Nature Communications (Sep 2023)

An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism

  • Joshua A. Lees,
  • João M. Dias,
  • Francis Rajamohan,
  • Jean-Philippe Fortin,
  • Rebecca O’Connor,
  • Jimmy X. Kong,
  • Emily A. G. Hughes,
  • Ethan L. Fisher,
  • Jamison B. Tuttle,
  • Gabrielle Lovett,
  • Bethany L. Kormos,
  • Rayomand J. Unwalla,
  • Lei Zhang,
  • Anne-Marie Dechert Schmitt,
  • Dahui Zhou,
  • Michael Moran,
  • Kimberly A. Stevens,
  • Kimberly F. Fennell,
  • Alison E. Varghese,
  • Andrew Maxwell,
  • Emmaline E. Cote,
  • Yuan Zhang,
  • Seungil Han

DOI
https://doi.org/10.1038/s41467-023-41646-3
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 12

Abstract

Read online

Abstract 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.