2. Academic Validation
  3. An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism

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

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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