一个国际研究小组在最新一期《自然》杂志上报告说,他们发现了人体内胰岛素发挥作用的分子机制。这意味着,医药行业将有望研制出更有效和更方便的糖尿病药物,以替代每日注射胰岛素的现有疗法。
胰岛素控制葡萄糖在体内的水平,在Ⅰ型糖尿病患者体内胰腺不能产生胰岛素,从而导致高血糖,需要每天注射补充胰岛素,而Ⅱ型糖尿病患者细胞不能对胰岛素作出适当反应。
澳大利亚墨尔本沃尔特·伊丽莎研究所的一个研究小组与来自美国、英国和捷克的研究人员合作进行了这项研究,他们揭示了胰岛素分子如何与人体细胞的蛋白质结合,这是医学研究者近20年来一直试图破解的问题。
研究小组发现,胰岛素受体是细胞表面的一种大蛋白质,胰岛素与这种蛋白质分子结合,对细胞从血液中摄取糖分作为能源非常必要。研究团队的主要负责人之一迈克·劳伦斯说,他们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,也有助于未来设计新药物。理解胰岛素与其受体蛋白如何互相作用对开发新药物具有奠基性意义。
澳大利亚大约有100万糖尿病患者,每年的新增患者则有10万人。这一研究发现对于那些每日注射胰岛素的患者是个福音。(生物谷Bioon.com)
doi:10.1038/nature11781
PMC:
PMID:
How insulin engages its primary binding site on the insulin receptor
John G. Menting, Jonathan Whittaker, Mai B. Margetts, Linda J. Whittaker, Geoffrey K.-W. Kong, Brian J. Smith, Christopher J. Watson, Lenka Žáková, Emília Kletvíková, Jiří Jiráček,Shu Jin Chan, Donald F. Steiner, Guy G. Dodson, Andrzej M. Brzozowski, Michael A. Weiss,Colin W. Ward & Michael C. Lawrence
Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival1, 2. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer’s disease3; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R)4. 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 kinases5. 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.