A Refined Open State of the Glycine Receptor Obtained Via Molecular Dynamics Simulations
A Refined Open State of the Glycine Receptor Obtained Via Molecular Dynamics Simulations
复制标题
通过分子动力学模拟获得的甘氨酸受体的精细开放状态
DOI：
10.1101/668830
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Dämgen M
中科院分区：
文献类型：
--
作者：
Dämgen M
五聚体配基门控离子通道是调节快速神经传递的关键分子。甘氨酸受体是该受体家族中氯离子选择性的成员，介导抑制性突触传递，并与包括自闭症和亢进在内的神经疾病有关。用X射线结晶学和低温电子显微镜(Cryo-EM)研究了它们的结构，后者导致了可能的开放状态。然而，最近的工作质疑这种开放状态结构的生理学相关性，因为它在分子动力学模拟中迅速崩溃。这里，我们表明，崩溃可以通过仔细的平衡协议来避免，该协议协调了原始密度图中更有问题的区域，并提供了稳定的开放状态，显示了频繁的选择性氯渗透。这项工作中开发的协议提供了一种手段来精炼整个五聚体配体门控离子通道超家族的开放类结构，并将先前的问题与Cryo-EM结构相一致。
Pentameric ligand-gated ion channels are key players in mediating fast neurotransmission. Glycine receptors are chloride-selective members of this receptor family that mediate inhibitory synaptic transmission and are implicated in neurological disorders including autism and hyperekplexia. They have been structurally characterized by both X-ray crystallography and cryoelectron microscopy (cryo-EM) studies, with the latter giving rise to what was proposed as a possible open state. However, recent work has questioned the physiological relevance of this open state structure, since it rapidly collapses in molecular dynamics simulations. Here, we show that the collapse can be avoided by a careful equilibration protocol that reconciles the more problematic regions of the original density map and gives a stable open state that shows frequent selective chloride permeation. The protocol developed in this work provides a means to refine open-like structures of the whole pentameric ligand-gated ion channel superfamily and reconciles the previous issues with the cryo-EM structure.