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.
摘要：
R型电压门控钙通道CaV2.3主要位于突触前，并与不同类型的癫痫发作有关。因此，它已成为癫痫治疗中的分子靶标。这里,我们以3.0分辨率确定了托吡酯结合状态下CaV2.3-α2δ1-β1复合物的低温EM结构。我们提供了托吡酯结合位点的快照，广泛使用的抗癫痫药，在电压门控离子通道上。结合位点位于细胞内膜近膜亲水腔。进一步的结构分析表明，托吡酯可能会变构地促进通道失活。这些发现为托吡酯对CaV和NaV通道的抑制作用的潜在机制提供了基本见解。阐明以前未见过的调节剂结合位点，从而指向新药开发的途径。
