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

  • Nat Commun. 2023 Sep 23;14(1):5938. doi: 10.1038/s41467-023-41646-3.
Joshua A Lees  #  1 ,  João M Dias  #  1 ,  Francis Rajamohan  1 ,  Jean-Philippe Fortin  2 ,  Rebecca O'Connor  1 ,  Jimmy X Kong  2 ,  Emily A G Hughes  2 ,  Ethan L Fisher  3 ,  Jamison B Tuttle  4 ,  Gabrielle Lovett  4 ,  Bethany L Kormos  4 ,  Rayomand J Unwalla  4 ,  Lei Zhang  4 ,  Anne-Marie Dechert Schmitt  3 ,  Dahui Zhou  3 ,  Michael Moran  3 ,  Kimberly A Stevens  2 ,  Kimberly F Fennell  1 ,  Alison E Varghese  1 ,  Andrew Maxwell  1 ,  Emmaline E Cote  1 ,  Yuan Zhang  4 ,  Seungil Han  5
Affiliations
  • 1. Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • 2. Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, USA.
  • 3. Internal Medicine, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • 4. Internal Medicine, Medicine Design, Pfizer Inc., Cambridge, MA, USA.
  • 5. Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA. [email protected].
  • # Contributed equally.
PMID: 37741852 DOI: 10.1038/s41467-023-41646-3
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.

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