Time-optimized NMR spectroscopy for the investigation of challenging biological systems

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The main focus of the proposed group lays on the development of novel nuclear magnetic resonance (NMR) methods with an emphasis on the applicability in demanding biological systems. In this context we aim to improve the use of existing NMR resources by simultaneous detection of several experiments on different resonance frequencies. This can significantly reduce the amount of expensive NMR measurement time required to record the same amount of data (time-optimized NMR). Since a reduction of NMR measurement time is in particular crucial for the investigation of larger biological systems, NMR methods will be developed with a strong emphasis on these systems. Membrane protein folding and function was selected to offer a well suited (i.e. challenging) target for the application of the new techniques. In addition the selected targets represent very interesting areas of research on its own and the group will use this possibility to investigate e.g. how a not functional protein can insert itself into a cell-membrane to carry out its specific function. This aspect will be initially investigated using the protein Bacteriorhodopsin as our first target. A more detailed insight into this fundamental process may help to develop alternate drugs targeting membrane protein folding or may improve computer predictions of membrane protein structure and function.Furthermore we will study folding and function of our second target, the melanocortin-4 receptor (MC4R), which belongs to the pharmacologically very important class of G-Protein coupled receptors (GPCRs). Although about half of all current drugs are estimated to directly act on GPCRs, high resolution insights into these systems are very limited. We will combine the most promising conventional and non-conventional approaches to investigate structure und dynamics of the MC4R ligand system as well as ligand induced changes on the receptor side. The ligands themselves consist of several hormones (e.g adrenocorticotropic and melanocyte-stimulating hormone). The MC4R signaling pathways are involved in the control of body weight and appetite, regulation of blood pressure and the inhibition of inflammation. It is anticipated, that any high resolution insights into this system in particular in respect to receptor and ligand dynamics may on the one hand help to develop new and improved drugs targeting the MC4R signaling pathway and on the other hand may improve our understanding of GPCR function in general. The application of time-optimized NMR techniques for the investigation of the two biological targets will not only reduce the required NMR measurement time, but will also provide unique possibilities, such as the simultaneous detection of different folding states or dynamically distinct regions of the protein. Hence a strong synergy between the different aspects of the group is expected.