在多巴胺D1受体上识别迷幻LSD的结构基础1
Luyu Fan1, Youwen Zhuang2, Hongyu Wu3
1Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
Lysergic 酸二甲基胺 (LSD) 由于灵活的细胞外循环,迅速与多巴胺D1受体分离. 结合G蛋白稳定了这一循环,减缓了LSD解离,影响了信号通路.
科学领域:
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
- 结构生物学 结构生物学
背景情况:
- lysergic acid diethylamide (LSD) 的精神活性和治疗作用与其受体动力学和信号传递有关.
- 虽然LSD与血清素受体的相互作用得到了充分研究,但其对多巴胺受体的影响仍然不太清楚.
研究的目的:
- 阐明LSD在多巴胺D1受体 (DRD1) 的结合模式和动力学.
- 在LSD的存在下,研究DRD1的G蛋白与β-arrestin合的决定因素.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于确定LSD/PF6142结合的DRD1-腿体复合物的结构.
- 利用一个模仿β-arrestin的纳米体 (NBA3) 来探测合机制.
- 动力测试用于测量配体解离率.
主要成果:
- 确定了与DRD1结合的LSD的冷-EM结构,揭示了TM4附近与ergoline部分的独特结合姿势.
- 观察到LSD与DRD1的异常快速解离率,这归因于细胞外循环2 (ECL2) 的灵活性.
- 证明G蛋白结合稳定了ECL2,显著减缓了LSD的解离速度.
结论:
- 在DRD1.1,LSD表现出明显的结合和快速解离动力学.
- ECL2的灵活性是LSD与DRD1.1快速分离的一个关键因素.
- 参与G蛋白调节DRD1构造和配体-受体相互作用,影响与GPCR相关的信号转导通路.
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