How Peptide Hormones Activate Their Receptors: The Science Behind GLP-1 and Multi-Agonist Drugs

Class B1 GPCRs use an evolutionarily conserved two-step activation mechanism: the C-terminus of the peptide ligand binds to an extracellular hydrophobic groove, then the N-terminus engages a large transmembrane pocket. This mechanism is shared across GLP-1, GIP, and glucagon receptors, which has enabled engineering of multifunctional agonists (like tirzepatide for GLP-1/GIP and emerging triple agonists for GLP-1/GIP/glucagon). Cryo-EM structures reveal how these polypharmacologic ligands interact with multiple receptors simultaneously.

Comprehensive review combining receptor pharmacology, signal transduction analysis, receptor trafficking studies, and comparative structural biology using high-resolution cryo-EM structures of receptors in complex with native ligands and engineered multifunctional agonists.

Understanding exactly how peptide hormones activate their receptors at the structural level is what makes it possible to design multi-agonist drugs. This knowledge underpins the entire new generation of obesity and diabetes treatments — from semaglutide (single GLP-1 target) to tirzepatide (dual GLP-1/GIP) to retatrutide (triple GLP-1/GIP/glucagon).

The ability to engineer one drug molecule that activates multiple peptide hormone receptors is arguably the biggest pharmacological advance of the last decade. This review provides the structural and mechanistic foundation explaining why it works.

Review article — no new experimental data. Structural analysis from cryo-EM provides snapshots but may not capture the full dynamics of receptor activation. The field is evolving rapidly, and newer multi-agonists may have features not covered here.