Locating ligand-binding sites in 7TM receptors by protein engineering

Over the past year, mutational analysis of peptide receptors has started to change our understanding of the interaction between G protein coupled receptors and their ligands, an area previously almost totally dominated by results from studies of monoamine receptors. A picture is currently emerging, in which small ligands appear to bind in three (more or less) overlapping ligand-binding pockets in between the transmembrane segments. In contrast, contact residues for peptide and protein ligands have mainly been found in exterior regions of peptide and protein receptors. It is also becoming increasingly clear that agonists and antagonists may interact in vastly different manners, even though they are competitive ligands for a common receptor.