The crystal structure of a voltage-gated sodium channel.
The crystal structure of a voltage-gated sodium channel.
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DOI：
10.1038/nature10238
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发表时间：
2011-07-10
期刊：
影响因子：
64.8
通讯作者：
Catterall, William A.
中科院分区：
文献类型：
--
作者：
Payandeh, Jian;Scheuer, Todd;Zheng, Ning;Catterall, William A.
电压门控钠通道在可兴奋细胞中启动电信号，并且是药物和疾病突变的分子靶点，但其电压依赖性激活、离子选择性和药物阻断的结构基础尚不清楚。在这里，我们报告了来自Arcobacter butzleri（NavAb）的电压门控Na+通道的晶体结构，该通道被四个激活的电压传感器以2.7 Å的分辨率捕获在闭孔构象中。精氨酸门控电荷在电压传感器内产生多种亲水性相互作用，包括与蛋白质骨架的意外氢键。与以前的开孔钾通道结构的比较表明，电压传感器结构域和S4-S5接头通过围绕孔模块基部的铰链一起枢转来扩张中心孔。NavAb选择性过滤器较短，约6.5 μ m宽，充满水，在离子传导途径的最西部周围有四条酸性侧链。这种独特的结构提供了高场强阴离子配位位点，其通过与谷氨酸侧链的直接相互作用通过部分脱水赋予Na+选择性。孔模块侧面的开窗意外地被延伸到中心腔中的脂肪酰基链穿透，并且这些入口足够大以供小的疏水性孔阻断药物进入。
Voltage-gated sodium channels initiate electrical signaling in excitable cells and are the molecular targets for drugs and disease mutations, but the structural basis for their voltage-dependent activation, ion selectivity, and drug block is unknown. Here, we report the crystal structure of a voltage-gated Na+-channel from Arcobacter butzleri (NavAb) captured in a closed-pore conformation with four activated voltage-sensors at 2.7 Å resolution. The arginine gating charges make multiple hydrophilic interactions within the voltage-sensor, including unanticipated hydrogen bonds to the protein backbone. Comparisons to previous open-pore potassium channel structures suggest that the voltage-sensor domains and the S4-S5 linkers dilate the central pore by pivoting together around a hinge at the base of the pore module. The NavAb selectivity filter is short, ~6.5 Å wide, and water-filled, with four acidic side-chains surrounding the narrowest part of the ion conduction pathway. This unique structure presents a high field-strength anionic coordination site, which confers Na+-selectivity through partial dehydration via direct interaction with glutamate side-chains. Fenestrations in the sides of the pore module are unexpectedly penetrated by fatty acyl chains that extend into the central cavity, and these portals are large enough for the entry of small, hydrophobic pore-blocking drugs.
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影响因子：
56.9
作者：
Doyle, DA;Cabral, JM;MacKinnon, R
通讯作者：
MacKinnon, R
DOI：
10.1073/pnas.0806486105
发表时间：
2008-09-30
影响因子：
11.1
作者：
DeCaen, Paul G.;Yarov-Yarovoy, Vladimir;Catterall, William A.
通讯作者：
Catterall, William A.
影响因子：
16.2
作者：
ELLINOR, PT;YANG, J;TSIEN, RW
通讯作者：
TSIEN, RW
影响因子：
3.4
作者：
Favre, I;Moczydlowski, E;Schild, L
通讯作者：
Schild, L
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH