Molecular mechanism of the wake-promoting agent TAK-925.

ABSTRACT: 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

SUBMITTER: Yin J 

PROVIDER: S-EPMC9133036 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature