Gating mechanism of the human α1β GlyR by glycine.
Gating mechanism of the human α1β GlyR by glycine.
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甘氨酸的人类α1β GlyR 的门控机制。
DOI：
10.1101/2023.08.08.552474
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Wang,Weiwei
中科院分区：
文献类型：
--
作者：
Liu,Xiaofen;Wang,Weiwei
甘氨酸受体（GlyR）是构成哺乳动物神经递质受体的主要部分的Cys环受体的成员。最近的决议异聚体GlyR结构在多个功能状态提出了基本问题的门控机制的GlyR，一般的Cys-环家族受体。在这里，我们详细的平衡特性，以及功能状态之间的过渡动力学。我们发现，虽然所有变构位点都与甘氨酸协同结合，但在α-α界面占据2个位点足以激活，并且是高效门控所必需的。差异甘氨酸浓度依赖的脱敏率，程度，其恢复表明单独的，但协调的作用，配体结合和离子载体重组。基于这些观察和现有的结构信息，我们开发了一个定量门控模型，准确地预测整个甘氨酸门控循环的平衡和动力学性质。该模型可能普遍适用于Cys环受体，并为制药工作提供信息。
Glycine receptors (GlyRs) are members of the Cys-loop receptors that constitute a major portion of mammalian neurotransmitter receptors. Recent resolution of heteromeric GlyR structures in multiple functional states raised fundamental questions regarding the gating mechanism of GlyR, and generally the Cys-loop family receptors. Here, we characterized in detail equilibrium properties as well as the transition kinetics between functional states. We show that, while all allosteric sites bind cooperatively to glycine, occupation of 2 sites at the α-α interfaces is sufficient for activation and necessary for high-efficacy gating. Differential glycine concentration dependence of desensitization rate, extent, and its recovery suggests separate but concerted roles of ligand-binding and ionophore reorganization. Based on these observations and available structural information, we developed a quantitative gating model that accurately predicts both equilibrium and kinetical properties throughout the glycine gating cycle. This model likely applies generally to the Cys-loop receptors and informs on pharmaceutical endeavors.