The importance of ligands for G protein-coupled receptor stability.

ABSTRACT

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.