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The Glucagon-like Peptide-1 Receptor (GLP-1R) has a wide range of physiological functions and is a well-established therapeutic target for metabolic diseases. Despite recent progress in elucidating the structure of the GLP-1R, a full mechanistic understanding of how various peptides create dramatic variations in G protein-mediated signalling is still absent. To investigate the mechanism and implications of GLP-1R binding to four peptide agonists, we used cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis, and pharmacological experiments. These findings show that differences in peptide N-terminal contacts and dynamics with the GLP-1R transmembrane domain are linked to variances in G protein allosteric coupling.
