Action Mechanism of antiepileptic drugs elucidated

April 18, 2024

Promise to contribute to the development of new antiepileptics and PET tracers

A joint research group of the RIKEN Center for Biosystems Dynamics Research, the RIKEN CSRS, and the University of Tokyo elucidated the action mechanism of antiepileptics levetiracetam (LEV) and brivaracetam (BRV) based on the structure of the drugs’ target membrane protein.

LEV and BRV are drawing attention as new-generation antiepileptic drugs that work on synaptic vesicle glycoprotein 2A (SV2A), a membrane protein in neurons. SV2A is found in the synaptic vesicles, which are responsible for releasing neurotransmitters at synapses, the connections between neurons. This protein is also known as a receptor for botulinum neurotoxin (BoNT). SV2A is a medically valuable target, but much of its function remains unclear.

In this study, the joint group used a cryo-electron microscope to analyze the structure of the SV2A in complex with BoNT and either LEV or BRV. This analysis elucidated how SV2A binds to antiepileptics and BoNT, suggesting the structural basis for why BRV has higher efficacy than LEV.

The outcomes of this research hold promise for developing novel antiepileptics and positron emission tomography (PET) tracers.

Original article

Nature Communications doi: 10.1038/s41467-024-47322-4

A. Yamagata, K. Ito, T. Suzuki, N. Dohmae, T. Terada, M. Shirouzu,

"Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A".

Contact

Naoshi Dohmae
Unit Leader
Biomolecular Characterization Unit