Mutant bacterial sodium channels as models for local anesthetic block of eukaryotic proteins

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Natalie E. Smith, B. Corry
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引用次数: 9

Abstract

ABSTRACT Voltage gated sodium channels are the target of a range of local anesthetic, anti-epileptic and anti-arrhythmic compounds. But, gaining a molecular level understanding of their mode of action is difficult as we only have atomic resolution structures of bacterial sodium channels not their eukaryotic counterparts. In this study we used molecular dynamics simulations to demonstrate that the binding sites of both the local anesthetic benzocaine and the anti-epileptic phenytoin to the bacterial sodium channel NavAb can be altered significantly by the introduction of point mutations. Free energy techniques were applied to show that increased aromaticity in the pore of the channel, used to emulate the aromatic residues observed in eukaryotic Nav1.2, led to changes in the location of binding and dissociation constants of each drug relative to wild type NavAb. Further, binding locations and dissociation constants obtained for both benzocaine (660 μM) and phenytoin (1 μ M) in the mutant channels were within the range expected from experimental values obtained from drug binding to eukaryotic sodium channels, indicating that these mutant NavAb may be a better model for drug binding to eukaryotic channels than the wild type.
突变细菌钠通道作为真核蛋白局部麻醉阻滞的模型
电压门控钠通道是一系列局部麻醉、抗癫痫和抗心律失常化合物的靶点。但是,从分子水平上理解它们的作用方式是困难的,因为我们只有细菌钠通道的原子分辨率结构,而不是真核细胞的对应结构。在这项研究中,我们使用分子动力学模拟来证明局麻药苯佐卡因和抗癫痫苯妥英与细菌钠通道NavAb的结合位点可以通过引入点突变而显着改变。自由能技术表明,通道孔中的芳香性增加,用于模拟真核生物Nav1.2中观察到的芳香残基,导致每种药物相对于野生型NavAb的结合位置和解离常数发生变化。此外,突变体通道中苯佐卡因(660 μM)和苯妥英(1 μM)的结合位置和解离常数均在真核钠通道药物结合实验值的预期范围内,表明这些突变体可能比野生型更适合药物与真核通道的结合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Channels
Channels 生物-生化与分子生物学
CiteScore
5.90
自引率
0.00%
发文量
21
审稿时长
6-12 weeks
期刊介绍: Channels is an open access journal for all aspects of ion channel research. The journal publishes high quality papers that shed new light on ion channel and ion transporter/exchanger function, structure, biophysics, pharmacology, and regulation in health and disease. Channels welcomes interdisciplinary approaches that address ion channel physiology in areas such as neuroscience, cardiovascular sciences, cancer research, endocrinology, and gastroenterology. Our aim is to foster communication among the ion channel and transporter communities and facilitate the advancement of the field.
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