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Structure of the Cardiac Sodium Channel.
Cell ( IF 45.5 ) Pub Date : 2019-12-19 , DOI: 10.1016/j.cell.2019.11.041
Daohua Jiang 1 , Hui Shi 2 , Lige Tonggu 1 , Tamer M Gamal El-Din 1 , Michael J Lenaeus 3 , Yan Zhao 4 , Craig Yoshioka 4 , Ning Zheng 2 , William A Catterall 1
Affiliation  

Voltage-gated sodium channel Nav1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of NaV1.5 at 3.2-3.5 Å resolution. NaV1.5 is distinguished from other sodium channels by a unique glycosyl moiety and loss of disulfide-bonding capability at the NaVβ subunit-interaction sites. The antiarrhythmic drug flecainide specifically targets the central cavity of the pore. The voltage sensors are partially activated, and the fast-inactivation gate is partially closed. Activation of the voltage sensor of Domain III allows binding of the isoleucine-phenylalanine-methionine (IFM) motif to the inactivation-gate receptor. Asp and Ala, in the selectivity motif DEKA, line the walls of the ion-selectivity filter, whereas Glu and Lys are in positions to accept and release Na+ ions via a charge-delocalization network. Arrhythmia mutation sites undergo large translocations during gating, providing a potential mechanism for pathogenic effects. Our results provide detailed insights into Nav1.5 structure, pharmacology, activation, inactivation, ion selectivity, and arrhythmias.

中文翻译:

心脏钠通道的结构。

电压门控钠通道 Nav1.5 产生心脏动作电位并启动心跳。在这里,我们以 3.2-3.5 Å 的分辨率报告 NaV1.5 的结构。NaV1.5 与其他钠通道的区别在于其独特的糖基部分和在 NaVβ 亚基相互作用位点丧失二硫键结合能力。抗心律失常药物氟卡尼专门针对毛孔的中心腔。电压传感器部分激活,快速失活门部分关闭。域 III 电压传感器的激活允许异亮氨酸-苯丙氨酸-蛋氨酸 (IFM) 基序与失活门受体结合。在选择性基序 DEKA 中,Asp 和 Ala 排列在离子选择性过滤器的壁上,而 Glu 和 Lys 处于通过电荷离域网络接受和释放 Na+ 离子的位置。心律失常突变位点在门控期间经历大的易位,为致病作用提供了潜在的机制。我们的结果提供了对 Nav1.5 结构、药理学、激活、失活、离子选择性和心律失常的详细见解。
更新日期:2019-12-19
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