Decrypting the sequence of structural events during the gating transition of pentameric ligand-gated ion channels based on an interpolated elastic network model.
Decrypting the sequence of structural events during the gating transition of pentameric ligand-gated ion channels based on an interpolated elastic network model.
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DOI：
10.1371/journal.pcbi.1001046
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发表时间：
2011-01-06
影响因子：
4.3
通讯作者：
Auerbach A
中科院分区：
文献类型：
--
作者：
Zheng W;Auerbach A
尽管对五聚体配体门控离子通道（pLGIC）的门控转变进行了许多实验和计算研究，但配体结合如何耦合到通道门控的结构基础仍然未知。通过使用新开发的插值弹性网络模型（iENM），我们尝试计算由两个原核 pLGIC 的晶体结构捕获的 pLGIC 从封闭通道构象到开放通道构象的可能转变路径。 iENM 途径预测一系列结构事件，该事件从配体结合环开始，随后是细胞外和跨膜结构域之间界面处两个关键环（环 2 和环 7）的位移、孔衬 M2 螺旋的倾斜/弯曲，以及随后跨膜结构域中 M4、M3 和 M1 螺旋的运动。结构事件的预测顺序与烟碱乙酰胆碱受体突变体α亚基的Φ值分析基本一致，这支持了pLGIC中配体门控通道开放的保守核心机制。进一步的扰动分析支持了某些亚基内和亚基间相互作用在决定上述事件序列中的关键作用。五聚体配体门控离子通道是一类膜蛋白，可响应特定配体的结合而打开/关闭离子传导通道。该家族的一些成员，包括烟碱乙酰胆碱受体，在突触信号转导中发挥关键的生理作用。尽管对这些五聚体离子通道的门控转变进行了许多实验和计算研究，但配体结合如何耦合通道开放的结构基础仍然不确定。特别是，门控跃迁的全原子计算机模拟仅限于纳秒～微秒的时间尺度，而整个跃迁需要数十微秒。在这项研究中，我们采用了高效的粗粒度建模方法来剖析门控转换背后的结构事件序列。该模型的预测与烟碱乙酰胆碱受体突变体的动力学分析基本一致。这项研究建立了一个有用的计算框架来模拟五聚体配体门控离子通道的功能动力学。
Despite many experimental and computational studies of the gating transition of pentameric ligand-gated ion channels (pLGICs), the structural basis of how ligand binding couples to channel gating remains unknown. By using a newly developed interpolated elastic network model (iENM), we have attempted to compute a likely transition pathway from the closed- to the open-channel conformation of pLGICs as captured by the crystal structures of two prokaryotic pLGICs. The iENM pathway predicts a sequence of structural events that begins at the ligand-binding loops and is followed by the displacements of two key loops (loop 2 and loop 7) at the interface between the extracellular and transmembrane domain, the tilting/bending of the pore-lining M2 helix, and subsequent movements of M4, M3 and M1 helices in the transmembrane domain. The predicted order of structural events is in broad agreement with the Φ-value analysis of α subunit of nicotinic acetylcholine receptor mutants, which supports a conserved core mechanism for ligand-gated channel opening in pLGICs. Further perturbation analysis has supported the critical role of certain intra-subunit and inter-subunit interactions in dictating the above sequence of events. Pentameric ligand-gated ion channels are a family of membrane proteins that open/close an ion-conducting channel in response to the binding of specific ligands. Some members of the family, including nicotinic acetylcholine receptors, play key physiological roles in signal transduction at synapses. Despite many experimental and computational studies of the gating transition of these pentameric ion channels, the structural basis of how ligand binding couples to channel opening remains uncertain. In particular, the all-atom computer simulation of the gating transition is limited to nanosecond ∼ microsecond time scales while the entire transition takes tens of microseconds. In this study, we have employed a highly efficient coarse-grained modeling method to dissect the sequence of structural events underlying the gating transition. The model predictions are in broad agreement with the kinetic analysis of mutants of nicotinic acetylcholine receptors. This study has established a useful computational framework to simulate the functional dynamics of pentameric ligand-gated ion channels.
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