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

Aslihan Shenol, Ricardo Tenente, Michael Lückmann, Thomas M. Frimurer and Thue W. Schwartz ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49536-y

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