Abstract
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 OX 1 R-selective antagonist SB-674042 and the dual antagonist suvorexant at 2.8-Å and 2.75-Å 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 α-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.
Original language | English (US) |
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Pages (from-to) | 293-299 |
Number of pages | 7 |
Journal | Nature Structural and Molecular Biology |
Volume | 23 |
Issue number | 4 |
DOIs | |
State | Published - Apr 5 2016 |
ASJC Scopus subject areas
- Structural Biology
- Molecular Biology