Alternative Binding Mode of Full and Partial Agonists in a Pentameric Ligand-Gated Ion Channel Stabilises Loop C in an Open Conformation
Alternative Binding Mode of Full and Partial Agonists in a Pentameric Ligand-Gated Ion Channel Stabilises Loop C in an Open Conformation
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五聚体配体门控离子通道中完全和部分激动剂的替代结合模式使环 C 稳定在开放构象中
DOI：
10.1016/j.bpj.2017.11.1694
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发表时间：
2018
影响因子：
3.4
通讯作者：
Dämgen M
中科院分区：
文献类型：
--
作者：
Dämgen M
1英国牛津大学生物化学系，2英国伦敦大学学院神经科学、生理学和药理学系，伦敦大学学院，伦敦。五聚体配体门控离子通道对于快速突触传递和重要的药物靶点至关重要。在激动剂结合时，跨膜孔打开，允许离子流入细胞。虽然具有不同能力的激动剂打开离子通道是已知的，在原子分辨率的部分激动的解释仍然是一个未解决的问题。对这一点的理解可以用于药物设计，因为理想的治疗药物应该引起微调的离子流，即根据临床情况，在完全激动剂和沉默拮抗剂之间的光谱的特定位置。我们已经进行了分子动力学模拟的甘氨酸受体与完全和部分激动剂的正构结合位点。所观察到的主要结合模式的甘氨酸是在最近的晶体结构，其中密度的激动剂与一个稳定的水分子在结合口袋中是可辨别的非常一致。在这里，我们报告了一种替代的结合模式，位于稍微远离跨膜结构域，在亚基接口，稳定环C在一个开放的构象。对于完全和部分激动剂，这种替代姿势的稳定性不同，但结果与环C的构象与不同激动剂的效率相关的观点一致。将讨论的自由能计算的上下文中的一系列不同的激动剂的主要和这种替代的结合模式之间的差异。结果表明，这些受体中配体结合的动力学比最初设想的更为复杂。
1Department of Biochemistry, University of Oxford, Oxford, United Kingdom, 2Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. Pentameric ligand-gated ion channels are crucial for fast synaptic transmission and important drug targets. Upon agonist binding the transmembrane pore opens, allowing ions to flow into the cell. While agonists with varying ability to open the ion channel are known, an explanation of partial agonism at atomistic resolution remains an unsolved problem. An understanding of this could be exploited for drug design, as the ideal therapeutic drug should elicit a fine-tuned ion flow that is, depending on the clinical situation, at a specific position of the spectrum between a full agonist and a silent antagonist. We have performed molecular dynamics simulations of the glycine receptor with full and partial agonists in the orthosteric binding site. The observed principal binding mode of glycine is in excellent agreement with a recent crystal structure where density of the agonist with a stable water molecule in the binding pocket is discernible. Here, we report an alternative binding mode, located slightly further away from the transmembrane domain, at the subunit interface that stabilises loop C in an open conformation. The stability of this alternative pose varies for full and partial agonists, but the results are consistent with the view that the conformation of loop C is associated with the efficiency of different agonists. The differences between the principal and this alternative binding mode for a range of different agonists will be discussed in the context of free energy calculations. The results suggest the dynamics of ligand-binding in these receptors is even more complex than originally supposed.