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

Article · Fenghui Zhao, Qingtong Zhou, Zhaotong Cong, Kaini Hang, Xinyu Zou, Chao Zhang, Yan Chen, Antao Dai, Anyi Liang, Qianqian Ming, Mu Wang, Li-Nan Chen, Peiyu Xu, Rulve Chang, Wenbo Feng, Tian Xia, Yan Zhang, Beili Wu, Dehua Yang, Lihua Zhao, H. Eric Xu, Ming‐Wei Wang

- Archive id: doi:10.1038/s41467-022-28683-0
- Published: 2022-02-25
- Venue: Nature Communications
- DOI: https://doi.org/10.1038/s41467-022-28683-0
- PMID: 35217653
- PMCID: PMC8881610
- Citations: 149
- Source URL: https://doi.org/10.1038/s41467-022-28683-0
- PDF: https://www.nature.com/articles/s41467-022-28683-0.pdf
- Provenance: openalex+europepmc

## Abstract

Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20.

_Abstract reproduced under CC-BY (publisher license, via OpenAlex)._

Topics: [GLP-1 & Incretin Therapies](https://space-kitty.com/topics/glp1-metabolic)

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