| Autor: |
Joshua A. Lees, João M. Dias, Francis Rajamohan, Jean-Philippe Fortin, Rebecca O’Connor, Jimmy X. Kong, Emily Hughes, Ethan L. Fisher, Jamison B. Tuttle, Gabrielle Lovett, Bethany L. Kormos, Rayomand J. Unwalla, Lei Zhang, Anne-Marie Dechert Schmidt, Dahui Zhou, Kimberly A. Stevens, Kimberly F. Fennell, Alison E. Varghese, Andrew Maxwell, Emmaline E. Cote, Yuan Zhang, Seungil Han |
| Rok vydání: |
2023 |
| DOI: |
10.1101/2023.05.01.538732 |
| Popis: |
GPR61 is a biogenic amine receptor-related orphan GPCR associated with phenotypes relating to appetite and thus, is of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study its structure and function. Here, we report the first ever 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 unprecedented allosteric site and mode of action. These findings offer key mechanistic insights into an orphan GPCR, while providing both a new structural framework and tool compound to support further studies of GPR61 function and modulation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
