About the Project
Membrane protein transporters are integral membrane proteins that enable small molecules such as nutrients, ions, neurotransmitters, and toxins to be transported across cellular membranes. These transport proteins play a central role in cell physiology. They are important in drug discovery as they can be potential drug targets or may contribute to drug delivery to the cells. Upregulation of certain transporters that pump toxic molecules out of the cells can lead to multi-drug resistance. Projects available in my lab concern secondary transporters involved in the uptake of nutrients into cells. Secondary transporters harness the energy stored in electrochemical gradients across the membrane to drive transport. The question is how? We use a combination of structural and functional studies to investigate this. How does the substrate bind? How does the driving co-substrate bind? What conformational changes occur when either binds? How are the two linked? These projects will suit anybody who is interested in discovering the molecular details behind how these intricate machines are able to selectively pump molecules across membranes. Through building up a series of static pictures through X-ray crystallography/ cryo-EM and linking them through molecular dynamics studies we can really see them working.
Current projects revolve around two classes of membrane transport protein but projects are evolving continuously and, if this line of PhD interests you, you should contact me.
• Nucleobase transporters. These are secondary transporters from the LeuT superfamily. The superfamily contains members carrying out diverse functions, such as the serotonin transporter involved in neurotransmission, or the sodium glucose transporter involved in glucose uptake in the kidney. The transporters we are investigating are bacterial transporters from the Nucleobase Cation Symport 1 Family. The sodium-coupled hydantoin transporter, Mhp1, from this family was, in fact, the first member of the superfamily for which the structures of all three major conformations along the transport cycle were determined (1). It has given important information in understanding the superfamily as a whole, yet we still don’t understand how sodium ions drive transport.
• Homologues of bile acid transporters. This family of transporters was first characterized as transporting steroids. One of the founding members of the family, ASBT, is found in the ileum and inhibitors have been, or are currently in clinical trials as drugs to reduce cholesterol levels, to treat cholestatic liver diseases or to help manage diabetes. However, the family is also found in plants and bacteria, transporting a wide range of molecules. We solved the structure of a homologue from the bacteria Nesseria Meningitidis (2). Again we would like to further understand the mechanism of these proteins.
BBSRC Strategic Research Priority: Understanding the Rules of Life: Structural Biology
Techniques that will be undertaken during the project:
• Molecular biology
• Growth of bacterial cultures
• Solubilisation and purification of membrane proteins
• Protein crystallisation, X-ray data collection and structure solution
• There is scope for Cryo-EM, depending on the exact project.
• Biochemical assays
• Molecular Dynamics Simulations
N. J. Hu, S. Iwata, A. D. Cameron, D. Drew, Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT. Nature 478, 408-411 (2011).
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