How ligand binds to the type 1 insulin-like growth factor receptor
AuthorXu, Y; Kong, GK-W; Menting, JG; Margetts, MB; Delaine, CA; Jenkin, LM; Kiselyov, VV; De Meyts, P; Forbes, BE; Lawrence, MC
Source TitleNature Communications
PublisherNATURE PUBLISHING GROUP
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsXu, Y., Kong, G. K. -W., Menting, J. G., Margetts, M. B., Delaine, C. A., Jenkin, L. M., Kiselyov, V. V., De Meyts, P., Forbes, B. E. & Lawrence, M. C. (2018). How ligand binds to the type 1 insulin-like growth factor receptor. NATURE COMMUNICATIONS, 9 (1), https://doi.org/10.1038/s41467-018-03219-7.
Access StatusOpen Access
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.
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