Structure and mechanism of bile acid transporters

胆汁酸是我们体内产生的重要的洗涤剂样物质，用于乳化我们肠道中的脂肪。它们在肝脏中产生，并储存在胆囊中，直到需要它们来帮助分解我们消耗的食物。身体有自己的再循环系统，这意味着胆汁酸被重新使用。这个再循环过程需要胆汁酸在一些漂亮的蛋白质机器的帮助下重新进入血液。这些蛋白质机器，所谓的转运蛋白，识别并特异于胆汁酸的形状。有趣的是，如果我们能更详细地了解这个过程，我们可能能够阻止这个传输器工作。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排除。虽然这听起来很浪费，但它可能非常有益，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？最好的方法是首先确定转运蛋白在分子细节上的样子。就像一把钥匙被设计成适合某个钥匙孔一样，胆汁酸也被设计成适合它自己的运输工具。那么我们如何破译这些蛋白质的三维形状呢？为了实现这一点，我们需要使用X射线蛋白质晶体学。不幸的是，X射线晶体学需要从高浓度的纯化蛋白质中产生晶体。这种类型的蛋白质晶体的生产非常困难，科学界多年来一直在努力。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品，洗涤剂来分离它们。事实上，我们只知道我们身体里2,000个左右的转运蛋白中的3个的形状。然而，我们的实验室已经开发出了新的工具，这使得解决其中一些主要障碍成为可能。我们现在可以第一次分离出胆汁酸转运蛋白。此外，我们已经成功地生产出了小晶体，因此在获得其3D形状的道路上走得很好。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。一般来说，细菌蛋白质比哺乳动物蛋白质更容易处理。这项研究将是有用的，不仅为药物设计，而且还了解一般的转运机制。

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.