Towards the molecular mechanism of solute carrier proteins

各种基因组计划的结果表明，高达30%的人类蛋白质存在于细胞膜中。在这些膜蛋白中，膜转运蛋白是第二大家族。转运蛋白负责摄取和释放各种物质，包括糖，氨基酸，药物和矿物质进入或离开细胞。因此，膜转运蛋白在许多生物学功能中起着至关重要的作用，并且在医学和药理学中具有关键重要性。我们需要了解膜转运蛋白的结构，以便在分子水平上对生命有基本的了解。结构的知识对于药物发现也非常有用，使得能够合理设计新的小分子配体，其可以特异性抑制感兴趣的蛋白质而不影响其他蛋白质，从而产生具有较少副作用的药物。本申请旨在研究这些转运蛋白的结构和作用机制。为了研究转运蛋白的分子特性，我们使用称为“蛋白质X射线晶体学”的方法。对于这种方法，必须获得转运蛋白的晶体，然后对其进行X射线衍射实验。虽然我们已经获得了一些转运体的晶体，但要充分改进晶体以使我们能够收集高质量的X射线衍射数据仍然是一个困难的过程。这是因为膜转运蛋白是非常疏水的，并且不容易产生良好质量的晶体。因此，在与钻石光源相关的哈威尔新研究中心执行这个项目将是非常有用的。钻石光源的光束线产生的高质量X射线的良好获取对于从这些膜转运蛋白晶体成功收集数据至关重要。Diamond Light Source还容纳了Diamond Membrane Protein Laboratory，这是一个用于高通量膜蛋白结晶的用户设施，也有利于促进本提案中晶体的优化。

The results of various genome projects have shown that up to 30% of human proteins occur in cell membranes. The membrane transporters form the second largest family among these membrane proteins. The transporters are responsible for uptake and release of various substances including sugars, amino acids, drugs and minerals into or out of cells. Thus, membrane transporters play crucial roles in many biological functions and are of key importance for medicine and pharmacology. We need to understand membrane transporter structures to provide a basic understanding of life at the molecular level. Knowledge of the structure is also very useful for drug discovery enabling rational design of new small molecule ligands that can specifically inhibit the protein of interest and not affect other proteins, resulting in drugs with less side effects. This application is to study the structures and mechanisms of these transporters. To study the molecular properties of transporters, we use the method called ' protein X-ray crystallography'. For this method, it is essential to obtain crystals of the transporters, which are subsequently subjected to X-ray diffraction experiments. Although we have already obtained crystals of some transporters, it is still a difficult process to improve the crystals sufficiently to enable us to collect good quality X-ray diffraction data. This is because the membrane transporters are very hydrophobic and do not yield good quality crystals easily. Therefore, it would be extremely useful to perform this project at the new Research Complex at Harwell associated with Diamond Light Source. Good access to the high quality X-rays, produces by the beamlines at Diamond Light Source, are crucial for successful data collection from these membrane transporter crystals. The Diamond Light Source also accommodates the Diamond Membrane Protein Laboratory, a user facility for high throughput membrane protein crystallisation, which is also advantageous to facilitate optimisation of the crystals in this proposal.