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A Refined Open State of the Glycine Receptor Obtained via Molecular Dynamics Simulations.
Structure ( IF 5.7 ) Pub Date : 2019-11-18 , DOI: 10.1016/j.str.2019.10.019
Marc A Dämgen 1 , Philip C Biggin 1
Affiliation  

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.

中文翻译:

通过分子动力学模拟获得的甘氨酸受体的精制开放态。

五聚体配体门控离子通道是介导快速神经传递的关键因素。甘氨酸受体是该受体家族的氯化物选择性成员,其介导抑制性突触传递,并牵涉包括自闭症和上睑下垂的神经系统疾病。X射线晶体学和低温电子显微镜(cryo-EM)研究都对它们进行了结构表征,而后者引起了人们提出的可能的开放状态。但是,由于这种开放状态结构在分子动力学模拟中迅速崩溃,因此最近的工作对这种开放状态结构的生理相关性提出了质疑。这里,我们表明,可以通过仔细的平衡方案来避免崩溃,该方案可以调和原始密度图的更多问题区域,并提供稳定的开放状态,该状态显示出频繁的选择性氯离子渗透。在这项工作中开发的协议提供了一种手段,可以完善整个五聚体配体门控离子通道超家族的开放式结构,并与cryo-EM结构协调一致。
更新日期:2019-11-18
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