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

Jie Yin, Kerim Babaoglu, Chad A Brautigam, Lindsay Clark, Zhenhua Shao, Thomas H. Scheuermann, Charles M. Harrell, Anthony L. Gotter, Anthony J. Roecker, Christopher J. Winrow, John J. Renger, Paul J. Coleman, Daniel M Rosenbaum

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


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.

Original languageEnglish (US)
JournalNature Structural and Molecular Biology
StateAccepted/In press - Mar 7 2016

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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