心脏通道的开放状态结构和孔门机制
Daohua Jiang1, Richard Banh2, Tamer M Gamal El-Din3
1Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China.
Cell
|September 14, 2021
概括
研究人员捕获了心脏通道NaV1.5的开放状态,这对心跳至关重要. 这揭示了通道孔如何打开,使作用潜力和药物相互作用成为可能.
科学领域:
- 结构生物学
- 分子心脏病学
- 离子通道生理学
背景情况:
- 心脏通道NaV1.5通过产生动作潜力来启动心跳.
- 对于通道功能至关重要的NaV1.5的开放状态的结构机制仍然不太清楚.
研究的目的:
- 确定心脏道NaV1.5的开放状态的原子层结构.
- 阐明NaV1.5激活和快速失活的关闭机制.
- 绘制药物结合部位和心律失常相关突变的影响.
主要方法:
- 电子显微镜 (cryo-EM) 来捕捉开放状态的结构.
- 局部定向的突变,以阻止快速无效化.
- 分析离子导电性的分子动力学 (MD) 模拟.
- 与合结晶以研究药物结合.
主要成果:
- 确定了NaV1.5的开放状态结构,揭示了快速失活门的运动和S6段的不对称开放.
- 激活扩大到大约10 Å,允许Na+离子透.
- MD模拟证实了生理上的Na+导电率.
- 药物propafenone以高度亲和的姿势与开放通道结合,并确定了药物获取途径.
结论:
- 这项研究为NaV1.5的开放状态提供了前所未有的原子层面的洞察力,解释了动作潜力的产生.
- 阐明了开放状态药物阻断和快速失活的结构机制.
- 这为了解影响NaV1.5功能的心律失常突变提供了结构基础.
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