激活的GPR4-Gs信号复合体的冷电磁结构
Yitong Ma1, Yijie Wang1, Mengyuan Tang2
1Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
质子感应G蛋白结合受体4 (GPR4) 结构揭示了对pH感应机制的新见解. 这项研究确定了参与质子检测和信号通路的关键残留物,这对于理解GPR4至关重要.
科学领域:
- 结构生物学 结构生物学
- 生物化学 生物化学
- 分子生物学分子生物学
背景情况:
- G蛋白结合受体4 (GPR4) 是一种参与生理反应的质子感应受体.
- 在酸性瘤微环境和炎症中GPR4的过度活化突显了其病理相关性.
- GPR4的3D结构和详细的质子感应机制在很大程度上仍未被阐明.
研究的目的:
- 为了确定不同pH值的活跃斑马鱼GPR4的冷电子显微镜 (cryo-EM) 结构.
- 研究细胞外电离残留在GPR4的质子感应能力中的作用.
- 阐明GPR4.4中信号传播的结构基础.
主要方法:
- 电子显微镜 (cryo-EM) 用于结构的确定.
- 基于细胞的测定以评估质子感应能力.
- 在质子感应GPCRs (psGPCRs) 内的保存残留物的分析.
主要成果:
- 在pH 6.5和8.5.5下报告了活跃斑马鱼GPR4的冷-EM结构.
- 鉴定出细胞外的histidine和影响质子传感的酸性残留物,虽然不如 transmembrane三元体残留物那么显著.
- 揭示了一组芳香残留物在orthosteric口袋中,可能调解信号传播.
结论:
- 该研究提供了GPR4的高分辨率结构,为了解psGPCR功能提供了一个结构框架.
- 细胞外的可电离残留物对GPR4的pH敏感度有适度的贡献.
- 在GPR4信号传导中涉及的奥托斯特体口袋内的芳香残留物相互作用.
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