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Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

Author

Listed:
  • Zhaotong Cong

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

  • Li-Nan Chen

    (Zhejiang University School of Medicine)

  • Honglei Ma

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

  • Qingtong Zhou

    (Fudan University)

  • Xinyu Zou

    (Huazhong University of Science and Technology)

  • Chenyu Ye

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

  • Antao Dai

    (Chinese Academy of Sciences)

  • Qing Liu

    (Chinese Academy of Sciences)

  • Wei Huang

    (Qilu Regor Therapeutics, Inc.)

  • Xianqiang Sun

    (Qilu Regor Therapeutics, Inc.)

  • Xi Wang

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

  • Peiyu Xu

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

  • Lihua Zhao

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

  • Tian Xia

    (Huazhong University of Science and Technology)

  • Wenge Zhong

    (Qilu Regor Therapeutics, Inc.)

  • Dehua Yang

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

  • Yan Zhang

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine
    Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province
    Zhejiang University Medical Center)

  • Ming-Wei Wang

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

Abstract

The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.

Suggested Citation

  • Zhaotong Cong & Li-Nan Chen & Honglei Ma & Qingtong Zhou & Xinyu Zou & Chenyu Ye & Antao Dai & Qing Liu & Wei Huang & Xianqiang Sun & Xi Wang & Peiyu Xu & Lihua Zhao & Tian Xia & Wenge Zhong & Dehua Y, 2021. "Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24058-z
    DOI: 10.1038/s41467-021-24058-z
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    Cited by:

    1. 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.
    2. Yingna Xu & Wenbo Feng & Qingtong Zhou & Anyi Liang & Jie Li & Antao Dai & Fenghui Zhao & Jiahui Yan & Chuan-Wei Chen & Hao Li & Li-Hua Zhao & Tian Xia & Yi Jiang & H. Eric Xu & Dehua Yang & Ming-Wei , 2022. "A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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