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Updated: Sep 22, 2025
Polygraphic Recording Procedure for Measuring Sleep in Mice
Published on: January 25, 2016
Molecular mechanism of the wake-promoting agent TAK-925
Jie Yin1,2, Yanyong Kang3, Aaron P McGrath3
1Department of Biophysics, The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX, 75390, USA.
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.
Insights
The OX2 orexin receptor (OX2R) agonist TAK-925 selectively activates OX2R, offering a new therapeutic strategy for narcolepsy. Structural insights reveal its unique binding and activation mechanism, previously considered undruggable.
Area of Science:
- Neuroscience
- Structural Biology
- Pharmacology
Background:
- The OX2 orexin receptor (OX2R) regulates wakefulness and circadian rhythms.
- OX2R antagonism treats insomnia; agonism is a potential therapy for narcolepsy type 1.
- OX2R agonism was previously considered undruggable.
Purpose of the Study:
- To elucidate the structural mechanism of OX2R activation by the agonist TAK-925.
- To understand the selectivity of TAK-925 for OX2R over OX1R.
- To rationalize the G protein coupling selectivity of OX2R.
Main Methods:
- Cryo-electron microscopy of OX2R-G protein complexes.
- Determination of two distinct structures of TAK-925-bound OX2R.
- Mutagenesis studies to investigate receptor-ligand and receptor-G protein interactions.
Main Results:
- TAK-925 binds to OX2R at the antagonist site but triggers activation via transmembrane microswitches.
- Structural and mutagenesis data reveal TAK-925's subtype selectivity is due to subtle orthosteric pocket differences.
- Polarity of interactions at G protein interfaces explains OX2R's Gq signaling selectivity.
Conclusions:
- TAK-925 activates OX2R through a novel mechanism, overcoming the 'undruggable' barrier.
- Understanding TAK-925's binding and activation mechanism aids in developing agonists for narcolepsy and circadian disorders.
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