Visualizing the molecular mechanisms of synaptic vesicle transporters
EMSL Project ID
50746
Abstract
Approximately 1% of the population experiences seizures, making epilepsy one of the most common neurological disorders. The impact on the livelihood of an individual is, in many ways unfathomable and can frequently affect all aspects of work, relationships, and personal safety. The aim of the proposed research is to elucidate the molecular function, architecture, and high-affinity drug binding sites of synaptic vesicle transporters by determining single particle cryo-EM structures. This work will have a significant and long-lasting impact on the fields of neuroscience and membrane biophysics. It is not possible to determine the structures of these transporters by x-ray crystallography and the lack of structural information has hampered the progress of structure-function studies and understanding how small-molecules including widely prescribed antiepileptics modulate transporter function. I have developed methods for large-scale expression, stabilization by drugs, and for the production of toxins which recognize the extracellular domain of these transporters. The use of transporter-toxin complexes is essential in order to provide mass (~45 kDa) and molecular features to assist in cryo-EM reconstructions because these transporters are small (~80 kDa) membrane proteins which are largely ensconced within membrane. Atomic structures of transporters in complex with therapeutic drugs will be essential for the design of better antiepileptic drugs with higher specificity and fewer side-effects and will also advance efforts toward understanding the function of these transporters. Ultimately my work will also lead to the identification of new therapeutic targets improving the health and well-being of individuals with epilepsy and other neurological conditions.
Project Details
Start Date
2019-04-15
End Date
2019-10-15
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members