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Structural biology of bile acid transporters, important in disease

Principal Supervisor: Professor Alex Cameron

Secondary Supervisor(s): Professor Phill Stansfeld

University of Registration: University of Warwick

BBSRC Research Themes: Understanding the Rules of Life (Systems Biology)

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Deadline: 4 January, 2024


Project Outline

Secondary transporters are membrane transporters that move molecules across membranes. They are important in drug discovery, either as specific drug targets or because they allow the movement of drugs into or out of cells. The apical sodium-dependent bile acid transporter (ASBT) is a target for drugs currently in the clinic that help alleviate problems such as chronic constipation, irritable bowel syndrome, non-alcoholic liver disease or cholestatic puritis (1). ASBT is a sodium-coupled bile acid transporter and a member of the Solute Carrier (SLC) 10 family of secondary transporters. ASBT harnesses the sodium gradient to drive the movement of bile acids across the plasma membrane. Structures are available of related proteins from my group (2-3) and others (4) so the general principles of how these proteins function is known. However, it is not known how bile acids nor the inhibitors bind, making the process of drug development more difficult. This project seeks to examine the mechanism of bile acid transport in ASBT through a combination of experimental structural biology along with functional studies and use of molecular dynamics. There is, however, scope to investigate other membrane transport proteins using similar techniques eg (5).

References

  • Al-Dury, S. & Marschall, H.U. Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH. Front Pharmacol 9, 931 (2018).
  • Becker, P. et al. Mechanism of substrate binding and transport in BASS transporters. bioRxiv (2023).
  • Hu, N.J., Iwata, S., Cameron, A.D. & Drew, D. Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT. Nature 478, 408-11 (2011).
  • Goutam, K., Ielasi, F.S., Pardon, E., Steyaert, J. & Reyes, N. Structural basis of sodium-dependent bile salt uptake into the liver. Nature 606, 1015-1020 (2022).
  • Hatton, C.E., Brotherton, D.H., Spencer, M. & Cameron, A.D. Structure of cytosine transport protein CodB provides insight into nucleobase-cation symporter 1 mechanism. EMBO J 41, e110527 (2022).

Techniques

  • Molecular biology
  • Growth of bacterial cultures
  • Solubilisation and purification of membrane proteins
  • Cryo-EM
  • Assays
  • Molecular Dynamics Simulations