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

Author

Listed:
  • Fenghui Zhao

    (Fudan University
    Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • 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
    ShanghaiTech University
    University of Chinese Academy of Sciences)

  • Dehua Yang

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Research Center for Deepsea Bioresources)

  • Lihua Zhao

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • H. Eric Xu

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Ming-Wei Wang

    (Fudan University
    Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Fudan University
    ShanghaiTech University)

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.

Suggested Citation

  • 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 & T, 2022. "Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28683-0
    DOI: 10.1038/s41467-022-28683-0
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    1. Yan Chen & Qingtong Zhou & Jiang Wang & Youwei Xu & Yun Wang & Jiahui Yan & Yibing Wang & Qi Zhu & Fenghui Zhao & Chenghao Li & Chuan-Wei Chen & Xiaoqing Cai & Ross A .D. Bathgate & Chun Shen & H. Eri, 2023. "Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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