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Abstract：
Voltage-gated sodium (Nav) channels are responsible for the initiation and propagation of action potentials. Their abnormal functions are associated with numerous diseases, such as epilepsy, cardiac arrhythmia, and pain syndromes. Therefore, these channels represent important drug targets. Even in the post-resolution revolution era, a lack of structural information continues to impede structure-based drug discovery. The limiting factor for the structural determination of Nav channels using single particle cryo-electron microscopy (cryo-EM) resides in the generation of sufficient high-quality recombinant proteins. After extensive trials, we have been successful in determining a series of high-resolution structures of Nav channels, including NavPaS from American cockroach, Nav1.4 from electric eel, and human Nav1.1, Nav1.2, Nav1.4, Nav1.5, and Nav1.7, with distinct strategies. These structures established the framework for understanding the electromechanical coupling and disease mechanism of Nav channels, and for facilitating drug discovery. Here, we exemplify these methods with two specific cases, human Nav1.4 and Nav1.7, which may shed light on the structural determination of other membrane proteins.
摘要：
电压门控钠（Nav）通道负责动作电位的启动和传播。它们的异常功能与许多疾病相关，比如癫痫,心律失常,和疼痛综合症。因此,这些通道代表了重要的药物靶点。即使在后决议革命时代，缺乏结构信息继续阻碍基于结构的药物发现。使用单颗粒低温电子显微镜（cryo-EM）进行Nav通道结构测定的限制因素在于产生足够的高质量重组蛋白。经过广泛的试验,我们已经成功地确定了一系列高分辨率的导航通道结构，包括美国蟑螂的NavPaS,来自电鳗鱼的Nav1.4，和人类Nav1.1，Nav1.2，Nav1.4，Nav1.5和Nav1.7，具有不同的策略。这些结构为理解导航通道的机电耦合和疾病机制建立了框架，以及促进药物发现。这里,我们用两个具体案例来举例说明这些方法，人Nav1.4和Nav1.7，这可能有助于其他膜蛋白的结构测定。
