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The OX₂ orexin receptor (OX₂R) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OX₂R is a proven therapeutic strategy for insomnia drugs, and agonism of OX₂R is a potentially powerful approach for narcolepsy type 1, which is characterized by the death of orexinergic neurons. Until recently, agonism of OX₂R had been considered ‘undruggable.’ We harness cryo-electron microscopy of OX₂R-G protein complexes to determine how the first clinically tested OX₂R agonist TAK-925 can activate OX₂R in a highly selective manner. Two structures of TAK-925-bound OX₂R with either a G_q mimetic or G_i reveal that TAK-925 binds at the same site occupied by antagonists, yet interacts with the transmembrane helices to trigger activating microswitches. Our structural and mutagenesis data show that TAK-925’s selectivity is …