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.
MeSH terms
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Aminopyridines / chemistry*
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Aminopyridines / metabolism
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Azepines / chemistry*
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Azepines / metabolism
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Binding Sites
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Cloning, Molecular
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Cryoelectron Microscopy
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Gene Expression
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Genetic Vectors / chemistry
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Genetic Vectors / metabolism
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HEK293 Cells
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Humans
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Molecular Dynamics Simulation
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Orexin Receptor Antagonists / chemistry*
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Orexin Receptor Antagonists / metabolism
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Orexin Receptors / agonists
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Orexin Receptors / chemistry*
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Orexin Receptors / metabolism
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Peptides / chemistry*
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Peptides / metabolism
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sleep Aids, Pharmaceutical / chemistry*
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Sleep Aids, Pharmaceutical / metabolism
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Sulfonamides / chemistry*
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Sulfonamides / metabolism
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Triazoles / chemistry*
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Triazoles / metabolism
Substances
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Aminopyridines
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Azepines
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HCRTR2 protein, human
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N-ethyl-2-((6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)amino)-N-pyridin-3-ylmethyl-acetamide
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Orexin Receptor Antagonists
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Orexin Receptors
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Peptides
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Recombinant Proteins
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Sleep Aids, Pharmaceutical
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Sulfonamides
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Triazoles
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suvorexant