K2P2.1 (TREK-1) 激活器复合体显示了一个神秘的选择性过器结合点
Marco Lolicato1, Cristina Arrigoni1, Takahiro Mori2
1Cardiovascular Research Institute, University of California, San Francisco, California 941158-9001, USA.
Nature
|July 11, 2017
概括
研究人员发现小分子通过稳定它们来激活TREK通道
科学领域:
- 神经科学
- 结构生物学
- 药理学
背景情况:
- 双孔域 (K2P) 通道,特别是TREK子家族,调节神经元刺激性和感官感知.
- 这些通道与疼痛,温度感觉和麻醉反应有关.
- 目前对K2P通道机制的理解受到缺乏有效的药理工具的限制.
研究的目的:
- 识别和描述激活TREK子家族通道的小分子.
- 阐明K2P通道小分子激活的结构基础.
- 为研究K2P通道功能提供新的药理探针.
主要方法:
- 使用X射线结晶学来确定单独的K2P2.1 (TREK-1) 和与激活剂ML335和ML402组合的结构.
- 进行功能电生理学测试以评估对小分子的道活性.
- 使用基于结构的药物设计原则来了解结合性相互作用.
主要成果:
- 为TREK通道确定了一种新型小分子激活剂 (ML335和ML402).
- 结构研究发现一个独特的密码结合口袋不同于其他离子通道网站.
- 这些激活器作为分子子,通过子-π相互作用在"泄漏模式"中稳定C型门.
结论:
- 在K2P通道上确定了一个可用药物的结合点,使C型门的稳定成为可能.
- 这些发现为K2P道的选择性过提供了直接证据.
- 这些发现的激活剂为未来的K2P通道生理学和药理学研究提供了宝贵的工具.
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