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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists
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Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists

机译：胰岛素受体中串联激素结合元件的结构拆分及其对肽激动剂设计的启示

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摘要

The C-terminal segment of the human insulin receptor α-chain (designated αCT) is critical to insulin binding as has been previously demonstrated by alanine scanning mutagenesis and photo-cross-linking. To date no information regarding the structure of this segment within the receptor has been available. We employ here the technique of thermal-factor sharpening to enhance the interpret-ability of the electron-density maps associated with the earlier crystal structure of the human insulin receptor ectodomain. The αCT segment is now resolved as being engaged with the central β-sheet of the first leucine-rich repeat (L1) domain of the receptor. The segment is α-helical in conformation and extends 11 residues N-terminal of the classical αCTsegment boundary originally defined by peptide mapping. This tandem structural element (αCT-L1) thus defines the intact primary insulin-binding surface of the apo-recep-tor. The structure, together with isothermal titration calorimetry data of mutant αCT peptides binding to an insulin minireceptor, leads to the conclusion that putative "insulin-mimetic" peptides in the literature act at least in part as mimics of the αCT segment as well as of insulin. Photo-cross-linking by novel bifunctional insulin derivatives demonstrates that the interaction of insulin with the αCT segment and the L1 domain occurs in trans, i.e., these components of the primary binding site are contributed by alternate α-chains within the insulin receptor homodimer. The tandem structural element defines a new target for the design of insulin agonists for the treatment of diabetes mellitus.
机译：如先前已通过丙氨酸扫描诱变和光交联所证明的，人胰岛素受体α链的C末端片段（称为αCT）对于胰岛素结合至关重要。迄今为止，还没有关于受体内该区段的结构的信息。我们在这里采用热因子锐化技术来增强与人胰岛素受体胞外域的早期晶体结构相关的电子密度图的解释能力。现在解析为与受体的第一个富含亮氨酸的重复序列（L1）结构域的中央β-折叠相结合的αCT片段。该片段是α-螺旋构象，并延伸了最初由肽谱图定义的经典αCT片段边界N端的11个残基。因此，该串联结构元件（αCT-L1）定义了载脂蛋白受体的完整初级胰岛素结合表面。该结构以及与胰岛素微受体结合的突变体αCT肽的等温滴定量热数据，得出以下结论：文献中推定的“模拟胰岛素”肽至少部分充当αCT节段和胰岛素的模拟物。新型双功能胰岛素衍生物的光交联表明，胰岛素与αCT节段和L1结构域的相互作用是反式发生的，即主要结合位点的这些成分是由胰岛素受体同二聚体中的其他α链贡献的。串联结构元件为设计用于治疗糖尿病的胰岛素激动剂定义了新的靶标。

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    Brian J. Smith; Kun Huang; Geoffrey Kong; Shu Jin Chan; Satoe Nakagawa; John G. Meriting; Shi-Quan Hu; Jonathan Whittaker; Donald F. Steiner; Panayotis G. Katsoyannis; Colin W. Ward; Michael A. Weiss; Michael C. Lawrence;

  • 作者单位

    The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia;

    Departments of Biochemistry, Case Western Reserve University, Cleveland, OH 44106;

    The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia;

    Department of Medicine, University of Chicago, Chicago, IL 60637;

    Department of Medicine, University of Chicago, Chicago, IL 60637;

    The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia;

    Departments of Biochemistry, Case Western Reserve University, Cleveland, OH 44106 Department of Pharmacology and Biological Chemistry, Mt. Sinai School of Medicine of New York University, New York, NY 10029;

    Departments of Biochemistry, Case Western Reserve University, Cleveland, OH 44106;

    Department of Medicine, University of Chicago, Chicago, IL 60637;

    Department of Pharmacology and Biological Chemistry, Mt. Sinai School of Medicine of New York University, New York, NY 10029;

    The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia;

    Departments of Biochemistry, Case Western Reserve University, Cleveland, OH 44106 Medicine, Case Western Reserve University, Cleveland, OH 44106;

    The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    diabetes; IGF-1 receptor; insulin binding; photo-cross-linking protein crystallography;

    机译：糖尿病;IGF-1受体;胰岛素结合光交联蛋白晶体学;

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