Structure and function of key ABC Transporters in health and disease

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Human ABC transporters are a family 52 integral membrane proteins that transport diverse molecules across cell membranes. Mutations in ABC transporters causes a range of diseases, including diabetes (ABCC8 and ABCC9), cystic fibrosis (ABCC7, CFTR) and blindness (ABCA4).At the SGC in Oxford Profs. Liz Carpenter and Heidi de Wet's groups study the 3D structures and function of human ABC transporters, involved in diseases. In particular Liz Carpenter's group works with a range of proteins involved in neuropsychiatric disease, cancer, rare and metabolic disease, as well as inflammatory diseases. Although membrane proteins are thought to be challenging to study, this field is just now opening up with new technical developments, including novel methods for producing proteins, for crystallisation for X-ray crystallography and for obtaining high resolution structures by electron cryo-microscopy.As human integral membrane proteins are challenging to study at the protein level, the student would start with a range of projects, develop 2 or 3 projects of different levels of difficulty and then select the most interesting and well-behaved proteins to work on. We do have a number of projects where the proteins are already purified, as well as other interesting targets where this aspect of the project would require development.This project would involve production of a range of human ABC transporters, particularly those associated with disease. The student would then study their structures using cryo-EM with a range of nucleotides, nucleotide analogues, substrates and inhibitors. These structures will provide an atomic level understanding of how these proteins function. They would also use functional assays, including ATPase activity assays, transport assays and biophysical assays to further their understanding of the function of these proteins in health and disease. This work is in collaboration with supervisors at a major pharmaceutical company, who have expertise in producing and studying the structures of complex proteins. They are also experts in developing assays to identify small molecule stabilizers and activators for transporters, techniques that would be used by the student. The student will gain a strong working knowledge of ABC transporter structural and functional studies, including biochemical (ATPase activity, transport assays) and biophysical methods (thermostability, microscale thermophoresis, SPR) and structural techniques, including cryo-EM and X-ray crystallography. The student will spend most of their time working in Prof. Liz Carpenter's group at the SGC, in Oxford, with a team of 14 membrane protein structural biologists. They will also collaborate with Prof. Heidi de Wet, in DPAG, Oxford, for functional studies. This project provides an outstanding opportunity to work extensively with enthusiastic collaborators in industry, including a 3 or 4 months visit to work with your industrial supervisors in Boston, USA.