Mittal Anshumali, Martin Matthew F, Levin Elena J, Adams Christopher, Yang Meng, Provins Laurent, Hall Adrian, Procter Martin, Ledecq Marie, Hillisch Alexander, Wolff Christian, Gillard Michel, Horanyi Peter S, Coleman Jonathan A
Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA, USA.
UCB Pharma, Cambridge, MA, USA.
Nat Struct Mol Biol. 2024 Dec;31(12):1964-1974. doi: 10.1038/s41594-024-01335-1. Epub 2024 Jun 19.
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，其特征是神经网络活动异常，导致癫痫发作。吡拉西坦类抗癫痫药物特异性结合于神经元突触小泡中发现的一种膜蛋白，称为突触小泡蛋白2（SV2）A（SV2A）。SV2A属于溶质载体22有机离子转运体家族的一个孤儿亚家族，该家族还包括SV2B和SV2C。抗癫痫药物如何作用于SV2的分子基础仍然未知。在这里，我们报告了SV2A和SV2B处于腔内封闭构象并与抗惊厥配体复合的冷冻电子显微镜结构。抗惊厥药结合的构象类似于一种具有封闭腔内和细胞内门的受抑制转运体。抗惊厥药结合于SV2中一个高度保守的中心位点。这些结构为未来的药物设计提供了蓝图，并将促进对SV2生物学功能的进一步研究。
