Xu Yibin, Kirk Nicholas S, Venugopal Hariprasad, Margetts Mai B, Croll Tristan I, Sandow Jarrod J, Webb Andrew I, Delaine Carlie A, Forbes Briony E, Lawrence Michael C
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3050, Australia.
Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, VIC 3800, Australia.
Structure. 2020 Jul 7;28(7):786-798.e6. doi: 10.1016/j.str.2020.05.002. Epub 2020 May 26.
Human type 1 insulin-like growth factor receptor (IGF-1R) signals chiefly in response to the binding of insulin-like growth factor I. Relatively little is known about the role of insulin-like growth factor II signaling via IGF-1R, despite the affinity of insulin-like growth factor II for IGF-1R being within an order of magnitude of that of insulin-like growth factor I. Here, we describe the cryoelectron microscopy structure of insulin-like growth factor II bound to a leucine-zipper-stabilized IGF-1R ectodomain, determined in two conformations to a maximum average resolution of 3.2 Å. The two conformations differ in the relative separation of their respective points of membrane entry, and comparison with the structure of insulin-like growth factor I bound to IGF-1R reveals long-suspected differences in the way in which the critical C domain of the respective growth factors interact with IGF-1R.
人类1型胰岛素样生长因子受体（IGF-1R）主要在胰岛素样生长因子I结合时发出信号。尽管胰岛素样生长因子II对IGF-1R的亲和力与胰岛素样生长因子I的亲和力处于同一数量级，但关于胰岛素样生长因子II通过IGF-1R发出信号的作用却知之甚少。在此，我们描述了与亮氨酸拉链稳定的IGF-1R胞外域结合的胰岛素样生长因子II的冷冻电子显微镜结构，该结构以两种构象确定，最大平均分辨率为3.2 Å。这两种构象在它们各自进入膜的点的相对间距上有所不同，并且与结合到IGF-1R的胰岛素样生长因子I的结构进行比较，揭示了长期以来人们所怀疑的各个生长因子的关键C结构域与IGF-1R相互作用方式的差异。
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