5-HT2C受体结构揭示了GPCR多药学的结构基础
Yao Peng1, John D McCorvy2, Kasper Harpsøe3
1iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Cell
|February 6, 2018
概括
了解药物与多种向药物的相互作用是治疗肥胖和精神分裂症的关键. 这项研究揭示了药物如何与血清素受体结合的结构性见解, 帮助未来的复杂疾病药物设计.
科学领域:
- 神经科学
- 药理学
- 结构生物学
背景情况:
- 药物与多个目标相互作用的多药学对于治疗复杂疾病的疗效至关重要.
- 血清素受体,特别是5-HT2C,是包括肥胖,药物滥用和精神分裂症在内的疾病的关键目标.
- 为G蛋白结合受体 (GPCRs) 开发具有明确多药性特征的选择性联体或药物存在重大挑战.
研究的目的:
- 阐明GPCR多药学的结构基础.
- 提供有关联体受体相互作用和药理作用的机制性见解.
- 通过了解配体-受体结合模式,促进GPCR的合理药物设计.
主要方法:
- 确定与ergotamine和ritanserin复合的5-HT2C受体的晶体结构.
- 在高分辨率 (3.0 Å和2.7 Å) 分析的联体受体结合姿势.
- 研究受体识别和对抗药物效应的结构机制.
主要成果:
- 解决了 5-HT2C受体与混杂激动剂 (ergotamine) 和选择性逆激动剂 (ritanserin) 结合的两个不同的结构.
- 提供了结合姿势的详细分析, 揭示了控制受体识别的关键相互作用.
- 为结合的配体的不同药理作用提供了机制性的解释.
结论:
- 对配体- GPCR相互作用的结构见解可以解释多药学.
- 了解特征性的结合模式有助于设计针对多个GPCR的药物.
- 这项工作为设计具有量身定制的多药性特征的新疗法奠定了基础.
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