Molecular basis of peptide activation of the GLP-1 receptor.

Abstract

Understanding the molecular basis of agonist ligand binding and activation of a receptor provides important insights that can be useful in the design of more effective drugs. It is now appreciated that agonists of the glucagon-like peptide-1 (GLP-1) receptor provide a highly useful class of drugs for the management of type 2 diabetes mellitus [1]. In this issue of Molecular Metabolism, Patterson et al. [2] examine the function of a series of structurally-related peptide ligands, based on the structures of GLP-1, exendin-4, and glucagon, and chimeric variants of each, at the GLP-1 receptor and at receptor mutants representing alanine replacements for key residues believed to be important for the differential action of GLP-1 and its exendin-4 analog. Exendin-4 has a longer half-life than GLP-1, attributed to its having a different residue in position two (Gly rather than Ala), known to make it more resistant to the proteolytic action of dipeptidyl peptidaseIV [3]. The amino-terminally truncated antagonist, exendin-4(9-39), has been shown in a co-crystal structure with the isolated receptor amino terminus to be in close contact with hydrophilic receptor residues Glu127 and Glu128 and hydrophobic residue Leu32 [4], while these residues were not in contact with the agonist peptide, GLP-1, in an analogous structure [5]. By studying the action of this series of peptides at these receptor constructs, the authors have been able to demonstrate the interdependence of ligand–receptor interactions involving the peptide mid-region and the peptide amino terminus. They have also clearly demonstrated the relative importance of the hydrophobic interactions between the helical portion in the middle of the peptide ligand and the peptide-binding cleft within the receptor amino terminus to direct the peptide amino terminus toward its site of action. This extends the prevailing ‘‘two domain’’ hypothesis for this family of receptors [6], emphasizing that both sets of interactions must work in tandem for optimal receptor activation. Natural agonist ligands for the class B1 group of G protein-coupled receptors (GPCRs) all represent moderate length peptides having diffuse pharmacophoric domains, with a tendency to form alpha helical conformations in their mid-regions and carboxyl-terminal regions [7]. Truncations, mutations, and chimeric analysis of these peptides have established that their carboxyl-terminal regions are important for binding affinity, while their amino-terminal regions are most important for their biological activity [8]. Receptor mutagenesis, chimeric receptor studies, and photoaffinity labeling studies have complemented these structure-activity series to suggest that the carboxyl-terminal regions of these peptides interact with the amino-terminal domains of their

DOI: 10.1016/j.molmet.2013.02.003

Cite this paper

@article{Miller2013MolecularBO, title={Molecular basis of peptide activation of the GLP-1 receptor.}, author={Laurence J. Miller}, journal={Molecular metabolism}, year={2013}, volume={2 2}, pages={60-1} }