Towards the molecular mechanism of solute carrier proteins

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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.