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

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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. © 2013 Elsevier GmbH.

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Patterson, J. T., Li, P., Day, J. W., Gelfanov, V. M., & DiMarchi, R. D. (2013). A hydrophobic site on the GLP-1 receptor extracellular domain orients the peptide ligand for signal transduction. Molecular Metabolism, 2(2), 86–91. https://doi.org/10.1016/j.molmet.2013.01.003

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