Cheng Xiaolin, Ivanov Ivaylo, Wang Hailong, Sine Steven M, McCammon J Andrew
Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA.
Biophys J. 2009 Jun 3;96(11):4502-13. doi: 10.1016/j.bpj.2009.03.018.
The ligand-gated ion channel from Erwinia chrysanthemi (ELIC) is a prokaryotic homolog of the eukaryotic nicotinic acetylcholine receptor (nAChR) that responds to the binding of neurotransmitter acetylcholine and mediates fast signal transmission. ELIC is similar to the nAChR in its primary sequence and overall subunit organization, but despite their structural similarity, it is not clear whether these two ligand-gated ion channels operate in a similar manner. Further, it is not known to what extent mechanistic insights gleaned from the ELIC structure translate to eukaryotic counterparts such as the nAChR. Here we use molecular-dynamics simulations to probe the conformational dynamics and hydration of the transmembrane pore of ELIC. The results are compared with those from our previous simulation of the human alpha7 nAChR. Overall, ELIC displays increased stability compared to the nAChR, whereas the two proteins exhibit remarkable similarity in their global motion and flexibility patterns. The majority of the increased stability of ELIC does not stem from the deficiency of the models used in the simulations, and but rather seems to have a structural basis. Slightly altered dynamical correlation features are also observed among several loops within the membrane region. In sharp contrast to the nAChR, ELIC is completely dehydrated from the pore center to the extracellular end throughout the simulation. Finally, the simulation of an ELIC mutant substantiates the important role of F246 on the stability, hydration and possibly function of the ELIC channel.
来自菊欧文氏菌的配体门控离子通道（ELIC）是真核生物烟碱型乙酰胆碱受体（nAChR）的原核同源物，它对神经递质乙酰胆碱的结合作出反应并介导快速信号传递。ELIC在其一级序列和整体亚基组织方面与nAChR相似，但尽管它们结构相似，尚不清楚这两种配体门控离子通道是否以相似的方式运作。此外，从ELIC结构中获得的机制性见解在多大程度上适用于诸如nAChR等真核生物对应物尚不清楚。在这里，我们使用分子动力学模拟来探究ELIC跨膜孔的构象动力学和水合作用。将结果与我们之前对人类α7 nAChR的模拟结果进行比较。总体而言，与nAChR相比，ELIC显示出更高的稳定性，而这两种蛋白质在其整体运动和灵活性模式上表现出显著的相似性。ELIC稳定性增加的大部分并非源于模拟中使用的模型的缺陷，而是似乎有结构基础。在膜区域内的几个环之间也观察到了略有改变的动力学相关特征。与nAChR形成鲜明对比的是，在整个模拟过程中，ELIC从孔中心到细胞外末端完全脱水。最后，对ELIC突变体的模拟证实了F246对ELIC通道的稳定性、水合作用以及可能的功能的重要作用。
