使用可光切换连接逆激素对多巴胺受体进行光学控制
Prashant C Donthamsetti1, Nils Winter2, Matthias Schönberger2
1Department of Molecular and Cell Biology, University of California , Berkeley, California 94720, United States.
Journal of the American Chemical Society
|November 23, 2017
概括
科学家使用可光切换的绑定配体设计了多巴胺受体 (DAR) 来远程控制光线. 这一突破使GPCRs的精确时空调节成为可能, 提供新的治疗策略.
科学领域:
- 生物化学
- 分子生物学
- 神经科学
背景情况:
- 甲族G蛋白结合受体 (GPCR) 对生物过程和临床应用至关重要.
- 由于与视网膜的共价键,Rhodopsin是一种A家族的GPCR,对光敏感.
- 大多数GPCR缺乏光敏感性和共价配体结合,限制了远程控制的可能性.
研究的目的:
- 设计光不敏感的A家族GPCR来实现远程精确控制,模仿罗多的光敏感性.
- 开发一种特定于受体和细胞类型的GPCR活性时空调节方法.
- 研究可光切换绑定配体 (PTL) 控制多巴胺受体 (DAR) 的潜力.
主要方法:
- 将多巴胺受体连接体 (PPHT) 的亚博衍生物与在多巴胺结合部位附近的工程基因残留物结合.
- 使用PTL来实现多巴胺D1和D2受体 (D1R和D2R) 的快速,可逆和选择性阻塞.
- 根据结合部位,研究作为可光开关的结合中性抗剂或反向抗剂的结合体行为.
主要成果:
- 通过光线进行选择性遥控的化学工程.
- 使用PTL证明了D1R和D2R的快速,可逆和选择性阻断.
- 根据PTL结合部位观察到不同的联体活性 (对抗剂或反抗剂).
结论:
- 多巴胺受体可以通过光激活的配体进行精确的远程控制.
- 这种方法为各种A家族GPCR的精度控制提供了一个多功能模板.
- 这些发现为针对GPCR的新疗法开辟了道路.
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