Crystallographic Studies of Membrane Transporters
Transport of molecules across biological membranes is a crucial process essential for the livelihood of every cell. Small molecules and ions need to enter and exit cells and sub-cellular compartments where they are utilized as energy sources, used as building materials for essential cellular molecules or serve as signaling agents. Synaptic transmission is only possible because of the rounds of release and uptake of neurotransmitters. Communication between cells in an organism is mediated by release of signaling molecules, whose concentration is controlled in the intercellular space by regulated uptake. All these processes depend on the successful crossing of the polar, often charged molecules across the hydrophobic barriers of lipid membranes. Numerous membrane transporters have evolved, which utilize either ATP or energy stored in the form of ion gradients to drive transport of their substrates across membranes. The later class, so-called secondary transporters, is the focus of study in our lab. We are relying on combination of X-ray crystallography and biochemistry to understand the structure of these transporters and the molecular mechanism of substrate transport. Recently, new methodologies have been developed to facilitate structural studies of membrane proteins and we will use these advances as well as develop new approaches. Crystallography of membrane proteins is an area of research, which is only now starting to enjoy an accelerated development and as a result every new structure reveals novel folds and molecular designs. In addition, every structure generates new avenues for drug discovery both because membrane transporters may serve as access points for drugs to the intracellular spaces and because transporters themselves serve as important drug targets.