7SQO

Structure of the orexin-2 receptor(OX2R) bound to TAK-925, Gi and scFv16

7SQO の概要

• エントリーDOI: 10.2210/pdb7sqo/pdb
• EMDBエントリー: 25389
• 分子名称: Orexin receptor type 2, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (7 entities in total)
• 機能のキーワード: class a gpcr, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 165739.63

構造登録者

McGrath, A.P.,Kang, Y.,Flinspach, M. (登録日: 2021-11-05, 公開日: 2022-05-25, 最終更新日: 2024-11-06)

主引用文献

Yin, J.,Kang, Y.,McGrath, A.P.,Chapman, K.,Sjodt, M.,Kimura, E.,Okabe, A.,Koike, T.,Miyanohana, Y.,Shimizu, Y.,Rallabandi, R.,Lian, P.,Bai, X.,Flinspach, M.,De Brabander, J.K.,Rosenbaum, D.M.
Molecular mechanism of the wake-promoting agent TAK-925.
Nat Commun, 13:2902-2902, 2022

PubMed Abstract: The OX orexin receptor (OXR) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OXR is a proven therapeutic strategy for insomnia drugs, and agonism of OXR is a potentially powerful approach for narcolepsy type 1, which is characterized by the death of orexinergic neurons. Until recently, agonism of OXR had been considered 'undruggable.' We harness cryo-electron microscopy of OXR-G protein complexes to determine how the first clinically tested OXR agonist TAK-925 can activate OXR in a highly selective manner. Two structures of TAK-925-bound OXR with either a G mimetic or G 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 and OX receptor subtypes at the orthosteric pocket. Finally, differences in the polarity of interactions at the G protein binding interfaces help to rationalize OXR's coupling selectivity for G signaling. The mechanisms of TAK-925's binding, activation, and selectivity presented herein will aid in understanding the efficacy of small molecule OXR agonists for narcolepsy and other circadian disorders.

PubMed: 35614071
DOI: 10.1038/s41467-022-30601-3

実験手法

ELECTRON MICROSCOPY (3.17 Å)