Orexin and Orexin receptor

From Proteopedia

Contents 1 Function 2 Disease 3 Relevance 4 Structural highlights Function The orexin neuropeptides, Orexin-A and Orexin-B, can excite neurons in the brain and affect multiple systems, including the acetylcholine, dopamine, histamine, and norepinephrine systems [1][2][3]. These orexin neuropeptides bind to two subtypes of orexin receptors, Orexin receptor 1 and Orexin receptor 2, both of which are G protein-coupled receptors (GPCRs) [4]. The GPCRs can sense a molecule outside the cell and send a signal through transduction in order to cause the cells to respond [5]. Thus, binding of the two can control wakefulness in humans. In studies, Orexin-B has shown to be more selective in binding, choosing to bind to Orexin receptor type 2 a majority of the time. Orexin-A has shown an equal selectivity at both types of receptors [1]. See also Hypocretin and receptors Transmembrane (cell surface) receptors Disease Defects in orexin signaling are responsible for the human diseases of narcolepsy and insomnia[6]. Relevance Belsomra or Suvorexant is a dual orexin receptor antagonist, and has the ability to block both Orexin receptors 1 and 2, thus inhibiting the neuropeptides from binding. By blocking this interaction, sleep can occur [7]. Structural highlights The suvorexant-binding pocket is open to the extracellular space through a constricted solvent-accessible channel. A complex network of electrostatic interactions includes salt bridges between the protein and the drug, on both sides of the entry channel[8]. See also: Receptor Transmembrane (cell surface) receptors G protein-coupled receptors

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3D Structures of orexin and orexin receptor

Updated on 20-August-2023

Orexin

1wso, 1r02 – hOrx-A – human - NMR

1cq0 – hOrx-B - NMR

1uvq – hOrx-B + antibody

Orexin receptor

6tod – hOrxR-1 (mutant) + EMPA

6tos, 6tq6, 6tq7 – hOrxR-1 (mutant) + pyridine derivative

6tp4 – hOrxR-1 (mutant) + pyrrolydine derivative

6tq4 – hOrxR-1 (mutant) + benzoxazole derivative

6tq9 – hOrxR-1 (mutant) + quinoline derivative

6tot, 6to7, 6tp3, 6tp6 – hOrxR-1 (mutant) + insomnia drug

4s0v – hOrxR-1/glycogen synthase + insomnia drug

4zj8, 4zjc, 5wqc, 5ws3, 6tpg, 6v9s – hOrxR-1/glycogen synthase + antagonist

7xrr – hOrxR-2 + insomnia drug

7sqoj, 7sr8 – hOrxR-2 + Gi + nanobody + wake-promoting drug – Cryo EM

6tpj – hOrxR-2/glycogen synthase (mutant) + insomnia drug

6tpn – hOrxR-2/glycogen synthase + antagonist

7l1u, 7l1v – mOrxR-2 + G protein + nanobody + agonist – Cryo EM

References

1. ↑ ^{1.0 1.1} Krystal AD, Benca RM, Kilduff TS. Understanding the sleep-wake cycle: sleep, insomnia, and the orexin system. J Clin Psychiatry. 2013;74 Suppl 1:3-20. doi: 10.4088/JCP.13011su1c. PMID:24107804 doi:http://dx.doi.org/10.4088/JCP.13011su1c
2. ↑ Kim HY, Hong E, Kim JI, Lee W. Solution structure of human orexin-A: regulator of appetite and wakefulness. J Biochem Mol Biol. 2004 Sep 30;37(5):565-73. PMID:15479620
3. ↑ Lee JH, Bang E, Chae KJ, Kim JY, Lee DW, Lee W. Solution structure of a new hypothalamic neuropeptide, human hypocretin-2/orexin-B. Eur J Biochem. 1999 Dec;266(3):831-9. PMID:10583376
4. ↑ 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. Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. Nat Struct Mol Biol. 2016 Apr;23(4):293-9. doi: 10.1038/nsmb.3183. Epub 2016 Mar , 7. PMID:26950369 doi:http://dx.doi.org/10.1038/nsmb.3183
5. ↑ Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998 Feb 20;92(4):573-85. PMID:9491897
6. ↑ Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, Lines C, Roth T, Michelson D. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology. 2012 Dec 4;79(23):2265-74. doi: 10.1212/WNL.0b013e31827688ee. Epub, 2012 Nov 28. PMID:23197752 doi:http://dx.doi.org/10.1212/WNL.0b013e31827688ee
7. ↑ Norman JL, Anderson SL. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia - critical appraisal of suvorexant. Nat Sci Sleep. 2016 Jul 14;8:239-47. doi: 10.2147/NSS.S76910. eCollection 2016. PMID:27471419 doi:http://dx.doi.org/10.2147/NSS.S76910
8. ↑ Yin J, Mobarec JC, Kolb P, Rosenbaum DM. Crystal structure of the human OX orexin receptor bound to the insomnia drug suvorexant. Nature. 2014 Dec 22. doi: 10.1038/nature14035. PMID:25533960 doi:http://dx.doi.org/10.1038/nature14035