抑制和激活NMDA受体的机制
Shujia Zhu1, Richard A Stein2, Craig Yoshioka3
1Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Cell
|April 12, 2016
概括
N-甲基-D-酸盐受体 (NMDARs) 对记忆非常重要. 这项研究揭示了NMDAR如何使用冷EM在活性和非活性状态之间过渡,显示了药物如何与控制通道关口结合.
科学领域:
- 神经科学
- 分子生物学
- 结构生物学
背景情况:
- N-甲基-D-酸盐受体 (NMDARs) 是突触传输,学习和记忆的重要离子通道.
- NMDAR功能障碍与神经疾病,如和缺血有关.
- 了解NMDAR关口机制和小分子的调制是至关重要的.
研究的目的:
- 阐明NMDAR激活和抑制的结构机制.
- 调查竞争性抗剂,激动剂和全抑制剂如何影响NMDAR结构.
- 揭示联体结合域 (LBD) 结合环在NMDAR功能中的作用.
主要方法:
- 电子冷显微镜 (cryo-EM) 用于确定GluN1-GluN2BNMDA受体的高分辨率结构.
- 双电子共振 (DEER) 实验以探测形状变化.
- 对抗剂结合,激动剂结合和激动剂/抑制剂结合的结构分析.
主要成果:
- 竞争对手破坏了LBD的封闭环结构.
- 激动剂使LBD稳定在二次的二次结构中.
- 阿洛斯特抑制剂通过氨基终端域的相互作用进一步稳定了LBD层.
- LBD隔离环是NMDAR信号传导和离子通道隔离的核心.
结论:
- LBD封闭环是NMDAR通道封闭的一个基本决定因素.
- 结构洞察力解释了不同类型的调节器如何控制NMDAR活动.
- 这项工作为了解NMDAR相关疾病和药物开发提供了框架.
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