nature20130110-8

澳大利亚、美国、英国和捷克等国组成的国际研究小组具有里程碑意义地发现了人体内胰岛素发挥作用的分子机制,并首次获得了胰岛素及其受体相结合的三维图像。这项研究完善了对胰岛素作用机制的认识,改善了胰岛素治疗1型和2型糖尿病,也有助于未来设计新药物。

-2013年1月10日版《自然》

中文翻译


【译文】胰岛素如何与胰岛素受体上的主要结合位点结合

【译文】胰岛素受体信号在哺乳动物生物学中扮演核心较色,如调控细胞代谢、生长、分裂、分化和生存。胰岛素耐受有助于2型糖尿病的发病以及阿尔茨海默症的起始;异常信号发生在多种癌症中,通过与同源的1型胰岛素样生长因子受体(IGF1R)之间的信号交叉而加剧。尽管已有超过三十年的研究,但胰岛素-胰岛素受体复合物的三维结构还很难被解析,主要障碍是产生的受体蛋白的复杂性。在结合至截短的胰岛素受体的4种胰岛素晶体结构的基础上,本研究首次报道了胰岛素与其在胰岛素受体上的主要结合位点的相互作用。胰岛素与胰岛素受体的第一富含亮氨酸结构域之间的相互作用似乎很少见,而激素取而代之出现了胰岛素受体羧基端α链(αCT)片段,胰岛素结合时,该片段自己在L1表面上改型。L1与胰岛素之间的联系受到胰岛素B链残基的限制。αCT片段将B链C末端β链移至远离激素核心,揭示了胰岛素与其受体衔接时长期以来一直探讨的构象开关的机制。激素-受体识别的这种模式在受体酪氨酸激酶广泛家族中是全新的。将这种相互作用置于全受体的条件下光交联反应数据和解析了激素-胰岛素受体界面的等温滴定热量测定数据支持这些我们的发现。总之,我们的发现为胰岛素受体和与治疗性胰岛素类似物设计相关的IGF1R系统中生化数据的丰富提供了一种解释。

英文原稿


[Title]: How insulin engages its primary binding site on the insulin receptor

[Authors]:John G. Menting,1, 8 Jonathan Whittaker,2, 8 Mai B. Margetts,1 Linda J. Whittaker,2 Geoffrey K.-W. Kong,1 Brian J. Smith,1, 3 Christopher J. Watson,4 Lenka Žáková,5 Emília Kletvíková,5 Jiří Jiráček,5 Shu Jin Chan,6 Donald F. Steiner,6 Guy G. Dodson,4, 9 Andrzej M. Brzozowski,4 Michael A. Weiss,2 Colin W. Ward1 & Michael C. Lawrence1, 7

[Abstract]Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer’s disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin–insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal α-chain (αCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The αCT segment displaces the B-chain C-terminal β-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone–receptor recognition is novel within the broader family of receptor tyrosine kinases. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone–insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues.

原文地址

http://www.nature.com/nature/journal/v493/n7431/full/nature11781.html

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