Department of Biophysical Chemistry, School of Pharmaceutical Sciences, Wakayama Medical University, 25-1, Shichibancho, Wakayama, 640-8156, Japan.
Cellular and Structural Physiology Institute (CeSPI), Nagoya University, Furo-cho, Chikusa, Nagoya, 464-8601, Japan.
Nat Commun. 2023 Jul 15;14(1):4236. doi: 10.1038/s41467-023-39987-0.
Divalent cation block is observed in various tetrameric ion channels. For blocking, a divalent cation is thought to bind in the ion pathway of the channel, but such block has not yet been directly observed. So, the behaviour of these blocking divalent cations remains still uncertain. Here, we elucidated the mechanism of the divalent cation block by reproducing the blocking effect into NavAb, a well-studied tetrameric sodium channel. Our crystal structures of NavAb mutants show that the mutations increasing the hydrophilicity of the inner vestibule of the pore domain enable a divalent cation to stack on the ion pathway. Furthermore, non-equilibrium molecular dynamics simulation showed that the stacking calcium ion repel sodium ion at the bottom of the selectivity filter. These results suggest the primary process of the divalent cation block mechanism in tetrameric cation channels.
二价阳离子阻塞在各种四聚体离子通道中都有观察到。对于阻塞，二价阳离子被认为结合在通道的离子通道中，但这种阻塞尚未被直接观察到。因此，这些阻断二价阳离子的行为仍然不确定。在这里，我们通过将阻塞效应复制到 NavAb 中来阐明二价阳离子阻塞的机制，NavAb 是一种研究得很好的四聚体钠通道。我们的 NavAb 突变体晶体结构表明，增加孔域内小室亲水性的突变使二价阳离子能够堆积在离子通道上。此外，非平衡分子动力学模拟表明，堆积的钙离子排斥位于选择性过滤器底部的钠离子。这些结果表明了四聚体阳离子通道中二价阳离子阻塞机制的主要过程。
Zotero 插件
