(From left to right) Researchers Matt Martin, Anshu Mittal and Jonathan Coleman pose in front of the Titan Krios electron microscope, which was used to collect all the data for their recently published paper in PNAS, at the University of Pittsburgh.
By Kat Procyk
Nearly three million adults are living with epilepsy, a neurological disorder that causes recurrent seizures, in the United States, according to the Centers for Disease Control and Prevention.
Antiseizure medications are the first line of defense against the condition. Levetiracetam and brivaracetam were designed and developed by UCB Pharma, a global biopharmaceutical company focused on discovering and developing treatments for severe diseases. Levetiracetam and brivaracetam are third generation antiseizure medications that work by targeting the synaptic vesicle protein 2A (SV2A), a protein found in synaptic vesicles that helps regulate neurotransmitter release in the brain.
A research team at the University of Pittsburgh School of Medicine partnered with UCB Pharma to understand how antiseizure medications and other molecules act on these proteins to eventually design novel therapies.
In their most recent study led by Anshumali Mittal, research assistant professor, and Matthew Martin, a graduate student, both within the lab of Assistant Professor Jonathan Coleman in Pitt’s Department of Structural Biology, they discovered the mechanism of how an allosteric molecule identified by UCB Pharma in 2013 enhances the binding of levetiracetam or brivaracetam to the SV2A protein.
“Because it’s allosteric, this molecule binds to a specific site in the protein that’s different from the protein’s main active site,” Coleman explained. “This binding causes the protein to change shape and our study allows us to understand how these structural changes enable this protein to bind these molecules.”
Coleman’s group used cryo-electron microscopy (cryo-EM), a technique that allows scientists to visualize proteins at near-atomic resolution, to closely examine how molecules bind to SV2A. In doing so, they discovered a second binding site directly above the primary binding site. Since the allosteric molecule sits on top of the primary site, it can modulate the binding properties of levetiracetam and brivaracetam to the SV2A protein.
“Levetiracetam and brivaracetam have proven effective and well tolerated in treating seizures,” Coleman said. “Identifying a new binding site in SV2A opens new avenues for developing therapies that modulate synaptic function and eventually treat neurological disorders.”
The paper, “Mechanisms Underlying Allosteric Modulation of Antiseizure Medication Binding to Synaptic Vesicle Protein 2A (SV2A),” was published in the journal PNAS on September 2, 2025.