IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-14934-5.html
   My bibliography  Save this article

Full-length human GLP-1 receptor structure without orthosteric ligands

Author

Listed:
  • Fan Wu

    (ShanghaiTech University
    ShanghaiTech University
    University of Chinese Academy of Sciences)

  • Linlin Yang

    (Zhengzhou University)

  • Kaini Hang

    (ShanghaiTech University
    ShanghaiTech University
    University of Chinese Academy of Sciences)

  • Mette Laursen

    (Novo Nordisk A/S, Novo Nordisk Park)

  • Lijie Wu

    (ShanghaiTech University)

  • Gye Won Han

    (University of Southern California)

  • Qiansheng Ren

    (Novo Nordisk Research Center)

  • Nikolaj Kulahin Roed

    (Novo Nordisk A/S, Novo Nordisk Park)

  • Guangyao Lin

    (ShanghaiTech University
    University of Chinese Academy of Sciences)

  • Michael A. Hanson

    (GPCR Consortium)

  • Hualiang Jiang

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

  • Ming-Wei Wang

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

  • Steffen Reedtz-Runge

    (Novo Nordisk A/S, Novo Nordisk Park)

  • Gaojie Song

    (East China Normal University)

  • Raymond C. Stevens

    (ShanghaiTech University
    ShanghaiTech University
    University of Southern California)

Abstract

Glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that plays an important role in glucose homeostasis and treatment of type 2 diabetes. Structures of full-length class B receptors were determined in complex with their orthosteric agonist peptides, however, little is known about their extracellular domain (ECD) conformations in the absence of orthosteric ligands, which has limited our understanding of their activation mechanism. Here, we report the 3.2 Å resolution, peptide-free crystal structure of the full-length human GLP-1R in an inactive state, which reveals a unique closed conformation of the ECD. Disulfide cross-linking validates the physiological relevance of the closed conformation, while electron microscopy (EM) and molecular dynamic (MD) simulations suggest a large degree of conformational dynamics of ECD that is necessary for binding GLP-1. Our inactive structure represents a snapshot of the peptide-free GLP-1R and provides insights into the activation pathway of this receptor family.

Suggested Citation

  • Fan Wu & Linlin Yang & Kaini Hang & Mette Laursen & Lijie Wu & Gye Won Han & Qiansheng Ren & Nikolaj Kulahin Roed & Guangyao Lin & Michael A. Hanson & Hualiang Jiang & Ming-Wei Wang & Steffen Reedtz-R, 2020. "Full-length human GLP-1 receptor structure without orthosteric ligands," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14934-5
    DOI: 10.1038/s41467-020-14934-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-14934-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-14934-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.
    3. Xiuwen Zhai & Chunyou Mao & Qingya Shen & Shaokun Zang & Dan-Dan Shen & Huibing Zhang & Zhaohong Chen & Gang Wang & Changming Zhang & Yan Zhang & Zhihong Liu, 2022. "Molecular insights into the distinct signaling duration for the peptide-induced PTH1R activation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14934-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.