Structure and Function of Voltage-Gated Ion Channels and their Applications for Rational Drug Design

钠通道是一种膜蛋白，能够调节钠离子穿过细胞膜的流动。它们存在于所有真核生物和一系列细菌中。在人类中，它们在健康生物体中表现出广泛的功能，并且是用于治疗神经和心脏疾病的许多药物的靶标。在昆虫中，它们是许多杀虫剂的靶位点，也是抗性发展的来源。本提案旨在确定一些天然和突变钠通道及相关离子通道的晶体结构，并将其结构与功能研究进行比较，以更好地了解通道打开和关闭以及选择性转运钠离子的方式。通过研究这些通道与实际和潜在的药物和配体的复合物，这将促进新的和高度特异性的杀虫剂和药物的合理开发。

Sodium channels are membrane proteins which enable the regulation and flow of sodium ions across cell membranes. They are found in all eukaryotic organisms and a range of bacteria. In humans they exhibit a wide range of functions in the healthy organism, and are the targets for many pharmaceutical drugs for treatment of neurological and cardiac diseases. In insects they are the target sites of many insecticides, and also the source of development of resistance. This proposal is to determine the crystal structures of a number of natural and mutant sodium channels and related ion channels, and compare their structures with functional studies to better understand the means by which the channels open and close and selectively translocate sodium ions. By examining complexes of these channels with actual and potential drugs and ligands, this should enhance the rational development of new and highly specific insecticides and pharmaceuticals.