. The researchers combined crystallography with molecular modeling to look at the cause of this selectivity. They found similarities in the binding mode of ligands to both OX1R and OX2R, but also subtle differences in the size of the binding pocket.
The OX1R structures revealed that the N-terminus, which sits outside of the cell, is helical and plays a role in encouraging the natural orexin peptides to bind to their receptors. Although previously unseen in OX2R, this region is common to both subtypes. These results are a step forward in understanding how drugs might be better designed to tune sleep and other behavioral functions in humans.
- Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors,
Jie Yin, Kerim Babaoglu, Chad A. Brautigam, Lindsay Clark, Zhenhua Shao, Thomas H. Scheuermann, Charles M. Harrell, Anthony L. Gotter, Anthony J. Roecker, Christopher J. Winrow, John J. Renger, Paul J. Coleman, Daniel M. Rosenbaum,
Nat. Struct. Mol. Biol. 2016, 23, 293–299.