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The signalling conformation of the insulin receptor ectodomain

Author

Listed:
  • Felix Weis

    (Structural and Computational Biology Unit)

  • John G. Menting

    (The Walter and Eliza Hall Institute of Medical Research)

  • Mai B. Margetts

    (The Walter and Eliza Hall Institute of Medical Research)

  • Shu Jin Chan

    (University of Chicago
    6515 North Knox Avenue)

  • Yibin Xu

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Norbert Tennagels

    (TA Diabetes and Integrated Drug Discovery)

  • Paulus Wohlfart

    (TA Diabetes and Integrated Drug Discovery)

  • Thomas Langer

    (TA Diabetes and Integrated Drug Discovery)

  • Christoph W. Müller

    (Structural and Computational Biology Unit)

  • Matthias K. Dreyer

    (TA Diabetes and Integrated Drug Discovery)

  • Michael C. Lawrence

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

Abstract

Understanding the structural biology of the insulin receptor and how it signals is of key importance in the development of insulin analogs to treat diabetes. We report here a cryo-electron microscopy structure of a single insulin bound to a physiologically relevant, high-affinity version of the receptor ectodomain, the latter generated through attachment of C-terminal leucine zipper elements to overcome the conformational flexibility associated with ectodomain truncation. The resolution of the cryo-electron microscopy maps is 3.2 Å in the insulin-binding region and 4.2 Å in the membrane-proximal region. The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin’s negative cooperativity of binding likely arises. Our structure further provides insight into the high affinity of certain super-mitogenic insulins. Together, these findings provide a new platform for insulin analog investigation and design.

Suggested Citation

  • Felix Weis & John G. Menting & Mai B. Margetts & Shu Jin Chan & Yibin Xu & Norbert Tennagels & Paulus Wohlfart & Thomas Langer & Christoph W. Müller & Matthias K. Dreyer & Michael C. Lawrence, 2018. "The signalling conformation of the insulin receptor ectodomain," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06826-6
    DOI: 10.1038/s41467-018-06826-6
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    Cited by:

    1. Junhee Park & Jie Li & John P. Mayer & Kerri A. Ball & Jiayi Wu & Catherine Hall & Domenico Accili & Michael H. B. Stowell & Xiao-chen Bai & Eunhee Choi, 2022. "Activation of the insulin receptor by an insulin mimetic peptide," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Nicholas S. Kirk & Qi Chen & Yingzhe Ginger Wu & Anastasia L. Asante & Haitao Hu & Juan F. Espinosa & Francisco Martínez-Olid & Mai B. Margetts & Faiz A. Mohammed & Vladislav V. Kiselyov & David G. Ba, 2022. "Activation of the human insulin receptor by non-insulin-related peptides," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Junhong Kim & Na-Oh Yunn & Mangeun Park & Jihan Kim & Seongeun Park & Yoojoong Kim & Jeongeun Noh & Sung Ho Ryu & Yunje Cho, 2022. "Functional selectivity of insulin receptor revealed by aptamer-trapped receptor structures," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Francois Moreau & Nicholas S. Kirk & Fa Zhang & Vasily Gelfanov & Edward O. List & Martina Chrudinová & Hari Venugopal & Michael C. Lawrence & Veronica Jimenez & Fatima Bosch & John J. Kopchick & Rich, 2022. "Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Cristina M. Viola & Orsolya Frittmann & Huw T. Jenkins & Talha Shafi & Pierre Meyts & Andrzej M. Brzozowski, 2023. "Structural conservation of insulin/IGF signalling axis at the insulin receptors level in Drosophila and humans," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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