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哺乳动物NMDA受体功能转换的结构基础

Tsung-Han Chou¹, Nami Tajima¹, Annabel Romero-Hernandez²

¹WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

|July 2, 2020

概括

了解N-甲基-D-酸盐受体 (NMDARs) 的激活和抑制是大脑功能的关键. 新的结构数据揭示了联体与NMDAR子单元的结合如何控制离子通道门和竞争性抑制.

科学领域:

神经科学
分子生物学
结构生物学

背景情况:

由谷氨酸受体,特别是N-甲基-D-亚斯巴酸受体 (NMDARs) 介导的刺激性神经传递对大脑发育和功能至关重要.
NMDARs是包含GluN1和GluN2子单元的异质四酶,对于结合甘氨酸和谷氨酸来激活离子通道至关重要.
通过子单元特定的连接体结合来控制NMDAR激活和抑制的确切机制尚未完全理解.

研究的目的:

阐明NMDAR在激活和抑制过程中的细节形状变化和重定向.
提供高分辨率的结构洞察力,了解对抗剂对子单元的竞争性抑制.
揭示NMDAR药理和功能的机制基础.

主要方法:

使用冷电子显微镜 (cryo-EM) 在4 Å分辨率或更高的分辨率下,在不同的联体结合状态下确定多个NMDAR结构.
分析形状变化和子单位/领域间的重定位.
关联结构发现与agonist-gating和antagonist抑制的功能机制.

主要成果:

在NMDAR激活和抑制过程中发现了形状变化和重定向的详细模式.
在不同的连接体状态中的结构阐明了激素-关口和子单元依赖的竞争性抑制机制.
显示抗体的激活和竞争性抑制是由连接连体结合域和GluN2子单元的跨膜域的链接器的张力控制的.

结论:

这项研究为NMDAR激活和抑制提供了前所未有的机械洞察力.
了解GluN2链接器张力的作用为NMDAR药理提供了新的视角.
这些发现对于理解大脑生理学和开发有针对性的治疗方法至关重要.

关键词:

甲基-D-酸盐受体抗NMDAR药物的使用没有NMDAR 射线晶体学道激活和抑制机制化电磁场电子冷显微镜链接离子通道

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