Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, 08826, Korea.
Nat Commun. 2024 Oct 25;15(1):9223. doi: 10.1038/s41467-024-53587-6.
Connexin 36 (Cx36) forms interneuronal gap junctions, establishing electrical synapses for rapid synaptic transmission. In disease conditions, inhibiting Cx36 gap junction channels (GJCs) is beneficial, as it prevents abnormal synchronous neuronal firing and apoptotic signal propagation, mitigating seizures and progressive cell death. Here, we present cryo-electron microscopy structures of human Cx36 GJC in complex with known channel inhibitors, such as mefloquine, arachidonic acid, and 1-hexanol. Notably, these inhibitors competitively bind to the binding pocket of the N-terminal helices (NTH), inducing a conformational shift from the pore-lining NTH (PLN) state to the flexible NTH (FN) state. This leads to the obstruction of the channel pore by flat double-layer densities of lipids. These studies elucidate the molecular mechanisms of how Cx36 GJC can be modulated by inhibitors, providing valuable insights into potential therapeutic applications.
连接蛋白 36（Cx36）形成神经元间缝隙连接，建立用于快速突触传递的电突触。在疾病状态下，抑制 Cx36 缝隙连接通道（GJCs）是有益的，因为它可以防止异常同步神经元放电和凋亡信号传播，减轻癫痫发作和进行性细胞死亡。在这里，我们展示了与人 Cx36 GJC 复合物的冷冻电镜结构，这些复合物与已知的通道抑制剂，如甲氟喹、花生四烯酸和 1-己醇结合。值得注意的是，这些抑制剂竞争性地结合到 N 端螺旋（NTH）的结合口袋中，诱导从孔衬 NTH（PLN）状态到灵活 NTH（FN）状态的构象转变。这导致由双层脂质的扁平密度阻塞通道孔。这些研究阐明了 Cx36 GJC 如何被抑制剂调节的分子机制，为潜在的治疗应用提供了有价值的见解。
