Structure and Molecular Mechanism of Signaling for the Glucagon-like Peptide‑1 Receptor Bound to Gs Protein and Exendin-P5 Biased Agonist

The glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of blood glucose and a prime target for the treatment of type II diabetes and obesity with multiple public drugs. Here we present a comprehensive computational analysis of the interactions of the activated GLP-1R–Gs signaling complex with a G protein biased agonist, Exendin P5 (ExP5), which possesses a unique N-terminal sequence responsible for the signal bias. Using a refined all-atom model of the ExP5–GLP-1R–Gs complex in molecular dynamics (MD) simulations, we propose a novel mechanism of conformation transduction in which the unique interaction network of ExP5 N-terminus propagates the binding signal across an array of conserved residues at the transmembrane domain to enhance Gs protein coupling at the cytoplasmic end of the receptor. Our simulations reveal previously unobserved interactions important for activation by ExP5 toward GDP-GTP signaling, providing new insights into the mechanism of class B G protein-coupled receptor (GPCR) signaling. These findings offer a framework for the structure-based design of more effective therapeutics.