Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA.
Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080, USA.
J Mol Biol. 2021 Aug 20;433(17):166967. doi: 10.1016/j.jmb.2021.166967. Epub 2021 Mar 29.
Voltage-gated sodium (Na) channels initiate and propagate action potentials in excitable tissues to mediate key physiological processes including heart contraction and nervous system function. Accordingly, Na channels are major targets for drugs, toxins and disease-causing mutations. Recent breakthroughs in cryo-electron microscopy have led to the visualization of human Na1.1, Na1.2, Na1.4, Na1.5 and Na1.7 channel subtypes at high-resolution. These landmark studies have greatly advanced our structural understanding of channel architecture, ion selectivity, voltage-sensing, electromechanical coupling, fast inactivation, and the molecular basis underlying Na channelopathies. Na channel structures have also been increasingly determined in complex with toxin and small molecule modulators that target either the pore module or voltage sensor domains. These structural studies have provided new insights into the mechanisms of pharmacological action and opportunities for subtype-selective Na channel drug design. This review will highlight the structural pharmacology of human Na channels as well as the potential use of engineered and chimeric channels in future drug discovery efforts.
电压门控钠离子（Na）通道在可兴奋组织中启动和传播动作电位，介导包括心脏收缩和神经系统功能在内的关键生理过程。因此，Na 通道是药物、毒素和致病突变的主要靶点。冷冻电子显微镜技术的最新突破使人们能够以高分辨率可视化人类 Na1.1、Na1.2、Na1.4、Na1.5 和 Na1.7 通道亚型。这些具有里程碑意义的研究极大地促进了我们对通道结构、离子选择性、电压感应、机电偶联、快速失活以及 Na 通道病的分子基础的结构理解。Na 通道结构也越来越多地与靶向孔模块或电压传感器域的毒素和小分子调节剂复合物确定。这些结构研究为药理学作用机制提供了新的见解，并为 Na 通道药物设计的亚型选择性提供了机会。本综述将重点介绍人类 Na 通道的结构药理学，以及工程化和嵌合通道在未来药物发现工作中的潜在用途。
