Nuffield Department of Clinical Medicine
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Protein Science and Structural Biology
Membrane proteins are the gateways to the cell. All cells and organelles are surrounded by an oily, impermeable lipid bilayer and many small molecules can only cross this barrier by passing through protein molecules embedded in the bilayer. Many nutrients, ions, waste products and even DNA and proteins enter and leave cells only via proteins which are tightly controlled, thus maintaining the integrity of the cell. Communication between cells is also mediated by these proteins often by binding signaling molecules outside cells and amplifying the signal by triggering chemical reactions inside the cell. These diverse functions are fulfilled by a huge variety of membrane proteins, in fact approximately 25% of all the genes in the human genome code for these proteins. Given their location on the surfaces of cells, it is not surprising that membrane proteins are often found to be the targets for drugs, such as the calcium channel blockers used to treat heart disease and potassium channel blockers which are used in diabetes treatment. Indeed membrane proteins are involved in the development of many diseases, including heart disease, cancer, cystic fibrosis, Alzheimer’s, Parkinson’s and other neurological diseases, kidney disease and epilepsy.
The three dimensional structures of these large macromolecules are the key to understanding their function and designing drugs to inhibit them. In the Integral Membrane Protein group at the SGC we use the technique of X-ray crystallography to solve membrane protein structures. We then study the structures in complex with inhibitors and drugs, using this information to improve and extend the available treatments for disease. The IMP group at the SGC studies proteins from a variety membrane protein families, including ion channels which are critical for heart and nerve function, transporters which move solutes, nutrients and waste products across membranes and ABC transporters which move waste products and drugs into and out of cells. In the past two years we have established a working high-throughput system for the producing human membrane proteins for structural studies. This system has allowed us to obtain crystals for three human membrane proteins and pure protein from more than 30 proteins and we are developing these projects for structure function studies. In less than two years we obtained our first structure, the first structure of a human ABC transporter, the mitochondrial ABCB10 protein which is thought to be involved in protecting the heart during oxidative stress.