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- W3126819640 abstract "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 (OX 2 R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX 2 R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX 2 R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX 2 R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX 2 R 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." @default.
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- W3126819640 date "2021-02-05" @default.
- W3126819640 modified "2023-10-11" @default.
- W3126819640 title "Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation" @default.
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- W3126819640 doi "https://doi.org/10.1038/s41467-021-21087-6" @default.
- W3126819640 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7864924" @default.
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- W3126819640 hasPublicationYear "2021" @default.
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