Understanding Sodium Channel Function and Modulation Using Atomistic Simulations of Bacterial Channel Structures.
Understanding Sodium Channel Function and Modulation Using Atomistic Simulations of Bacterial Channel Structures.
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DOI：
10.1016/bs.ctm.2016.07.002
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发表时间：
2016
影响因子：
--
通讯作者：
Allen TW
中科院分区：
文献类型：
--
作者：
Boiteux C;Allen TW
钠通道是神经系统中参与电信号的主要蛋白质，使心跳和大脑活动等关键功能得以实现。细菌钠离子通道的新的高分辨率X射线结构为观察这些蛋白质在分子水平上如何运作创造了机会。要克服的一个重要挑战是建立哺乳动物和细菌通道的结构和功能之间的关系。已知细菌钠通道表现出哺乳动物对应物的主要结构特征，以及几个关键的功能特征，包括选择性离子传导、电压依赖性门控、基于孔的失活以及通过局部麻醉剂、抗癫痫药和抗癫痫药的调节。在过去的几年里，模拟已经开始揭示这些特征。尽管细菌和哺乳动物通道的选择性特征存在偏差，但模拟已经揭示了与Na+结合到由带电谷氨酸侧链建立的高场强位点相关的多离子传导机制的性质。模拟表明蛋白质的灵活性达到了令人惊讶的水平，表明这些侧链是渗透过程的积极参与者。他们还发现了蛋白质结构的变化，导致激活门的不对称崩溃，这被认为与失活的结构相对应。这些观察结果提供了检查状态依赖性药物活性的机制的可能性，重点是细菌通道中的孔阻塞和基于孔的缓慢失活，而没有在真核通道中看到的多个时间尺度上的失活的复杂性。模拟提供了药物相互作用的分子观点，与哺乳动物通道中预测的位点一致，以及丰富的其他位点作为潜在的新药靶点。在这一章中，我们调查的钠通道功能的新见解，已经出现了从简单的细菌通道的研究，提供了一个很好的学习平台，和有前途的途径，机制的发现和药理学的发展。
Sodium channels are chief proteins involved in electrical signaling in the nervous system, enabling critical functions like heartbeat and brain activity. New high-resolution X-ray structures for bacterial sodium channels have created an opportunity to see how these proteins operate at the molecular level. An important challenge to overcome is establishing relationships between the structures and functions of mammalian and bacterial channels. Bacterial sodium channels are known to exhibit the main structural features of their mammalian counterparts, as well as several key functional characteristics, including selective ion conduction, voltage-dependent gating, pore-based inactivation and modulation by local anesthetic, anti-arrhythmic and anti-epileptic drugs. Simulations have begun to shed light on each of these features in the past few years. Despite deviations in selectivity signatures for bacterial and mammalian channels, simulations have uncovered the nature of the multi-ion conduction mechanism associated with Na+ binding to a high field strength site established by charged glutamate side chains. Simulations demonstrated a surprising level of flexibility of the protein, showing that these side chains are active participants in the permeation process. They have also uncovered changes in protein structure, leading to asymmetrical collapses of the activation gate that have been proposed to correspond to inactivated structures. These observations offer the potential to examine the mechanisms of state-dependent drug activity, focusing on pore-blocking and pore-based slow inactivation in bacterial channels, without the complexities of inactivation on multiple timescales seen in eukaryotic channels. Simulations have provided molecular views of the interactions of drugs, consistent with sites predicted in mammalian channels, as well as a wealth of other sites as potential new drug targets. In this chapter we survey the new insights into sodium channel function that have emerged from studies of simpler bacterial channels, which provide an excellent learning platform, and promising avenues for mechanistic discovery and pharmacological development.
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影响因子：
3.8
作者：
Allen, Toby W;Andersen, O S;Roux, Benoit
通讯作者：
Roux, Benoit
DOI：
10.1085/jgp.200910211
发表时间：
2009-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
Boda D;Valiskó M;Henderson D;Eisenberg B;Gillespie D;Nonner W
通讯作者：
Nonner W
影响因子：
3.4
作者：
Ballesteros, JA;Deupi, X;Pardo, L
通讯作者：
Pardo, L
影响因子：
5.5
作者：
Balser, JR;Nuss, HB;Tomaselli, GF
通讯作者：
Tomaselli, GF
影响因子：
3.8
作者：
BEAN, BP;COHEN, CJ;TSIEN, RW
通讯作者：
TSIEN, RW