McKern Neil M, Lawrence Michael C, Streltsov Victor A, Lou Mei-Zhen, Adams Timothy E, Lovrecz George O, Elleman Thomas C, Richards Kim M, Bentley John D, Pilling Patricia A, Hoyne Peter A, Cartledge Kellie A, Pham Tam M, Lewis Jennifer L, Sankovich Sonia E, Stoichevska Violet, Da Silva Elizabeth, Robinson Christine P, Frenkel Maurice J, Sparrow Lindsay G, Fernley Ross T, Epa V Chandana, Ward Colin W
CSIRO Molecular & Health Technologies, 343 Royal Parade, Parkville, Victoria 3052, Australia.
Nature. 2006 Sep 14;443(7108):218-21. doi: 10.1038/nature05106. Epub 2006 Sep 6.
The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding.
胰岛素受体是一种在进化上古老的酪氨酸激酶受体，在诸如刺胞动物和昆虫等原始生物中也能找到。在高等生物中，它对葡萄糖稳态至关重要，而与之密切相关的胰岛素样生长因子受体（IGF-1R）则参与正常的生长和发育。胰岛素受体以两种异构体IR-A和IR-B的形式表达；前者还作为IGF-II的高亲和力受体发挥作用，并且与IGF-1R一起参与恶性转化。在此，我们展示了与来自单克隆抗体83-7和83-14的四个Fab片段（参考文献4）复合的IR-A胞外域二聚体在3.8埃分辨率下的晶体结构，该结构是在一种胰岛素模拟肽片段存在的情况下生长得到的。该结构揭示了二硫键连接的胞外域二聚体中的结构域排列情况，表明胰岛素受体采用了一种折叠构象，使配体结合区域并列。这种排列与之前的模型有很大不同。它表明两个L1结构域位于二聚体的相对两侧，距离太远，无法像之前所提出的那样使胰岛素同时结合两个L1结构域。相反，该结构表明第一个III型纤连蛋白结构域的羧基末端表面是参与高亲和力结合的第二个结合位点。
