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

Author

Listed:
  • Joshua A. Lees

    (Medicine Design, Pfizer Inc.)

  • João M. Dias

    (Medicine Design, Pfizer Inc.)

  • Francis Rajamohan

    (Medicine Design, Pfizer Inc.)

  • Jean-Philippe Fortin

    (Internal Medicine Research Unit, Pfizer Inc.)

  • Rebecca O’Connor

    (Medicine Design, Pfizer Inc.)

  • Jimmy X. Kong

    (Internal Medicine Research Unit, Pfizer Inc.)

  • Emily A. G. Hughes

    (Internal Medicine Research Unit, Pfizer Inc.)

  • Ethan L. Fisher

    (Internal Medicine, Medicine Design, Pfizer Inc.)

  • Jamison B. Tuttle

    (Internal Medicine, Medicine Design, Pfizer Inc.)

  • Gabrielle Lovett

    (Internal Medicine, Medicine Design, Pfizer Inc.)

  • Bethany L. Kormos

    (Internal Medicine, Medicine Design, Pfizer Inc.)

  • Rayomand J. Unwalla

    (Internal Medicine, Medicine Design, Pfizer Inc.)

  • Lei Zhang

    (Internal Medicine, Medicine Design, Pfizer Inc.)

  • Anne-Marie Dechert Schmitt

    (Internal Medicine, Medicine Design, Pfizer Inc.)

  • Dahui Zhou

    (Internal Medicine, Medicine Design, Pfizer Inc.)

  • Michael Moran

    (Internal Medicine, Medicine Design, Pfizer Inc.)

  • Kimberly A. Stevens

    (Internal Medicine Research Unit, Pfizer Inc.)

  • Kimberly F. Fennell

    (Medicine Design, Pfizer Inc.)

  • Alison E. Varghese

    (Medicine Design, Pfizer Inc.)

  • Andrew Maxwell

    (Medicine Design, Pfizer Inc.)

  • Emmaline E. Cote

    (Medicine Design, Pfizer Inc.)

  • Yuan Zhang

    (Internal Medicine, Medicine Design, Pfizer Inc.)

  • Seungil Han

    (Medicine Design, Pfizer Inc.)

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.

Suggested Citation

  • 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. K, 2023. "An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41646-3
    DOI: 10.1038/s41467-023-41646-3
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