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

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 and Michael C. Lawrence ()
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Yibin Xu: The Walter and Eliza Hall Institute of Medical Research
Geoffrey K.-W. Kong: The Walter and Eliza Hall Institute of Medical Research
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
Briony E. Forbes: Flinders University of South Australia
Michael C. Lawrence: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03219-7

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