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How ligand binds to the type 1 insulin-like growth factor receptor

Author

Listed:
  • Yibin Xu

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

  • Geoffrey K.-W. Kong

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

  • John G. Menting

    (The Walter and Eliza Hall Institute of Medical Research)

  • Mai B. Margetts

    (The Walter and Eliza Hall Institute of Medical Research)

  • Carlie A. Delaine

    (Flinders University of South Australia)

  • Lauren M. Jenkin

    (The Walter and Eliza Hall Institute of Medical Research)

  • Vladislav V. Kiselyov

    (Eli Lilly and Company)

  • Pierre De Meyts

    (de Duve Institute
    Novo Nordisk A/S
    De Meyts R&D Consulting)

  • Briony E. Forbes

    (Flinders University of South Australia)

  • Michael C. Lawrence

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

Abstract

Human type 1 insulin-like growth factor receptor is a homodimeric receptor tyrosine kinase that signals into pathways directing normal cellular growth, differentiation and proliferation, with aberrant signalling implicated in cancer. Insulin-like growth factor binding is understood to relax conformational restraints within the homodimer, initiating transphosphorylation of the tyrosine kinase domains. However, no three-dimensional structures exist for the receptor ectodomain to inform atomic-level understanding of these events. Here, we present crystal structures of the ectodomain in apo form and in complex with insulin-like growth factor I, the latter obtained by crystal soaking. These structures not only provide a wealth of detail of the growth factor interaction with the receptor’s primary ligand-binding site but also indicate that ligand binding separates receptor domains by a mechanism of induced fit. Our findings are of importance to the design of agents targeting IGF-1R and its partner protein, the human insulin receptor.

Suggested Citation

  • Yibin Xu & Geoffrey K.-W. Kong & John G. Menting & Mai B. Margetts & Carlie A. Delaine & Lauren M. Jenkin & Vladislav V. Kiselyov & Pierre De Meyts & Briony E. Forbes & Michael C. Lawrence, 2018. "How ligand binds to the type 1 insulin-like growth factor receptor," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03219-7
    DOI: 10.1038/s41467-018-03219-7
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    Cited by:

    1. 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.
    2. 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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