甘氨酸对人类 α1β GlyR 的门控机制

IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
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引用次数: 0

摘要

甘氨酸受体(GlyRs)是 Cys 环状受体的成员,构成哺乳动物神经递质受体的主要部分。最近对多种功能状态下异构 GlyR 结构的解析提出了有关 GlyR 以及 Cys 环状家族受体门控机制的基本问题。在这里,我们详细描述了平衡特性以及功能状态之间的转换动力学。我们的研究表明,虽然所有的别构位点都与甘氨酸合作结合,但在α-α界面上占据两个位点就足以激活,并且是高效门控的必要条件。脱敏率、脱敏程度及其恢复对甘氨酸浓度的不同依赖性表明,配体结合和离子团重组起着独立但协同的作用。根据这些观察结果和现有的结构信息,我们建立了一个定量门控模型,该模型能准确预测整个甘氨酸门控周期的平衡和动力学特性。该模型可能普遍适用于 Cys 环受体,并对制药工作有所启发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Gating mechanism of the human α1β GlyR by glycine

Gating mechanism of the human α1β GlyR by glycine

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.

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来源期刊
Structure
Structure 生物-生化与分子生物学
CiteScore
8.90
自引率
1.80%
发文量
155
审稿时长
3-8 weeks
期刊介绍: Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.
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