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

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.