1. Structural insights into the allosteric effects of the antiepileptic drug topiramate on the Ca V 2.3 channel.
- Author
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Gao Y, Bai Q, Zhang XC, and Zhao Y
- Subjects
- Humans, Allosteric Regulation drug effects, Binding Sites, Models, Molecular, HEK293 Cells, Protein Conformation, Fructose chemistry, Fructose analogs & derivatives, Fructose metabolism, Animals, Cation Transport Proteins, Anticonvulsants chemistry, Anticonvulsants pharmacology, Topiramate chemistry, Topiramate pharmacology, Cryoelectron Microscopy, Calcium Channels, R-Type chemistry, Calcium Channels, R-Type metabolism
- Abstract
The R-type voltage-gated calcium channel Ca
V 2.3 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 CaV 2.3-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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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