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

By Yibin Xu, G.K.-W. Kong, J. Menting, M. Margetts, C. Delaine, Lauren M. Jenkin, V. Kiselyov, P. De Meyts, B. Forbes, M. Lawrence. 2018

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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.The human type 1 insulin-like growth factor receptor (IGF-1R) is important for normal human growth and development. Here, the authors present the crystal structures of the IGF-1R ectodomain both in its apo form and in complex with its ligand insulin-like growth factor I and discuss the receptor activation mechanism.

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology