Abstract：
Nav1.7 represents a preeminent target for next-generation analgesics for its critical role in pain sensation. Here we report a 2.2-Å resolution cryo-EM structure of wild-type (WT) Nav1.7 complexed with the β1 and β2 subunits that reveals several previously indiscernible cytosolic segments. Reprocessing of the cryo-EM data for our reported structures of Nav1.7(E406K) bound to various toxins identifies two distinct conformations of S6IV, one composed of α helical turns only and the other containing a π helical turn in the middle. The structure of ligand-free Nav1.7(E406K), determined at 3.5-Å resolution, is identical to the WT channel, confirming that binding of Huwentoxin IV or Protoxin II to VSDII allosterically induces the α → π transition of S6IV. The local secondary structural shift leads to contraction of the intracellular gate, closure of the fenestration on the interface of repeats I and IV, and rearrangement of the binding site for the fast inactivation motif.
摘要：
Nav1.7由于其在痛觉中的关键作用而代表了下一代镇痛药的重要目标。在这里，我们报告了与β1和β2亚基复合的野生型（WT）Nav1.7的2.2_分辨率低温EM结构，该结构揭示了几个以前无法识别的胞浆片段。我们报告的Nav1.7（E406K）与各种毒素结合的结构的低温EM数据的再处理鉴定了S6IV的两种不同构象，一个仅由α螺旋圈组成，另一个在中间包含π螺旋圈。无配体的结构Nav1.7（E406K），在3.5-贝达分辨率下确定，与WT通道相同，确认HuwentoxinIV或原毒素II与VSDII的结合变构诱导了S6IV的α→π转变。局部的二级结构转变导致细胞内门收缩,重复I和IV的界面上的开窗闭合，以及快速失活基序的结合位点的重排。
