Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA.
Molecular Medicine, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
Nat Commun. 2021 Jan 4;12(1):128. doi: 10.1038/s41467-020-20078-3.
Voltage-gated sodium (Na) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac Na1.5 channels with IC = 11.4 nM. Here we reveal the structure of LqhIII bound to Na1.5 at 3.3 Å resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na permeation, revealing why LqhIII slows inactivation of Na channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of Na channels.
电压门控钠离子 (Na) 通道在可兴奋细胞中引发动作电位，其功能可被强效门控调节剂毒素改变。来自死亡追踪者蝎子的 α-毒素 LqhIII 抑制心脏 Na1.5 通道的快速失活，IC = 11.4 nM。在这里，我们通过 cryo-EM 揭示了与 Na1.5 结合的 LqhIII 的结构，分辨率为 3.3Å。LqhIII 锚定在电压感应域 IV 上方，楔入 S1-S2 和 S3-S4 接头之间，将 S4 段的门控电荷困在由四个离子对稳定的独特中间激活状态。这种构象变化向内传播，削弱了快速失活门的结合，有利于打开激活门。然而，这些变化不允许 Na 渗透，这解释了为什么 LqhIII 会减缓 Na 通道的失活但不会打开它们。我们的研究结果为门控调节剂毒素结合、电压传感器捕获和 Na 通道快速失活的结构基础提供了重要见解。
