Understanding the Molecular Mechanisms of a Sodium Dependent Vitamin Transporter

Secondary transporters are important in health and disease. They are important drug targets and can be hijacked in drug discovery to deliver prodrugs into the cells. Sodium-coupled secondary active transporters use the downhill sodium gradient to drive the uphill transport of molecules into the cells. In this way essential nutrients can be delivered to the cell. One such sodium-coupled secondary transporter is the multivitamin transporter SMVT. SMVT transports a range of vitamins including pantothenic acid (vitamin B5) and biotin (vitamin B6), both vitamins are essential and actively imported into the brain. Recently several publications found an emerging role for SMVT variants in multisystemic disorders. Multiple studies have also found high SMVT expression in cancer and it is a biomarker of gastric cancer. Despite the importance of SMVT in disease and its possibility of being exploited as a drug target the protein remains poorly characterised. This PhD takes a structural biology approach to investigate the mechanistic details: how do substrates bind, how is this driven and to understand transport in membrane proteins such as SMVT. There are many mechanistic details that have still to be discovered. To achieve this the atomic structures will be investigated using X-ray crystallography or Cryo-Electron Microscopy. This approach will be combined with Molecular Dynamic simulations to computationally model the binding of sodium ions and the transport of solutes. This research combines traditional lab-based techniques with computational Molecular Dynamic simulations. This will increase the understanding of the molecular mechanisms underpinning proteins such as SMVT both physiologically but also in disease states.