1. Structures of synaptic vesicle protein 2A and 2B bound to anticonvulsants
- Author
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Mittal, Anshumali, Martin, Matthew F., Levin, Elena J., Adams, Christopher, Yang, Meng, Provins, Laurent, Hall, Adrian, Procter, Martin, Ledecq, Marie, Hillisch, Alexander, Wolff, Christian, Gillard, Michel, Horanyi, Peter S., and Coleman, Jonathan A.
- Abstract
Epilepsy is a common neurological disorder characterized by abnormal activity of neuronal networks, leading to seizures. The racetam class of anti-seizure medications bind specifically to a membrane protein found in the synaptic vesicles of neurons called synaptic vesicle protein 2 (SV2) A (SV2A). SV2A belongs to an orphan subfamily of the solute carrier 22 organic ion transporter family that also includes SV2B and SV2C. The molecular basis for how anti-seizure medications act on SV2s remains unknown. Here we report cryo-electron microscopy structures of SV2A and SV2B captured in a luminal-occluded conformation complexed with anticonvulsant ligands. The conformation bound by anticonvulsants resembles an inhibited transporter with closed luminal and intracellular gates. Anticonvulsants bind to a highly conserved central site in SV2s. These structures provide blueprints for future drug design and will facilitate future investigations into the biological function of SV2s.
- Published
- 2024
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