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

Nat Commun. 2024 Jun 25;15(1):5364. doi: 10.1038/s41467-024-49536-y.

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.

Publication types

  • Review

MeSH terms

  • 3-Hydroxybutyric Acid / chemistry
  • 3-Hydroxybutyric Acid / metabolism
  • Allosteric Regulation
  • Binding Sites
  • GTP-Binding Proteins* / metabolism
  • Humans
  • Ligands
  • Molecular Dynamics Simulation
  • Niacin / chemistry
  • Niacin / metabolism
  • Protein Binding*
  • Receptors, G-Protein-Coupled* / agonists
  • Receptors, G-Protein-Coupled* / chemistry
  • Receptors, G-Protein-Coupled* / metabolism

Substances

  • Ligands
  • Receptors, G-Protein-Coupled
  • GTP-Binding Proteins
  • HCAR2 protein, human
  • Niacin
  • 3-Hydroxybutyric Acid