Peptide interactions with G‐protein coupled receptors

Peptide recognition by G‐protein coupled receptors (GPCRs) is reviewed with an emphasis on the indirect approach used to determine the receptor‐bound conformation of peptide ligands. This approach was developed in response to the lack of detailed structural information available for these receptors. Recent advances in the structural determination of rhodopsin (the GPCR of the visual system) by crystallography have provided a scaffold for homology modeling of the inactive state of a wide variety of GPCRs that interact with peptide messages. Additionally, the ability to mutate GPCRs and assay compounds of similar chemical structure to test a common binding site on the receptor provides a firm experimental basis for structure–activity studies. Recognition motifs, common in other well‐studied systems such as proteolytic enzymes and major histocompatibility class receptors (MHC) are reviewed briefly to provide a basis of comparison. Finally, the development of true peptidomimetics is contrasted with nonpeptide ligands, discovered through combinatorial chemistry. In many systems, the evidence suggests that the peptide ligands bind at the interface between the transmembrane segments and the extracellular loops, while nonpeptide antagonists bind within the transmembrane segments. Plausible models of GPCRs and the mechanism by which they activate G‐proteins on binding peptides are beginning to emerge. © 2001 John Wiley & Sons, Inc. Biopolymers (Pept Sci) 60: 246–277, 2001