Structure of the insulin receptor ectodomain reveals a folded-over conformation
Structure of the insulin receptor ectodomain reveals a folded-over conformation
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DOI：
10.1038/nature05106
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发表时间：
2006-09-14
期刊：
影响因子：
64.8
通讯作者：
Ward, Colin W.
中科院分区：
文献类型：
--
作者：
McKern, Neil M.;Lawrence, Michael C.;Ward, Colin W.
胰岛素受体是一种古老的酪氨酸激酶受体，发现于原始生物如蛇类和昆虫中。在高等生物体中，胰岛素样生长因子受体(IGF-1R)是维持葡萄糖稳态所必需的(1)，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(2)。胰岛素受体以IR-A和IR-B两种异构体表达，前者也是IGF-II的高亲和力受体，与IGF-1R一起参与恶性转化(3)。在这里，我们提出了3.8埃分辨率的IR-A胞外结构域二聚体的晶体结构，它与来自单抗83-7和83-14的四个Fabs络合(参考文献1)。4)，在胰岛素模拟肽片段(5)的存在下生长。该结构揭示了二硫键连接的胞外结构域二聚体中的结构域排列，表明胰岛素受体采用折叠构象，将配体结合区放置在并列位置。这种安排与以前的模式有很大的不同(6)。研究表明，这两个L1结构域位于二聚体的相反两侧，相距太远，无法让胰岛素像先前提出的那样同时结合两个L1结构域(7)。相反，该结构意味着第一个纤维连接蛋白III型结构域的羧基末端表面是参与高亲和力结合的第二结合位点。
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(1), whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development(2). 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(3). Here we present the crystal structure at 3.8 angstrom 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(5). 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(6). 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(7). 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.