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

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 () and Ming-Wei Wang ()
Additional contact information
Fenghui Zhao: Fudan University
Qingtong Zhou: Fudan University
Zhaotong Cong: Fudan University
Kaini Hang: ShanghaiTech University
Xinyu Zou: Huazhong University of Science and Technology
Chao Zhang: ShanghaiTech University
Yan Chen: Fudan University
Antao Dai: The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Anyi Liang: Huazhong University of Science and Technology
Qianqian Ming: Zhejiang University School of Medicine
Mu Wang: ShanghaiTech University
Li-Nan Chen: Zhejiang University School of Medicine
Peiyu Xu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Rulve Chang: Fudan University
Wenbo Feng: Fudan University
Tian Xia: Huazhong University of Science and Technology
Yan Zhang: Zhejiang University School of Medicine
Beili Wu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Dehua Yang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Lihua Zhao: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
H. Eric Xu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Ming-Wei Wang: Fudan University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28683-0

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