一個國際研究小組在最新一期《自然》雜志上報(bào)告說,，他們發(fā)現(xiàn)了人體內(nèi)胰島素發(fā)揮作用的分子機(jī)制,。這意味著,，醫(yī)藥行業(yè)將有望研制出更有效和更方便的糖尿病藥物，以替代每日注射胰島素的現(xiàn)有療法,。
胰島素控制葡萄糖在體內(nèi)的水平,，在Ⅰ型糖尿病患者體內(nèi)胰腺不能產(chǎn)生胰島素，從而導(dǎo)致高血糖,，需要每天注射補(bǔ)充胰島素,，而Ⅱ型糖尿病患者細(xì)胞不能對胰島素作出適當(dāng)反應(yīng)。
澳大利亞墨爾本沃爾特·伊麗莎研究所的一個研究小組與來自美國,、英國和捷克的研究人員合作進(jìn)行了這項(xiàng)研究,，他們揭示了胰島素分子如何與人體細(xì)胞的蛋白質(zhì)結(jié)合,，這是醫(yī)學(xué)研究者近20年來一直試圖破解的問題,。
研究小組發(fā)現(xiàn)，胰島素受體是細(xì)胞表面的一種大蛋白質(zhì),，胰島素與這種蛋白質(zhì)分子結(jié)合,，對細(xì)胞從血液中攝取糖分作為能源非常必要。研究團(tuán)隊(duì)的主要負(fù)責(zé)人之一邁克·勞倫斯說,，他們首次獲得了胰島素及其受體相結(jié)合的三維圖像,。
這項(xiàng)研究完善了對胰島素作用機(jī)制的認(rèn)識,，也有助于未來設(shè)計(jì)新藥物。理解胰島素與其受體蛋白如何互相作用對開發(fā)新藥物具有奠基性意義,。
澳大利亞大約有100萬糖尿病患者,，每年的新增患者則有10萬人。這一研究發(fā)現(xiàn)對于那些每日注射胰島素的患者是個福音,。(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.
