The importance of ligands for G protein-coupled receptor stability

• Ligands stabilize GPCRs and affect their function.
• A case study on the A2A adenosine receptor and ligand influences.
• Ligand-induced receptor stabilization plays role in successful GPCR crystallography.

Traditionally, G protein-coupled receptor (GPCR) activity has been characterized by ligand properties including affinity (Ki), potency (IC50/EC50), efficacy (Emax), and kinetics (Kon/Koff). These properties are related to ligand residence time, a general index of drug–target interaction in vivo. Recent GPCR structure–function breakthroughs have all required ligand stabilization of the receptor in some manner, highlighting the natural instability of these important cell surface receptors. This research has initiated a new era of discovery that highlights the importance of ligand–receptor interactions beyond the traditional mindset. We propose that receptor stability is related to receptor folding and residence in the cell membrane, affording a new dimension that should be considered when studying receptor function.