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

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

  • Biochem Biophys Res Commun. 2024 Jun 15:725:150271. doi: 10.1016/j.bbrc.2024.150271.
Yiwei Gao 1,  Qinru Bai 1,  Xuejun Cai Zhang 2,  Yan Zhao 3
Affiliations

Affiliations

  • 1 Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: zhangc@ibp.ac.cn.
  • 3 Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. Electronic address: zhaoy@ibp.ac.cn.
PMID: 38901222 DOI: 10.1016/j.bbrc.2024.150271
Abstract

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.

Keywords

Allosteric modulation; Epilepsy; Topiramate; Voltage-gated calcium channel.

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