来自英国莱斯特生物化学研究所的John  教授及其团队（与来自日本和匈牙利的团队一起）对治疗II  型糖尿病一种重要的药物靶标蛋白质——PPAR  γ——进行了研究，从而在II  型糖尿病靶向治疗上又向前迈进一步。该研究发表在9月17  日Nature  Structural  and  Molecular  Biology  上，并被Nature  Chemical  Biology评为亮点文章。

X  射线晶体衍射是最主要的详细描述分子的三维结构——尤其是生物分子的方法。其原理是将X  射线射向目标，通过分析X  射线的衍射图构造分子结构。通过这种方式，莱斯特团队已展示PPAR  γ  如何与八种脂肪酸——其构造部分来自于食物——相结合。诸多脂肪酸不可逆的与蛋白质结合，从而使后者长期保持活性。研究结果还显示，有时两种脂肪酸同时结合PPAR  γ，这就意味着可以通过混合药物靶向PPAR  γ  蛋白。

研究人员称，发现PPAR  γ  的天然激活剂不可逆与PPAR  γ  受体结合将改变人们对受体活性的理解。新药物设计也考虑到以较低的剂量使PPAR  γ  保持长期的活性，且不产生任何副作用。

作为代谢型疾病，II  型糖尿病已影响全球1.8  亿人口，仅英国每天就为此花费960  万英镑，而这种疾病中PPAR  γ  起了关键的角色。实现PPAR  γ  活性目前最普遍采用方法是通过两种抗糖尿病药物，胰岛素增敏剂——Actos  与Avandia。而此前PPAR  γ  的天然激活剂还不太清楚。

这项研究第一次显示出蛋白质是如何被正常产生的脂肪酸影响活性的，从而有助于指导新药物的设计。尽管在这项研究中，通过X  射线晶体学技术已了解药物是怎样影响蛋白质的，但对于PPAR  γ  在机体中是如何发挥作用依然未知。

The advance -- described by the researchers as 'very significant' -- could lead to new drugs being developed to target a protein that plays a critical role in controlling the way the body breaks down sugar.

Professor John Schwabe and his team from the University of Leicester Department of Biochemistry (together with teams from Japan and Hungary) have been studying the protein, PPAR gamma. PPAR gamma is a major drug target for the treatment of type 2 diabetes. Although it was known how drugs are able to activate this protein, until this study, using the sophisticated technique of X-ray Crystallography, it was not clear how PPAR gamma is naturally activated in the body.

X-ray Crystallography is the principal method by which the detailed 3- dimensional structures of molecules - especially the molecules of living systems - have been discovered. It is achieved by firing X-rays at the target and creating its structures by analysing how the x-rays scatter into many different directions.

Through this method, the Leicester team have shown how PPAR gamma binds to eight different fatty acids, derived in part from what we eat. They found that many of these acids joined irreversibly with the protein and led to its long term activation. They have also shown that sometimes two fatty acids bind simultaneously, which might mean that PPAR gamma could be targeted by a mixture of drugs.

Professor John Schwabe, who led the Leicester project with his team, including Dr Toshimasa Itoh and Dr Louise Fairall, said: "The finding that natural activators for PPAR gamma couple irreversibly to the PPAR gamma receptor dramatically changes our understanding of how this receptor is activated.

"It may also allow for the design of novel pharmaceuticals that give longer term activation of PPAR gamma, at lower doses, without some of the side effects of the current generation of drugs."

Professor Schwabe said: "PPAR gamma is a critical player in the increasingly prevalent metabolic disease of type 2 diabetes which affects more than 180 million people worldwide (World Health Organisisation) and in the UK alone costs the NHS £9.6 million every day.

"PPARgamma is activated by two widely prescribed anti-diabetic insulin- sensitising drugs, Actos and Avandia. However the identity of the natural activators for PPAR gamma has remained unclear.

"Our breakthrough is important because it reveals for the first time that how this protein is activated by naturally-occuring fatty acids. This knowledge will help in the design of future novel pharmaceutical agents."

The research has been published in the journal Nature Structural and Molecular Biology. The paper will also be featured as a Highlight in the journal Nature Chemical Biology and has been designated a "Must Read" by the Faculty of 1000. The research was funded by the University of Leicester and the Wellcome Trust