Peptide interactions with G-protein coupled receptors

Abstract

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.

The Crystallographic Model of Rhodopsin and Its Use in Studies of Other G Protein–Coupled Receptors

“…Alignment of the amino acid sequences for these proteins is also complicated by variation in the lengths of the interhelical loops (84). In addition, the retinal binding pocket is completely buried in the protein and may make it an unsuitable model for the binding of ligands to most other GPCRs (69). If the dynamics of the protein permit occasional access to the binding site from the aqueous or membrane environment, this might not be an issue.…”

“…However, it is often difficult to assess the quality and relevance of molecular models. Concerns about the structures of the loops in rhodopsin have been expressed (21,69), as have questions about the validity of the rhodopsin structure as a general template for GPCRs (25,76,77).…”

The supramolecular structure of the GPCR rhodopsin in solution and native disc membranes

“…A dimeric or higher oligomeric functional form of rhodopsin is supported by the structural information available on G proteins and rhodopsin, and biophysical data that identify different interacting regions on the interface between these proteins [48]. In particular, the size of the G protein surface interacting with rhodopsin has been shown to be almost twice as large as the exposed cytoplasmic surface of a single rhodopsin molecule [49,50].…”

A Microdomain Formed by the Extracellular Ends of the Transmembrane Domains Promotes Activation of the G Protein-Coupled α-Factor Receptor

“…Interestingly, residues near the ends of transmembrane domains (TMDs) are often also functionally important. For example, residues at the extracellular ends of TMDs of GPCRs have been found to contribute to ligand binding (20,31), and residues near the intracellular ends have been implicated in G protein activation (5,53). Since GPCRs are comprised of a bundle of seven TMDs connected by extracellular and intracellular loops (36), the ends of the TMDs are likely to be in close spatial proximity, where they can contribute to receptor function.…”