Molecular mechanism of the wake-promoting agent TAK-925
Jie Yin, Yanyong Kang, Aaron P. McGrath, Karen Chapman, Megan Sjodt, Eiji Kimura, Atsutoshi Okabe, Tatsuki Koike, Yuhei Miyanohana, Yūji Shimizu, Rameshu Rallabandi, Peng Lian, Xiao‐chen Bai, Mack Flinspach, Jef K. De Brabander, Daniel M. Rosenbaum
Abstract
Abstract The OX 2 orexin receptor (OX 2 R) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OX 2 R is a proven therapeutic strategy for insomnia drugs, and agonism of OX 2 R is a potentially powerful approach for narcolepsy type 1, which is characterized by the death of orexinergic neurons. Until recently, agonism of OX 2 R had been considered ‘undruggable.’ We harness cryo-electron microscopy of OX 2 R-G protein complexes to determine how the first clinically tested OX 2 R agonist TAK-925 can activate OX 2 R in a highly selective manner. Two structures of TAK-925-bound OX 2 R 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 OX 1 and OX 2 receptor subtypes at the orthosteric pocket. Finally, differences in the polarity of interactions at the G protein binding interfaces help to rationalize OX 2 R’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 OX 2 R agonists for narcolepsy and other circadian disorders.