Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24

Significance Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious in the treatment of type 2 diabetes and obesity. While most clinically used agents require subcutaneous injection, Boc5, as the first orthosteric nonpeptidic agonist of GLP-1R, suffers from poor oral bioavailability that hinders its therapeutic development. The cryoelectron microscopy structures of Boc5 and its closely related analog WB4-24 presented here reveal a binding pocket located deeper in the transmembrane domain for nonpeptidic GLP-1R agonists. Molecular interaction with this site may facilitate a broad spectrum of in vivo agonistic activities, in addition to that with the upper helical bundles presumably responsible for biased signaling. These findings deepen our understanding of peptidomimetic agonism at GLP-1R and may help design better drug leads against this important target.