The\nG Protein-First Mechanism for Activation of the\nClass B Glucagon-like Peptide 1 Receptor Coupled to N‑Terminal\nDomain-Mediated Conformational Progression

Recently, there has been a great\ndeal of excitement about new glucagon-like\npeptide 1 receptor (GLP-1R) agonists (e.g., semaglutide and tirzepatide)\nthat have received FDA approval for type 2 diabetes and obesity. Although\neffective, these drugs come with side effects that limit their use.\nWhile research efforts continue to focus intensively on long-lasting,\norally administered GLP-1R medications with fewer side effects, a\nmajor impediment to developing improved GLP-1R medications is that\nthe mechanism by which an agonist activates GLP-1R to imitate signaling\nis not known. Here we present and validate the G protein (GP)-first\nmechanism for the GLP-1R supported by extensive atomistic simulations.\nWe propose that GLP-1R is preactivated through the formation of a\nGLP-1R–GP precoupled complex at the cell membrane prior to\nligand binding. Despite a transmembrane helix 6 (TM6)-bentout conformation\ncharacteristic of activated GLP-1R, this precoupled complex remains\nunactivated until an agonist binds to elicit signaling. Notably, this\nnew hypothesis offers a unified and predictive model for the activities\nof a series of full and partial agonists, including the peptides ExP5,\nGLP-1(7-36), and GLP-1(9-36). Most surprisingly, our simulations reveal\nan N-terminus domain (NTD)-swing/agonist-insertion mechanism wherein\nthe long extracellular NTD of GLP-1R tightly holds the C-terminal\nhalf of the peptide agonist and progressively shifts the N-terminal\nhead of the peptide to facilitate insertion into the orthosteric pocket.\nOur findings provide novel mechanistic insights into the activation\nand function of class B GPCRs and should provide a realistic basis\nfor structure-based ligand design.