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, Yuji Shimizu, Rameshu Rallabandi, Peng Lian, Xiaochen Bai, Mack Flinspach (), Jef K. Brabander () and Daniel M. Rosenbaum ()
Additional contact information
Jie Yin: The University of Texas Southwestern Medical Center
Yanyong Kang: Takeda Development Center Americas, Inc
Aaron P. McGrath: Takeda Development Center Americas, Inc
Karen Chapman: The University of Texas Southwestern Medical Center
Megan Sjodt: Takeda Development Center Americas, Inc
Eiji Kimura: Takeda Pharmaceutical Company Ltd.
Atsutoshi Okabe: Takeda Pharmaceutical Company Ltd.
Tatsuki Koike: Takeda Pharmaceutical Company Ltd.
Yuhei Miyanohana: Takeda Pharmaceutical Company Ltd.
Yuji Shimizu: Takeda Pharmaceutical Company Ltd.
Rameshu Rallabandi: The University of Texas Southwestern Medical Center
Peng Lian: The University of Texas Southwestern Medical Center
Xiaochen Bai: The University of Texas Southwestern Medical Center
Mack Flinspach: Takeda Development Center Americas, Inc
Jef K. Brabander: The University of Texas Southwestern Medical Center
Daniel M. Rosenbaum: The University of Texas Southwestern Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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 Gq mimetic or Gi 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 Gq 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.

Date: 2022
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DOI: 10.1038/s41467-022-30601-3

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