Nature communications · 2023
An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism.
СтатьяНазвание и аннотация: Перевод в очереди
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Lees Joshua A, Dias João M, Rajamohan Francis, Fortin Jean-Philippe, O'Connor Rebecca, Kong Jimmy X, Hughes Emily A G, Fisher Ethan L, Tuttle Jamison B, Lovett Gabrielle, Kormos Bethany L, Unwalla Rayomand J, Zhang Lei, Dechert Schmitt Anne-Marie, Zhou Dahui, Moran Michael, Stevens Kimberly A, Fennell Kimberly F, Varghese Alison E, Maxwell Andrew, Cote Emmaline E, Zhang Yuan, Han Seungil
Аннотация
GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation.