结合和动力学证明了NMDA受体GluN1子单元中S688Y突变的连接体结合的不稳定
Jake Zheng Chen1,2, William Bret Church1, Karine Bastard1
1Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia.
Molecules (Basel, Switzerland)
|May 27, 2023
概括
在N-甲基-D-酸盐受体 (NMDAR) 中的Ser688Tyr突变会破坏关键的协同激素的稳定,影响大脑功能并引起脑病变. 这种分子洞察力解释了先前观察到的受体活性变化.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 脑病是与认知,感官和运动障碍相关的脑功能障碍.
- 在N-甲基-D-酸盐受体 (NMDAR) 中的突变与脑病变有关.
- 对于NMDAR突变的精确分子机制的理解尚不完全.
研究的目的:
- 为了研究NMDAR GluN1联体结合域中Ser688Tyr突变的分子机制.
- 为了阐明这种突变如何影响主要协激剂,甘氨酸和D-氨酸的结合.
主要方法:
- 分子对接模拟. 分子对接模拟.
- 随机播种的分子动力学模拟.
- 对于野生类型和突变受体,具有约束力的自由能量计算.
主要成果:
- 这种Ser688Tyr突变会诱导NMDAR GluN1带结合部位的结构变化.
- 甘氨酸和D-氨酸都表现出稳定性降低和突变结合部位内的解离增加.
- 在S688Y突变受体中,两个协同激动剂的结合自由能量明显不那么有利.
结论:
- 这种 Ser688Tyr 突变通过破坏必不可少的协同激素结合,损害了 NMDAR 功能.
- 这些发现为观察到的体外电生理学数据提供了分子解释.
- 这项研究提供了对NMDAR GluN1突变对受体活性和大脑功能的影响的关键见解.
相关概念视频
Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.3K
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
2.3K
GPCR Desensitization
6.2K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
6.2K
Ligand-gated Ion Channels
12.5K
Ligand-gated ion channels are transmembrane proteins with a channel for ions to pass through and a binding site for a ligand. The channel opens only when a ligand attaches to the binding site.
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that...
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that...
12.5K
GPCRs Regulate Adenylyl Cylase Activity
5.7K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.7K


