Structure determination of the 7-helix transmembrane protein receptor pSRII by solution NMR

大多数生物体都是由大量的细胞组成的。这些细胞中的每一个都是一个专家，通过大量的活动来支持有机体。细胞主要由液体内部组成，其中容纳了宝贵的机器，包括生命的基石和产生蛋白质的所有信息。一层不溶于水的保护脂质层被称为膜包围着细胞。为了正常运作，也为了必要时调整细胞内部的工作以适应不断变化的外部需求，细胞需要不断地补充来自外部的营养和指令。为了解决这个问题，大量被称为膜蛋白的分子，如配体受体，嵌入在脂质层中，在那里它们跨越膜。它们是细胞的联络中心，在细胞内部和外部世界之间进行沟通，通过细胞界面传送信息和物质。它们参与了许多复杂的信息传递过程，并与许多疾病有关，这使它们成为市场上大多数现有药物的主要目标。生物学家和化学家研究这些分子的性质，以便更好地了解细胞和生物分子的过程。一个重要的方面是了解这些分子的三维结构。虽然这可以非常常规地获得水溶性分子，并且取得了巨大的成功，但使用传统的x射线晶体学和核磁共振（NMR）结构测定技术来实现膜嵌入蛋白质要困难得多。因此，不溶性膜蛋白的结构测定仍处于早期阶段。我们的建议旨在发展核磁共振技术来解决这类膜蛋白的结构。我们的研究集中在一个特定的成员上，对我们来说，这是一个模型系统，它属于一个蛋白质家族，与受体有许多相似之处。到目前为止，后者已被证明对结构研究特别回避，我们的研究努力将改善这种情况。

Most living organisms are assembled from a very large number of cells. Each of these cells is a specialist that contributes through a large number of activities to the support of an organism. Cells are composed mostly of a liquid interior that accommodates the precious machinery including the building blocks of life and all the information to produce proteins. A water insoluble protective lipid layer called a membrane surrounds the cell. To function properly and also when necessary to adjust the interior workings of the cell to changing external demands the cell needs to be continuously supplemented with nutrients and instructions that come from the outside. To help with this, a large number of molecules, called membrane proteins such as e.g. ligand receptors are embedded in the lipid layer, where they span the membrane. They are the liaison centres of the cell and communicate between interior and exterior worlds to shuttle information and material across the cell-interface. Their involvement in so many complex information transfer processes and their implication in a large number of diseases have made them prime targets for the majority of existing drugs on the market. Biologists and chemists study the properties of such molecules in order to better understand the cellular and biomolecular processes. One important aspect is to understand the three-dimensional organization of these molecules. While this can be obtained quite routinely and with great success for water-soluble molecules, it is much more difficult to achieve for membrane embedded proteins using the traditional structure determination techniques of X-ray crystallography and nuclear magnetic resonance (NMR). Consequently structure determination of insoluble membrane proteins is still in its early stages. Our proposal aims at the development of the NMR technique to solve the structure of such membrane proteins. We concentrate our studies on a particular member, for us a model system that belongs to a family of proteins with many analogies to receptors. The latter have proven particularly evasive to structural studies so far and our research efforts will improve this situation.