The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
Department of Medical Biology, University of Melbourne, Royal Parade, Parkville, VIC, 3050, Australia.
Nat Commun. 2018 Feb 26;9(1):821. doi: 10.1038/s41467-018-03219-7.
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.
人源 1 型胰岛素样生长因子受体是一种同二聚体受体酪氨酸激酶，可将信号传递至指导正常细胞生长、分化和增殖的途径，异常信号与癌症有关。胰岛素样生长因子结合被认为可放松同二聚体中的构象约束，从而启动酪氨酸激酶结构域的转磷酸化。然而，目前尚不存在受体胞外结构域的三维结构，无法从原子水平了解这些事件。在此，我们展示了apo 形式和与胰岛素样生长因子 I 复合物形式的胞外结构域的晶体结构，后者通过晶体浸泡获得。这些结构不仅提供了大量关于生长因子与受体主要配体结合位点相互作用的细节，还表明配体结合通过诱导契合机制将受体结构域分开。我们的发现对于靶向 IGF-1R 及其伴侣蛋白人胰岛素受体的药物设计具有重要意义。
