Structural insights into the allosteric effects of the antiepileptic drug topiramate on the CaV2.3 channel

The R-type voltage-gated calcium channel CaV2.3 is predominantly located in the presynapse and is implicated in distinct types of epileptic seizures. It has consequently emerged as a molecular target in seizure treatment. Here, we determined the cryo-EM structure of the CaV2.3-α2δ1-β1 complex in the topiramate-bound state at a 3.0 Å resolution. We provide a snapshot of the binding site of topiramate, a widely prescribed antiepileptic drug, on a voltage-gated ion channel. The binding site is located at an intracellular juxtamembrane hydrophilic cavity. Further structural analysis revealed that topiramate may allosterically facilitate channel inactivation. These findings provide fundamental insights into the mechanism underlying the inhibitory effect of topiramate on CaV and NaV channels, elucidating a previously unseen modulator binding site and thus pointing toward a route for the development of new drugs. •Topiramate binds to a novel binding site on CaV2.3 channel.•Critical residues stabilizing topiramate unveiled and validated by MD analysis.•An IFM-like allosteric modulation mechanism was revealed.•Provided new insights to rational drug discovery on CaV channels.