Structure and mechanism of bile acid transporters

胆汁酸转运蛋白的结构和机制

• 批准号: G0900990/1
• 负责人: Alexander Cameron
• 金额: $ 54.09万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0900990%2F1
• 关键词: Structure; mechanism; bile; acid; transporters

Bile acids are important detergent like substances produced in our body for emulsifying fat in our gut. They are made in the liver and are stored in the gall-bladder until they are needed to help break down the food we consume. The body has its own re-cycling system, which means that the bile acid is re-used. This re-cycling process requires that the bile acids are taken back up into the blood stream by the aid of some nifty protein machines. These protein machines, so-called transporters, recognize and are specific to the shape of bile acid. What is interesting is that if we can understand this process in greater detail, we may be able to stop this transporter from working. The result of doing this would mean that the bile acid usually kept in our body would be eliminated instead. Although this sounds wasteful, it could be very beneficial, as removing bile acid is one of the best ways of lowering cholesterol levels in the body. How do we do this? The best way is first determine what the transporter looks likes at the molecular detail. Just as a key is designed to fit a certain key-hole, so bile acid is made to fit its own transporter. So how do we decipher the three-dimensional shape of these proteins? To achieve this, we need to use X-ray protein crystallography. Unfortunately, X-ray crystallography requires the production of crystals from high concentrations of purified proteins. The production of protein crystals of this type is very difficult, and the scientific community has struggled over many years. These molecules are present in an oil-like environment and we need to use specific chemicals, detergents, to isolate them. In fact, we only know the shape of 3 of the 2,000 or so transporters in our body. However, our laboratory has developed new tools, which has made it possible to tackle some of these main hurdles. We can now isolate the bile acid transporters for the first time. Furthermore, we have managed to produce small crystals and so are well on the road to obtaining their 3D-shape. As bacteria, like us, also use a machine to transport bile acid we will also study this protein. In general bacterial proteins are rather easier to work with than their mammalian equivalents. This study will be useful, not only for drug design but also to understand the mechanisms of transporters in general.

胆汁酸是我们体内产生的一种重要的洗涤剂类物质，用于乳化我们肠道中的脂肪。它们是在肝脏中制造的，并储存在胆汁中，直到需要它们来帮助分解我们所摄入的食物。人体有自己的再循环系统，这意味着胆汁酸被重新利用。这个再循环过程需要在一些精巧的蛋白质机器的帮助下将胆汁酸带回血液中。这些蛋白质机器，即所谓的转运体，识别胆汁酸的形状，并针对胆汁酸的形状。有趣的是，如果我们能更详细地了解这一过程，我们或许能够阻止这个传送器工作。这样做的结果将意味着通常保存在我们体内的胆汁酸将被消除。尽管这听起来很浪费，但它可能是非常有益的，因为去除胆汁酸是降低体内胆固醇水平的最佳方法之一。我们该怎么做呢？最好的方法是首先确定转运蛋白在分子细节上的样子。正如钥匙被设计成适合特定的钥匙孔一样，胆汁酸的制造也是为了适应它自己的运输器。那么，我们如何破译这些蛋白质的三维形状呢？要做到这一点，我们需要使用X射线蛋白质结晶学。不幸的是，X射线结晶学需要从高浓度的纯化蛋白质中产生晶体。生产这种类型的蛋白质晶体是非常困难的，科学界已经奋斗了很多年。这些分子存在于类似石油的环境中，我们需要使用特定的化学物质，洗涤剂来分离它们。事实上，我们只知道我们体内大约2000个转运体中的3个的形状。然而，我们的实验室已经开发出新的工具，这使得解决这些主要障碍成为可能。我们现在可以第一次分离胆汁酸转运蛋白。此外，我们已经成功地生产了小晶体，因此在获得其3D形状的道路上进展顺利。由于细菌和我们一样，也使用机器来运输胆汁酸，我们也将研究这种蛋白质。一般说来，细菌蛋白质比它们的哺乳动物蛋白质更容易处理。这项研究不仅对药物设计有帮助，而且对了解转运蛋白的一般机制也有帮助。