7l1u Citations

Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation.

Abstract

Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX2R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX2R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX2R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.

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  1. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Wong TS, Li G, Li S, Gao W, Chen G, Gan S, Zhang M, Li H, Wu S, Du Y. Signal Transduct Target Ther 8 177 (2023)

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  1. Accelerating GPCR Drug Discovery With Conformation-Stabilizing VHHs. Laeremans T, Sands ZA, Claes P, De Blieck A, De Cesco S, Triest S, Busch A, Felix D, Kumar A, Jaakola VP, Menet C. Front Mol Biosci 9 863099 (2022)
  2. Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions. Couvineau A, Voisin T, Nicole P, Gratio V, Blais A. World J Gastroenterol 27 7582-7596 (2021)
  3. Characteristic structural difference between inactive and active states of orexin 2 receptor determined using molecular dynamics simulations. Yokoi S, Mitsutake A. Biophys Rev 14 221-231 (2022)
  4. Orexins/Hypocretins and Cancer: A Neuropeptide as Emerging Target. Alain C, Pascal N, Valérie G, Thierry V. Molecules 26 4849 (2021)
  5. Structural Insights into the Design of Synthetic Nanobody Libraries. Valdés-Tresanco MS, Molina-Zapata A, Pose AG, Moreno E. Molecules 27 2198 (2022)
  6. The Orexin receptors: Structural and anti-tumoral properties. Couvineau A, Nicole P, Gratio V, Voisin T. Front Endocrinol (Lausanne) 13 931970 (2022)
  7. Use of experimental medicine approaches for the development of novel psychiatric treatments based on orexin receptor modulation. Beckenstrom AC, Coloma PM, Dawson GR, Finlayson AK, Malik A, Post A, Steiner MA, Potenza MN. Neurosci Biobehav Rev 147 105107 (2023)

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