An inverse agonist of orphan receptor GPR61 reveals a novel allosteric mechanism

• Published in: bioRxiv
• Main Authors: Lees, Joshua A., Dias, João M., Rajamohan, Francis, Fortin, Jean-Philippe, O’Connor, Rebecca, Kong, Jimmy X., Hughes, Emily, Fisher, Ethan L., Tuttle, Jamison B., Lovett, Gabrielle, Kormos, Bethany L., Unwalla, Rayomand J., Zhang, Lei, Schmidt, Anne-Marie Dechert, Zhou, Dahui, Stevens, Kimberly A., Fennell, Kimberly F., Varghese, Alison E., Maxwell, Andrew, Cote, Emmaline E., Zhang, Yuan, Han, Seungil
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Laboratory 01.05.2023
• Edition: 1.1
• Subjects: Biophysics
• ISSN: 2692-8205
• DOI: 10.1101/2023.05.01.538732

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.