PDF(Pubmed)
Abstract：
Small-molecule modulators of diverse voltage-gated K+ (Kv) channels may help treat a wide range of neurological disorders. However, developing effective modulators requires understanding of their mechanism of action. We apply an orthogonal approach to elucidate the mechanism of action of an imidazolidinedione derivative (AUT5), a highly selective positive allosteric modulator of Kv3.1 and Kv3.2 channels. AUT5 modulation involves positive cooperativity and preferential stabilization of the open state. The cryo-EM structure of the Kv3.1/AUT5 complex at a resolution of 2.5 Å reveals four equivalent AUT5 binding sites at the extracellular inter-subunit interface between the voltage-sensing and pore domains of the channel\'s tetrameric assembly. Furthermore, we show that the unique extracellular turret regions of Kv3.1 and Kv3.2 essentially govern the selective positive modulation by AUT5. High-resolution apo and bound structures of Kv3.1 demonstrate how AUT5 binding promotes turret rearrangements and interactions with the voltage-sensing domain to favor the open conformation.
摘要：
不同电压门控K+(Kv)通道的小分子调节剂可以帮助治疗广泛的神经障碍。然而,开发有效的调节剂需要了解它们的作用机制。我们应用正交方法来阐明咪唑烷二酮衍生物（AUT5）的作用机理，Kv3.1和Kv3.2通道的高度选择性正变构调节剂。AUT5调制涉及开放状态的正协同性和优先稳定。Kv3.1/AUT5复合物的cryo-EM结构的分辨率为2.5µ，揭示了通道四聚体组装的电压感应和孔域之间的细胞外亚基间界面处的四个等效AUT5结合位点。此外，我们表明，Kv3.1和Kv3.2的独特细胞外转塔区域基本上控制了AUT5的选择性正调制。Kv3.1的高分辨率apo和结合结构展示了AUT5结合如何促进转塔重排和与电压感应域的相互作用以有利于开放构象。
