通过异形选择性小分子抗剂抑制Nav1.7的结构基础
Shivani Ahuja1, Susmith Mukund1, Lunbin Deng2
1Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA.
概括
研究人员设计了一种新的蛋白质策略来确定电压道Nav1.7的结构. 这揭示了选择性抑制剂的新结合部位,
科学领域:
- 分子生物学
- 结构生物学
- 神经科学
- 药理学
背景情况:
- 电压关闭的 (Nav) 通道对于可刺激细胞中的作用潜能传播至关重要.
- 导航通道是心血管和神经疾病的关键治疗点,但因高序列同样性而难以设计异型选择性抑制剂.
- 人类的Nav1.7通道与疼痛感知有关,使其成为一种重要的药物点.
研究的目的:
- 开发一种蛋白质工程策略,以克服Nav通道结构研究的挑战.
- 确定与异形选择性抗剂结合的人类Nav1. 7通道中的新型受体位的高分辨率结构.
- 阐明Nav1.7电压感应和抑制的分子基础.
主要方法:
- 采用蛋白质工程策略来促进Nav1.7通道的结晶.
- 与新型抗体 (例如GX-936) 复合的Nav1.7通道的确定晶体结构.
- 分析了同型选择性的结合相互作用和结构决定因素.
主要成果:
- 在Nav1.7通道的电压传感器域IV (VSD4) 中确定了一个新的受体位点.
- 证明抗体与激活的VSD4结合,通过电压传感器捕获机制对抗其失活.
- 发现S2和S3螺旋体中的特定残留物以及膜脂对Nav1.7抑制和选择性至关重要.
结论:
- 这项研究提供了对Nav1.7通道新型抑制位点的首次结构见解.
- 电压传感器捕获机制为Nav通道抑制提供了一个新的范式.
- 这些发现为设计强效和同位素选择性Nav1. 7抗剂来治疗疼痛建立了结构蓝图.
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