Epilepsy is a common neurological disorder characterized by abnormal activity of neuronal networks, leading to seizures. The racetam class of anti-seizure medications bind specifically to a membrane protein found in the synaptic vesicles of neurons called synaptic vesicle protein 2 (SV2) A (SV2A). SV2A belongs to an orphan subfamily of the solute carrier 22 organic ion transporter family that also includes SV2B and SV2C. The molecular basis for how anti-seizure medications act on SV2s remains unknown. Here we report cryo-electron microscopy structures of SV2A and SV2B captured in a luminal-occluded conformation complexed with anticonvulsant ligands. The conformation bound by anticonvulsants resembles an inhibited transporter with closed luminal and intracellular gates. Anticonvulsants bind to a highly conserved central site in SV2s. These structures provide blueprints for future drug design and will facilitate future investigations into the biological function of SV2s.

癫痫是一种常见的神经系统疾病，其特征是神经元网络异常活动，导致癫痫发作。西坦类抗癫痫药物与神经元突触小泡中发现的膜蛋白（称为突触小泡蛋白 2 (SV2) A (SV2A)）特异性结合。 SV2A 属于溶质载体 22 有机离子转运蛋白家族的孤儿亚家族，该家族还包括 SV2B 和 SV2C。抗癫痫药物如何作用于 SV2 的分子基础仍不清楚。在这里，我们报告了以与抗惊厥配体复合的腔闭塞构象捕获的 SV2A 和 SV2B 的冷冻电子显微镜结构。抗惊厥药结合的构象类似于具有封闭的管腔和细胞内门的受抑制的转运蛋白。抗惊厥药与 SV2 中高度保守的中心位点结合。这些结构为未来的药物设计提供了蓝图，并将有助于未来对 SV2 生物学功能的研究。