(MEMPHIS, Tenn. – December 1, 2025) A multi-institute team led by St. Jude Children's Research Hospital and UT Southwestern Medical Center investigators established for the first time how certain drugs used to treat epilepsy affect their target. Using cryo-electron microscopy, the team revealed the structural changes that occur to synaptic vesicle glycoprotein 2A (SV2A), a membrane protein found in nearly all neurons, when anti-epilepsy drugs bind. They further showed how experimental modulators bind an alternative site on SV2A to increase the potency of these drugs. The findings shed light on a poorly understood but therapeutically important protein and provide guidance for therapeutic optimization. The study was published in Nature Communications.
Before this work, researchers knew little about what happened to SV2A when anti-epilepsy drugs such as levetiracetam bind to the protein. Levetiracetam is the first and, to date, only three-dimensional (3D) printed drug product approved by the Food & Drug Administration (FDA). It is also on the World Health Organization's Essential Medicines List, making it even more important to understand the effect it has on its target protein.
"There are several compounds that bind to SV2A, but its biology is still largely unknown; its native substrate hasn't even been identified," explained co-corresponding author Chia-Hsueh Lee, PhD , St. Jude Department of Structural Biology . "SV2A is highly expressed in neurons, so its medical importance and unknown biology motivated us to learn more."
Lee and his colleagues obtained the structures of the SV2A protein by itself, and in combination with a panel of FDA-approved and experimental anti-seizure therapies. The researchers also investigated a secondary region on the protein, called an allosteric site, that can be targeted to modulate the primary region to which the drug binds to improve drug efficacy.
Secondary site may be key to more potent anti-seizure therapeutics
The structures revealed why one modulator improves the effects of levetiracetam and another approved therapeutic, brivaracetam, but intriguingly, not of the developmental anti-seizure drug padsevonil. While levetiracetam and brivaracetam exclusively bind the primary site and induce the structural changes typically seen in this family of transporter proteins, padsevonil binds both the primary and allosteric sites. This highlights the complexity of the protein–drug interactions and offers guidance for future therapeutic research targeting SV2A and other members of the major facilitator superfamily.
"Across the different members of this transporter family, the primary drug site is more conserved than the allosteric site. So, if you want a more specific compound, you should design it to bind only to the allosteric site," Lee said. "This will allow therapies to be more specific to SV2A, rather than drugs that inhibit other superfamily members and cause side effects."
Lee is continuing his work on the SV2A protein to clarify its biological role in neuronal cells. "Developing better inhibitors or modulators will allow us to dissect SV2A's functions and determine whether it truly works as a transporter," Lee said. "The more we understand this protein, even from a pharmacological perspective, the more tools we have to control or modulate it."
Authors and funding
The study's first author is Shabareesh Pidathala, St. Jude. The study's co-corresponding author is Fangyu Liu, UT Southwestern Medical Center. The study's other authors are Long Nguyen, National University of Singapore; Yiming Niu, The Rockefeller University; and Xiao Chen, Yaxin Dai and Christoph Gorgulla, St. Jude.
The study was supported by the National Institutes of Health (R01NS133147) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
