Crystal structure of a voltage-gated sodium channel in two potentially inactivated states

摘要

钾通道有很多已发表的结构，但关于“电压门rn控的钠”(Na_v)通道的结构信息却要少得多，rn尽管它们在神经细胞、肌肉细胞和心脏中的动rn作电位的启动和传播中有重要作用。细菌Narn通道为结构一功能分析提供了一个很好的模rn型系统，本期Nature上有两个小组报告了明显rn处于“非激活”构形的细菌Na通道的×-射线rn晶体结构。Nieng Yan及其同事以3.05埃的分rn辨率确定了来自名为“alplla proteobacterium rnHIMB114”的海洋细菌的Na.Rh的结构。William rnCatterall及其同事以33.2埃的分辨率报告了来自rnArcobacter butzleri、处于两个潜在“非激活”状rn态的Na.Ab)通道的晶体结构。将这些新获得的rn结构与以前所发表的、关于处在一种“pre-open”rn状态的Na.Ab的数据所做的对比，显示了可能rn决定这些通道的机电耦合机制的构形重排。rn这项工作对于各种“通道病”(channelopathies)、rn而且从更广泛意义上来说对于神经活性药物的rn设计都是具有相关性的。%In excitable cells, voltage-gated sodium (Na_v) channels activate to initiate action potentials and then undergo fast and slow inactiva-tion processes that terminate their ionic conductance. Inactivation is a hallmark of Na_v channel function and is critical for control of membrane excitability, but the structural basis for this process has remained elusive. Here we report crystallographic snapshots of the wild-type Na_vAb channel from Arcobacter butzleri captured in two potentially inactivated states at 3.2 A resolution. Compared to previous structures of Na_vAb channels with cysteine mutations in the pore-lining S6 helices (ref. 4), the S6 helices and the intracellular activation gate have undergone significant rearrangements: one pair of S6 helices has collapsed towards the central pore axis and the other S6 pair has moved outward to produce a striking dimer-of-dimers configuration. An increase in global structural asymmetry is observed throughout our wild-type Na_vAb models, reshaping the ion selectivity filter at the extracellular end of the pore, the central cavity and its residues that are analogous to the mammalian drug receptor site, and the lateral pore fenestrations. The voltage-sensing domains have also shifted around the perimeter of the pore module in wild-type Na_vAb, compared to the mutant channel, and local structural changes identify a conserved interaction network that connects distant molecular determinants involved in Na_v channel gating and inactivation. These potential inactivated-state structures provide new insights into Na_v channel gating and novel avenues to drug development and therapy for a range of debilitating Na_v channelopathies.