Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors

The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) regulate sleep and other behavioral functions in mammals, and are therapeutic targets for sleep and wake disorders. The human receptors hOX(1)R and hOX(2)R, which are 64% identical in sequence, have overlapping but distinct physiological functions and potential therapeutic profiles. We determined structures of hOX(1)R bound to the OX1R-selective antagonist SB-674042 and the dual antagonist suvorexant at 2.8-angstrom and 2.75-angstrom resolution, respectively, and used molecular modeling to illuminate mechanisms of antagonist subtype selectivity between hOX(1)R and hOX(2)R. The hOX(1)R structures also reveal a conserved amphipathic alpha-helix, in the extracellular N-terminal region, that interacts with orexin-A and is essential for high-potency neuropeptide activation at both receptors. The orexin-receptor crystal structures are valuable tools for the design and development of selective orexin-receptor antagonists and agonists.