期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-30601-3
关键词
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资金
- National Institutes of Health [R01NS097594, R35GM116387]
- Welch Foundation [I-1422, I-1770, I-1944]
- Edward Mallinckrodt, Jr. Foundation
- Julie and Louis Beecherl, Jr., Chair in Medical Science at The University of Texas Southwestern
- CPRIT Core Facility Support Award [RP170644]
The OX2 orexin receptor (OX2R) is a highly expressed GPCR in the brain that regulates wakefulness and circadian rhythms. This study investigates how the first clinically tested OX2R agonist TAK-925 can activate OX2R in a highly selective manner using cryo-electron microscopy.
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 mediated by subtle differences between OX1 and OX2 receptor subtypes at the orthosteric pocket. Finally, differences in the polarity of interactions at the G protein binding interfaces help to rationalize OX2R's coupling selectivity for G(q) signaling. The mechanisms of TAK-925's binding, activation, and selectivity presented herein will aid in understanding the efficacy of small molecule OX2R agonists for narcolepsy and other circadian disorders. The OX2 orexin receptor (OX2R) is a brain GPCR that regulates wakefulness and circadian rhythms in humans, and a potential drug target in insomnia and narcolepsy. Here, the authors use cryo-EM to determine how the first clinically tested OX2R agonist TAK-925 can activate OX2R in a selective manner.
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