title: Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors.
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.
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Kerim
authors.initials: K
authors.lastname: Babaoglu
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Brautigam
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Clark
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Scheuermann
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Harrell
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Roecker
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Rosenbaum
mesh_terms: D001381:Azepines / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology*; D064446:Orexin Receptors / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011759:Pyrrolidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D001381:Azepines; D008024:Ligands; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D011759:Pyrrolidines; C492260:SB674042; D013844:Thiazoles; D014230:Triazoles; C551624:suvorexant