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

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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.