Department of Physics, University at Buffalo, Buffalo, New York, United States of America.
PLoS Comput Biol. 2011 Jan 6;7(1):e1001046. doi: 10.1371/journal.pcbi.1001046.
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.
尽管已经有许多关于五聚体配体门控离子通道（pLGIC）门控转换的实验和计算研究，但配体结合如何与通道门控偶联的结构基础仍不清楚。通过使用新开发的内插弹性网络模型（iENM），我们尝试计算了由两个原核 pLGIC 晶体结构捕获的 pLGIC 从关闭构象到开放构象的可能转换途径。iENM 途径预测了一系列结构事件，这些事件始于配体结合环，随后是细胞外和跨膜域之间界面上的两个关键环（环 2 和环 7）的位移、孔衬 M2 螺旋的倾斜/弯曲以及随后的 M4、M3 和 M1 螺旋在跨膜域中的运动。预测的结构事件顺序与烟碱型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 中配体门控通道打开的保守核心机制。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顺序中的关键作用。
