A hydrophobic site on the GLP-1 receptor extracellular domain orients the peptide ligand for signal transduction.

ABSTRACT: Structure-function studies have analyzed substitutions within the glucagon-like peptide-1 (GLP-1) sequence that increase resistance to proteolysis, however, the investigation into how such substitutions alter interactions at the GLP-1 receptor (GLP-1R) has captured less attention. This work describes our efforts at identifying relevant interactions between peptide ligands and the GLP-1R extracellular domain that contribute to the positioning of the peptide N-terminus for receptor activation. Alanine substitutions at hydrophilic (Glu127? and Glu128?) and hydrophobic (Leu32?) GLP-1R residues were previously shown to differentially interact with GLP-1 and exendin-4. We examined if these receptor residues influence the activity of GLP-1- and exendin-4-based peptides containing either alanine or glycine at position 2. Additionally, a series of glucagon-based peptides were studied to determine how the central to C-terminal region affects activity. Our results suggest that peptide binding to the GLP-1R is largely driven by hydrophobic interactions with the extracellular domain that orient the N-terminus for activation.

SUBMITTER: Patterson JT 

PROVIDER: S-EPMC3817388 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature