Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, L8S 4K1, Canada.
Trends Pharmacol Sci. 2013 Mar;34(3):154-61. doi: 10.1016/j.tips.2013.01.002. Epub 2013 Feb 1.
Ion channels are targets for many naturally occurring toxins and small-molecule drugs. Despite great progress in the X-ray crystallography of ion channels, we still do not have a complete understanding of the atomistic mechanisms of channel modulation by ligands. In particular, the importance of the simultaneous interaction of permeant ions with the ligand and the channel protein has not been the focus of much attention. Considering these interactions often allows one to rationalize the highly diverse experimental data within the framework of relatively simple structural models. This has been illustrated in earlier studies on the action of local anesthetics, sodium channel activators, as well as blockers of potassium and calcium channels. Here, we discuss the available data with a view to understanding the use-, voltage-, and current carrying cation-dependence of the ligand action, paradoxes in structure--activity relationships, and effects of mutations in these ion channels.
离子通道是许多天然存在的毒素和小分子药物的靶标。尽管离子通道的 X 射线晶体学取得了很大进展，但我们仍然不完全了解配体对通道调节的原子机制。特别是，配体和通道蛋白与通透离子同时相互作用的重要性并没有引起太多关注。考虑到这些相互作用，通常可以在相对简单的结构模型框架内使高度多样化的实验数据合理化。这在以前关于局部麻醉剂、钠通道激活剂以及钾和钙通道阻滞剂作用的研究中已经得到了说明。在这里，我们讨论了现有数据，以期了解配体作用的用途、电压和电流依赖性、结构-活性关系中的矛盾以及这些离子通道突变的影响。
