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The Integral Membrane Proteins (IMP) group at the SGC aims to solve structures of some of the most challenging proteins encoded by the human genome, proteins that are embedded in the lipid bilayers of human cells. Membrane proteins represent around 20% of all the proteins produced by cells, and yet we have structures for less than 100 of the human versions of these essential proteins. These proteins form channels, transporters, enzymes, receptors and structural proteins. They are responsible for a host of important functions in cells: transport of small molecules and ions across membranes, removal of waste products and transfer of signals in and out of cells. The position of these proteins on the surfaces of cells makes them ideal targets for drugs, and in fact more than 50% of all small molecule drugs target proteins in membranes. There is therefore a pressing need for us to understand both the 3D structures of these proteins and how they function in cells.
Over the past four years we have developed methods to solve structures of human membrane proteins. We produce IMPs in insect cells, identify proteins that can be purified and crystallised, then solve their structures using X-ray crystallography. This work has lead to the structures of three human integral membrane proteins:
1. We solved the first structure of a human ABC transporter, the mitochondrial membrane protein, ABCB10, which is involved in protection of the mitochondria against oxidative stress and is also necessary for heme production.
2. We have obtained a structure for a nuclear membrane zinc metalloprotease, ZMPSTE24, which is involved in premature ageing syndromes. Its substrate, prelamin A, forms part of a scaffold structure underlying the inner membrane of the nucleus. ZMPSTE24 is responsible for part of the post-translational modification of prelamin A and when this processing fails, due to mutations in ZMPSTE24 or its substrate, prelamin A, the nucleus is deformed, leading to disease.
3. More recently we have focused on ion channels, the targets of many drugs. We have recently solved and deposited the structure of the K2P ion channel, TREK-2, a target for antidepressants, antipsychotics and anaesthetics.