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

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.