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Nat Struct Mol Biol. 2016 Apr;23(4):293-9. doi: 10.1038/nsmb.3183. Epub 2016 Mar 7.

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

Author information

1
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
2
Department of Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
3
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, USA.
4
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.

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 hOX1R and hOX2R, which are 64% identical in sequence, have overlapping but distinct physiological functions and potential therapeutic profiles. We determined structures of hOX1R bound to the OX1R-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 hOX1R and hOX2R. The hOX1R 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.

Comment in

PMID:
26950369
DOI:
10.1038/nsmb.3183
[Indexed for MEDLINE]

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