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 journalArticle

54 Citations (Scopus)

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.

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

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Orexin Receptors
Ligands
Neuropeptides
Mammals
Sleep
Therapeutics
Orexins

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. / Yin, Jie; Babaoglu, Kerim; Brautigam, Chad A; Clark, Lindsay; Shao, Zhenhua; Scheuermann, Thomas H.; Harrell, Charles M.; Gotter, Anthony L.; Roecker, Anthony J.; Winrow, Christopher J.; Renger, John J.; Coleman, Paul J.; Rosenbaum, Daniel M.

In: Nature Structural and Molecular Biology, 07.03.2016.

Research output: Contribution to journalArticle

Yin, J, Babaoglu, K, Brautigam, CA, Clark, L, Shao, Z, Scheuermann, TH, Harrell, CM, Gotter, AL, Roecker, AJ, Winrow, CJ, Renger, JJ, Coleman, PJ & Rosenbaum, DM 2016, 'Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors', Nature Structural and Molecular Biology. https://doi.org/10.1038/nsmb.3183
Yin, Jie ; Babaoglu, Kerim ; Brautigam, Chad A ; Clark, Lindsay ; Shao, Zhenhua ; Scheuermann, Thomas H. ; Harrell, Charles M. ; Gotter, Anthony L. ; Roecker, Anthony J. ; Winrow, Christopher J. ; Renger, John J. ; Coleman, Paul J. ; Rosenbaum, Daniel M. / Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. In: Nature Structural and Molecular Biology. 2016.
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