The human Nav1.1 sodium channel: Structure, Function, Drug Binding and Molecular Dynamics of Homologues Bearing Disease-Related Mutations

电压门控钠通道(NAV)在神经信号传递中起着至关重要的作用，因为它们的开放启动了动作电位。人类hNav1.1亚型的突变会导致一系列疾病，包括癫痫。因此，hNav1.1是药物开发的关键目标。使用原核生物NavM(我们已经确定了其晶体结构)，它具有与hNav1.1高度相似的结构和功能特性，学生将创建与hNav1.1疾病相关的突变，并使用结晶学、低温EM、分子动力学计算以及生物物理、生化和功能表征在分子水平上检查它们的影响，使用这些信息来探索潜在的新药候选。

Voltage-gated sodium channels (Navs) play essential roles in nerve signal transmission, as their opening initiates the action potential. Mutations in the human hNav1.1 isoform produce a range of diseases, including epilepsy. hNav1.1 therefore represents a key target for pharmaceutical drug development. Using the prokaryotic NavMs (whose crystal structure we have determined), which has highly similar structural and functional properties to hNav1.1, the student will create mutants associated with hNav1.1 diseases, and examine their effects on a molecular level using crystallography, cryoEM, molecular dynamics calculations, and biophysical, biochemical, and functional characterizations, using this information to explore potential new drug candidates.