title: 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.
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Patterson
authors.forename: Pengyun
authors.initials: P
authors.lastname: Li
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Day
authors.forename: Vasily M
authors.initials: VM
authors.lastname: Gelfanov
authors.forename: Richard D
authors.initials: RD
authors.lastname: Dimarchi
keywords: Exendin-4; GLP-1; GPCR; Glucagon; Receptor activation