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

  • Nat Struct Mol Biol. 2016 Apr;23(4):293-9. doi: 10.1038/nsmb.3183.
Jie Yin  1 ,  Kerim Babaoglu  2 ,  Chad A Brautigam  1 ,  Lindsay Clark  1 ,  Zhenhua Shao  1 ,  Thomas H Scheuermann  1 ,  Charles M Harrell  3 ,  Anthony L Gotter  3 ,  Anthony J Roecker  4 ,  Christopher J Winrow  3 ,  John J Renger  3 ,  Paul J Coleman  4 ,  Daniel M Rosenbaum  1
Affiliations
  • 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.
PMID: 26950369 DOI: 10.1038/nsmb.3183
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.