对血清素受体的脂质和配体调节的结构洞察
Peiyu Xu1,2,3, Sijie Huang2,3,4, Huibing Zhang1,5,6,7
1Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Nature
|March 25, 2021
概括
对血清素 (5-HT) 受体的结构洞察力揭示了脂质和水分子如何调节它们的活性. 这项研究阐明了这些关键的G蛋白结合受体中5-HT泛激素和药物识别背后的机制.
科学领域:
- 生物化学和结构生物学
- 神经科学
- 药理学
背景情况:
- 血清素 (5- 三胺,5-HT) 是通过G蛋白结合受体 (GPCR) 调节许多生理过程的关键神经递质.
- 5-HT受体表现出显著的基底活性,并由脂质调节,但这些现象和5-HT广泛的激动性仍然难以捉摸.
- 了解这些机制对于开发针对性治疗各种疾病至关重要.
研究的目的:
- 阐明5-HT GPCRs脂质和水分子调节的结构基础.
- 了解不同受体亚型中5-HT泛激应的基础结构机制.
- 在5-HT受体结合口袋中识别药物的结构决定因素.
主要方法:
- 使用冷电子显微镜确定了5HT受体-G蛋白复合体的五种不同的结构.
- 研究了与5-HT受体亚型 (5-HT1A,5-HT1D,5-HT1E) 的血清素 (5-HT),抗精神病药物阿里皮普拉和选择性激动剂 (BRL-54443) 的相互作用.
- 分析了脂质,特别是酸4-和胆固醇,以及结构化水分子在受体激活和连接物结合中的作用.
主要成果:
- 在5-HT1A-G蛋白界面发现酸4-酸盐,增强受体活性.
- 显示了胆固醇在塑造5-HT1A的联体结合口袋中的作用,影响了aripiprazole的特异性.
- 在apo-5-HT1A结合口袋中确定了结构化的水分子,模仿5-HT,有助于基底激活.
结论:
- 脂质和水分子在调节5-HT GPCR基底活性,配体结合和特异性方面发挥着至关重要的作用.
- 这些结构发现为5-HT的泛激素活性提供了机制性的解释.
- 这些见解为针对5-HT受体的新药的合理设计提供了结构基础.
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