Structure and mechanism of bile acid transporters

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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.