Dynamical Mechanisms of Glutamate Receptor Gating and Sub-Conductance
Dynamical Mechanisms of Glutamate Receptor Gating and Sub-Conductance
复制标题
谷氨酸受体门控和亚电导的动力学机制
DOI：
10.1016/j.bpj.2019.11.3151
复制
发表时间：
2020
影响因子：
3.4
通讯作者：
Scaranto, Jessica
中科院分区：
文献类型：
--
作者：
Kurnikova, Maria G.;Sakipov, Serzhan;Kottke, Christopher;Narangoda, Chamali;Scaranto, Jessica
离子型谷氨酸受体（iGluR）负责中枢神经系统（CNS）中兴奋性信号传递的起始。它们在突触可塑性和长时程增强中发挥重要作用，而它们的功能障碍导致多种疾病，包括神经退行性疾病和癫痫，因此它们是药物设计的潜在靶点。谷氨酸受体表现出明显的模块化多结构域结构，其中仅含有配体结合结构域（LBD）和跨膜结构域（TM）的截短蛋白形成最小的功能性谷氨酸门控通道。这些同源四聚体AMPA亚型谷氨酸受体门控和脱敏发生在毫秒时间尺度上，因此，这些是最小和最快的工作配体门控离子通道。在这项工作中，我们报告了广泛的多微秒分子动力学（MD）模拟AMPA受体门控和调节。这些模拟被设计成允许受体在它们的各种功能状态之间相互转换，例如开放和闭合的TM通道，以及配体结合的、活性的和脱敏的LBD结构域。我们已经使用了各种机器学习（ML）方法和系统的特征选择技术来表征LBD结构的哪些特定特征负责转导通道开放的信号。我们已经观察到与LBD裂缝闭合程度相关的通道部分闭合的多个事件，从中我们能够得出关于LBD结构域单体和四元结构之间的变构偶联的特定机制以及TM结构域的离子通道状态的结论。我们的研究是第一个能够成功地设计一个模拟的开放和关闭的TM离子通道的LBD域的状态，并表征迄今难以捉摸的子电导状态。
Ionotropic glutamate receptors (iGluR) are responsible for initiation of excitatory signal transmission in the central nervous system (CNS). They play important roles in synaptic plasticity and long-term potentiation, while their dysfunction causes variety of diseases including neurodegenerative diseases and epilepsy, therefore they are potential targets for drug design. Glutamate receptors exhibit a distinctly modular multi-domain structure, in which truncated proteins containing only the ligand binding domain (LBD) and the transmembrane domains (TM) form the smallest functional glutamate gated channels. These homo-tetrameric AMPA subtype glutamate receptors gating and desensitization occurs on millisecond time-scales, and thus, these are the smallest and fastest working ligand-gated ion channels. In this work we report on extensive multy-microsecond molecular dynamics (MD) simulations of the AMPA receptor gating and regulation. The simulations were designed to allow the receptors to inter-convert between their various functional states, such as open and closed TM channel, and ligand-bound, active and desensitized LBD domain. We have used a variety of machine learning (ML) methods and systematic feature selection techniques to characterize which specific features of the LBD structure are responsible for transducing the signal for channel opening. We have observed multiple events of partial closures of the channel correlated with the LBD cleft closure degree from which we are able to draw conclusions on specific mechanism of allosteric coupling between the LBD domains monomeric and quarternary structures, as well as the ion channel state of the TM domains. Our study is the first one that was able to successfully design a simulation for opening and closing of the TM ion channel in response to the state of the LBD domain and characterize thus far elusive sub-conductance states.