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Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode

Author

Listed:
  • Aslihan Shenol

    (University of Copenhagen)

  • Ricardo Tenente

    (University of Copenhagen)

  • Michael Lückmann

    (University of Copenhagen)

  • Thomas M. Frimurer

    (University of Copenhagen)

  • Thue W. Schwartz

    (University of Copenhagen)

Abstract

A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with G protein binding—and back – is revealed by a puzzle of thirty novel 3D structures of the hydroxycarboxylic acid receptor 2 (HCAR2) in complex with eight different orthosteric and a single allosteric agonist. HCAR2 is a sensor of β-hydroxybutyrate, niacin and certain anti-inflammatory drugs. Surprisingly, agonists with and without on-target side effects bound very similarly and in a completely occluded orthosteric binding site. Thus, despite the many structures we are still left with a pertinent need to understand the molecular dynamics of this and similar systems.

Suggested Citation

  • Aslihan Shenol & Ricardo Tenente & Michael Lückmann & Thomas M. Frimurer & Thue W. Schwartz, 2024. "Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49536-y
    DOI: 10.1038/s41467-024-49536-y
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