Overview

Orexin receptors are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or... [read more] orexin precursor, by proteolytic cleavage and some typical peptide modifications [1]. Currently the only orexin receptor ligands in clinical use are suvorexant and lemborexant, which are used as hypnotics. Orexin receptor crystal structures have been solved [2,3,4,5,6].

References

1. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998;92:573-85.
2. Yin J, Mobarec JC, Kolb P, et al. Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant. Nature 2015;519:247-50.
3. Yin J, Babaoglu K, Brautigam CA, et al. Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. Nat Struct Mol Biol 2016;23:293-9.
4. Hong C, Byrne NJ, Zamlynny B, et al. Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation. Nat Commun 2021;12:815.
5. Suno R, Kimura KT, Nakane T, et al. Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA. Structure 2018;26:7-19.e5.
6. Hellmann J, Drabek M, Yin J, et al. Structure-based development of a subtype-selective orexin 1 receptor antagonist. Proc Natl Acad Sci U S A 2020;117:18059-18067.

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