A comprehensive review of class B1 GPCR receptors explains how GLP-1, GIP, and glucagon bind their targets, and how this understanding enabled engineering of multi-agonist drugs like tirzepatide.
15 class B1 GPCRsThis receptor family coordinates key metabolic processes and has become the most important drug target family for diabetes and obesity treatment
What the researchers found
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.
Why it matters
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 numbers in context
15 members in the class B1 GPCR subfamily. Includes receptors for GLP-1, GIP, glucagon, and other metabolic hormones.
How the study worked
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.
Who was studied
Review of class B1 GPCR pharmacology and drug development
What this study cannot tell us
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.
How to read the evidence
Rated moderate: comprehensive review synthesizing structural biology, pharmacology, and clinical drug development. No new data but provides essential mechanistic context.
When this study was published
Published in 2024. Includes the latest cryo-EM structural data and covers the newest multi-agonist drugs in development.
The bigger picture
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.
Questions still open
- Could four-receptor agonists targeting even more class B1 GPCRs be engineered?
- Do different multifunctional agonists activate the same downstream signaling pathways?
- Can receptor trafficking differences explain why some multi-agonists work better than others?
Common questions
How do GLP-1 drugs work at the receptor level?
How can one drug activate multiple hormone receptors?
Read the original research
Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease.
American journal of physiology. Endocrinology and metabolism, 327(5), E600-E615
Citation
Sangwung, Panjamaporn; Ho, Joseph D; Siddall, Tessa; Lin, Jerry; Tomas, Alejandra; Jones, Ben; Sloop, Kyle W. (2024). Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease.. American journal of physiology. Endocrinology and metabolism, 327(5), E600-E615. https://doi.org/10.1152/ajpendo.00371.2023