Scientists Reveal How Tirzepatide Activates Two Hormone Receptors at Once — and Why Triple Agonists Could Be Even Better | Research

The takeaway

Near-atomic cryo-EM structures show how tirzepatide simultaneously activates both GIP and GLP-1 receptors, and reveal that adding glucagon receptor activity (triple agonism) may unlock even greater metabolic benefits.

5 cryo-EM structures
reveal the molecular blueprint for how tirzepatide and a triple agonist peptide simultaneously activate 2-3 different metabolic hormone receptors

What the researchers found

Cryo-EM structures revealed how tirzepatide (dual GIP/GLP-1 agonist) and peptide 20 (triple GIP/GLP-1/glucagon agonist) achieve their multiplexed receptor activation. The structures showed both common and unique binding features at near-atomic resolution, explaining how a single peptide can effectively activate two or three different receptors. Key finding: retention of glucagon receptor function is required for the triple agonist to achieve advantages over GLP-1 monotherapy alone.

Why it matters

Tirzepatide is producing unprecedented weight loss and metabolic improvements in clinical trials, but how one peptide activates two different receptors was unclear. These structures provide the molecular blueprint for designing even better multi-targeting peptide drugs — and reveal that triple agonism (adding glucagon activity) may be the next frontier beyond tirzepatide.

The numbers in context

5 cryo-EM structures solved · tirzepatide at GIPR + GLP-1R · peptide 20 at GIPR + GLP-1R + GCGR · near-atomic resolution

How the study worked

Cryo-electron microscopy was used to determine five receptor-peptide complex structures: tirzepatide bound to GIPR and GLP-1R, and peptide 20 bound to GIPR, GLP-1R, and GCGR. Structural analysis identified key binding interactions, conformational changes, and receptor-specific contacts that explain dual and triple agonism. Comparisons were made to monoagonist semaglutide's binding mode.

Who was studied

Structural biology study — no subjects; cryo-EM structures of purified receptor-peptide complexes

What this study cannot tell us

Structural biology study — structures represent snapshots of receptor-peptide complexes that may not capture the full dynamic signaling process. The clinical implications of specific structural features are inferred rather than directly demonstrated. Peptide 20 is a research compound, not yet in clinical development. Structures were determined in detergent/nanodisc conditions that differ from native cell membranes.

How to read the evidence

Published in Nature Communications, this is high-quality structural biology providing near-atomic resolution insights. While it doesn't directly measure clinical outcomes, it explains the molecular basis of tirzepatide's clinical success and guides future drug design.

When this study was published

Published in 2022, these structures were determined as tirzepatide was in late-stage clinical trials. The findings have since informed the development of triple agonist peptides and next-generation multi-receptor drugs now entering clinical testing.

The bigger picture

Multi-receptor peptide agonists represent the cutting edge of metabolic drug design. Tirzepatide's dual agonism has already produced clinical results superior to semaglutide, and this structural work shows why: the peptide adopts different binding conformations at each receptor. The revelation that triple agonism (adding glucagon) provides additional benefits has catalyzed development of several triple agonist peptides now entering clinical trials. These structures are essentially the instruction manual for designing the next generation of metabolic peptide drugs.

Questions still open

Can the structural insights guide the design of even more potent dual or triple agonist peptides with optimized receptor selectivity?
Would oral formulations of multi-receptor peptide agonists be possible based on understanding the key binding residues?
How do the structural differences between tirzepatide's GIP and GLP-1 receptor binding explain the clinical observation of reduced GI side effects compared to pure GLP-1 agonists?

Common questions

How can one peptide activate two or three different receptors?

The cryo-EM structures show that tirzepatide and peptide 20 adopt slightly different shapes (conformations) when binding to each receptor. Certain amino acids in the peptide make contacts specific to one receptor while others interact with both. It's like a master key that has different parts engaging with different locks — the same key, but using different teeth for each door.

Why might a triple agonist (GIP + GLP-1 + glucagon) be better than tirzepatide's dual approach?

Glucagon boosts energy expenditure and fat burning, effects that GIP and GLP-1 don't fully provide. Adding glucagon activity creates a three-pronged attack on metabolic disease: GLP-1 reduces appetite, GIP enhances insulin and may reduce nausea, and glucagon increases calorie burning. The structural data shows this triple activity is achievable in a single peptide molecule.

Read the original research

Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors.

Nature communications, 13(1), 1057

View on PubMed ↗Publisher’s paper ↗

Citation

Zhao, Fenghui; Zhou, Qingtong; Cong, Zhaotong; Hang, Kaini; Zou, Xinyu; Zhang, Chao; Chen, Yan; Dai, Antao; Liang, Anyi; Ming, Qianqian; Wang, Mu; Chen, Li-Nan; Xu, Peiyu; Chang, Rulve; Feng, Wenbo; Xia, Tian; Zhang, Yan; Wu, Beili; Yang, Dehua; Zhao, Lihua; Xu, H Eric; Wang, Ming-Wei. (2022). Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors.. Nature communications, 13(1), 1057. https://doi.org/10.1038/s41467-022-28683-0