Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation
| العنوان: | Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation |
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| المؤلفون: | Corey Strickland, Christina Minnick, Michael J. Breslin, Srivanya Tummala, Kaspar Hollenstein, Alexei Brooun, Vanessa L. Rada, Shawn J. Stachel, Beata Zamlynny, Kira A. Armacost, Dawn L. Hall, Li Xiao, Terrence P. McDonald, Chuan Hong, Kern Jeffrey, Scott A. Hollingsworth, Stephen M. Soisson, Julie A. O'Brien, Andrea T. Partridge, Jennifer M. Shipman, Michael T. Rudd, Noel Byrne |
| المصدر: | Nature Communications, Vol 12, Iss 1, Pp 1-11 (2021) Nature Communications |
| بيانات النشر: | Nature Portfolio, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Agonist, Protein Conformation, alpha-Helical, medicine.drug_class, Science, Genetic Vectors, General Physics and Astronomy, Aminopyridines, Gene Expression, Peptide, Plasma protein binding, Pharmacology, Molecular Dynamics Simulation, General Biochemistry, Genetics and Molecular Biology, Article, G protein-coupled receptors, Cryoelectron microscopy, Orexin Receptors, medicine, Escherichia coli, Humans, Protein Interaction Domains and Motifs, Cloning, Molecular, chemistry.chemical_classification, Sulfonamides, Multidisciplinary, Binding Sites, Chemistry, HEK 293 cells, digestive, oral, and skin physiology, General Chemistry, Azepines, Triazoles, medicine.disease, Small molecule, Orexin receptor, Recombinant Proteins, Orexin, HEK293 Cells, Sleep Aids, Pharmaceutical, Orexin Receptor Antagonists, Protein Conformation, beta-Strand, Peptides, Narcolepsy, Protein Binding |
| الوصف: | 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. Agonists of the orexin receptor 2 (OX2R) show promise in the treatment of narcolepsy. Cryo-EM structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist suggest a molecular mechanism that rationalizes both receptor activation and inhibition. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2e52de5a726dc2d15e8ae787fb1b0817 https://doaj.org/article/71020c0fdeec442e80fbd53a66967a19 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....2e52de5a726dc2d15e8ae787fb1b0817 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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