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Updated: Jun 23, 2025
07:41
A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
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Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode.
Aslihan Shenol1, Ricardo Tenente1, Michael Lückmann1
1Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Nature Communications
|June 25, 2024
Summary
Thirty novel 3D structures reveal the hydroxycarboxylic acid receptor 2 (HCAR2) allosteric mechanism. Agonists bound similarly, despite side effects, highlighting the need for further molecular dynamics studies.
Area of Science:
- Structural biology
- Pharmacology
- Biochemistry
Background:
- The hydroxycarboxylic acid receptor 2 (HCAR2) is a G protein-coupled receptor (GPCR) that senses beta-hydroxybutyrate, niacin, and certain anti-inflammatory drugs.
- Understanding the allosteric mechanisms of GPCRs is crucial for drug development.
- HCAR2 plays a role in metabolic and inflammatory processes.
Purpose of the Study:
- To elucidate the allosteric mechanism of HCAR2 activation by various agonists.
- To provide high-resolution 3D structures of HCAR2 in complex with different ligands.
- To investigate the structural basis for agonist binding and potential side effects.
Main Methods:
- X-ray crystallography was used to determine 30 novel 3D structures of HCAR2.
- Complexes were formed with eight orthosteric and one allosteric agonist.
- Structural analysis focused on the orthosteric binding site and receptor conformation.
Main Results:
- A clear picture of the allosteric mechanism connecting HCAR2 agonists to G protein binding was revealed.
- Agonists, both with and without on-target side effects, exhibited very similar binding modes.
- Ligand binding occurred within a completely occluded orthosteric binding site.
Conclusions:
- The structural data provides unprecedented insight into HCAR2 ligand binding and activation.
- Despite similar binding, the functional consequences (side effects) warrant further investigation.
- Molecular dynamics simulations are needed to fully understand the dynamic aspects of HCAR2 function.
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