Structural basis for gating pore current in periodic paralysis.
Structural basis for gating pore current in periodic paralysis.
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DOI：
10.1038/s41586-018-0120-4
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发表时间：
2018-05
期刊：
影响因子：
64.8
通讯作者：
Catterall WA
中科院分区：
文献类型：
--
作者：
Jiang D;Gamal El-Din TM;Ing C;Lu P;Pomès R;Zheng N;Catterall WA
钾敏感性低钾性和正常钾性周期性麻痹（HypoPP，NormoPP）是一种遗传性骨骼肌疾病，其特征是松弛性肌无力发作。它们是由电压门控钠通道Nav1.4或钙通道Cav1.1的电压传感器（VS）中S4跨膜片段中的一个门控电荷突变引起的。最外层精氨酸门控电荷（R1和R2）的突变通过在VS中产生致病性门控孔（阳离子在静息状态下通过该孔泄漏）而导致HypoPP。第三精氨酸门控电荷（R3）的突变由于激活/失活状态下的阳离子泄漏而引起NormoPP。在这里，我们展示了模型细菌钠通道NaVAb中这些致病性门控孔的高分辨率结构。NaVAb中R2的突变在静息状态下产生门控孔电流，而R3的突变在活化/失活状态下产生门控孔电流。R2 G和R3 G突变对VS的骨架结构没有影响，但在疏水收缩位点（HCS）附近产生了水空间，该疏水收缩位点控制通过VS的门控电荷运动。R3 G突变将细胞外水裂缝完全延伸通过活化的VS。尽管R2 G突变在活化状态下不产生连续的水通路，静止状态的分子模拟揭示了一个完整的水可进入的途径。与胍盐复合的NaVAb/R2 G的晶体结构定义了潜在的药物靶位点。分子动力学模拟说明了Na+渗透通过突变门控孔与门控电荷R4的构象波动一致的机制。我们的研究结果揭示了原子水平上周期性麻痹的致病机制，并建议设计可以防止离子泄漏并缓解这些发作性疾病症状的药物。
Potassium-sensitive Hypokalemic and Normokalemic Periodic Paralysis (HypoPP, NormoPP) are inherited skeletal muscle diseases characterized by episodes of flaccid muscle weakness. They are caused by mutations in one gating charge in an S4 transmembrane segment in the voltage sensor (VS) of voltage-gated sodium channel Nav1.4 or calcium channel Cav1.1. Mutations of the outermost arginine gating charges (R1 and R2) cause HypoPP by creating a pathogenic gating pore in the VS through which cations leak in the resting state. Mutations of the third arginine gating charge (R3) cause NormoPP owing to cationic leak in activated/inactivated states. Here we present high-resolution structures of these pathogenic gating pores in the model bacterial sodium channel NaVAb. Mutation of R2 in NaVAb gives gating pore current in resting states, whereas mutation of R3 gives gating pore current in activated/inactivated states. Mutations R2G and R3G have no effect on backbone structures of VS, but create aqueous space near the hydrophobic constriction site (HCS) that controls gating charge movement through VS. The R3G mutation extends the extracellular aqueous cleft completely through the activated VS. Although the R2G mutation does not create a continuous aqueous pathway in the activated state, molecular modeling of the resting state reveals a complete water-accessible pathway. Crystal structures of NaVAb/R2G in complex with guanidinium define a potential drug target site. Molecular dynamics simulations illustrate the mechanism of Na+ permeation through the mutant gating pore in concert with conformational fluctuations of gating charge R4. Our results reveal pathogenic mechanisms of periodic paralysis at the atomic level and suggest designs of drugs that may prevent ionic leak and provide symptomatic relief from these episodic diseases.
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DOI：
10.1085/jgp.201311012
发表时间：
2013-09
期刊：
The Journal of general physiology
影响因子：
--
作者：
Gamal El-Din TM;Martinez GQ;Payandeh J;Scheuer T;Catterall WA
通讯作者：
Catterall WA
影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.5
作者：
Hess, Berk
通讯作者：
Hess, Berk
影响因子：
2.9
作者：
HOOVER, WG
通讯作者：
HOOVER, WG