The Human Orexin/Hypocretin Receptor Crystal Structures
The human orexin/hypocretin receptors (hOX1R and hOX2R) are G protein-coupled receptors (GPCRs) that mediate the diverse functions of the orexin/hypocretin neuropeptides. Orexins/hypocretins produced by neurons in the lateral hypothalamus stimulate their cognate GPCRs in multiple regions of the central nervous system to control sleep and arousal, circadian rhythms, metabolism, reward pathways, and other behaviors. Dysfunction of orexin/hypocretin signaling is associated with human disease, and the receptors are active targets in a number of therapeutic areas. To better understand the molecular mechanism of the orexin/hypocretin neuropeptides, high-resolution three-dimensional structures of hOX1R and hOX2R are critical. We have solved high-resolution crystal structures of both human orexin/hypocretin receptors bound to high-affinity antagonists. These atomic structures have elucidated how different small molecule antagonists bind with high potency and selectivity, and have also provided clues as to how the native ligands may associate with their receptors. The orexin/hypocretin receptor coordinates, now available to the broader academic and drug discovery community, will facilitate rational design of new therapeutics that modulate orexin/hypocretin signaling in humans.
KeywordsAntagonist Crystal structure GPCR High-resolution Hypocretin Orexin
- 33.Malherbe P, Roche O, Marcuz A et al (2010) Mapping the binding pocket of dual antagonist almorexant to human orexin 1 and orexin 2 receptors: comparison with the selective OX1 antagonist SB-674042 and the selective OX2 antagonist N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). Mol Pharmacol 78:81–93. doi: 10.1124/mol.110.064584CrossRefPubMedGoogle Scholar
- 41.Cox CD, Breslin MJ, Whitman DB et al (2010) Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J Med Chem 53:5320–5332. doi: 10.1021/jm100541cCrossRefPubMedGoogle Scholar
<SimplePara><Emphasis Type="Bold">Open Access</Emphasis> This chapter is licensed under the terms of the Creative Commons Attribution-NonCommercial 2.5 International License (http://creativecommons.org/licenses/by-nc/2.5/), which permits any noncommercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. </SimplePara> <SimplePara>The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.</SimplePara>