通过G蛋白合受体进行质子传感的分子基础
Matthew K Howard1, Nicholas Hoppe2, Xi-Ping Huang3
1Tetrad graduate program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Therapeutic Science, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell
|January 3, 2025
概括
感知质子的G蛋白合受体 (GPCR) 使用残留物网络来检测pH值的变化,而不是单个位点. 这一发现有助于我们更好地理解这些关键受体的功能.
科学领域:
- 生物化学
- 分子生物学
- 结构生物学
背景情况:
- 已知三个G蛋白合受体 (GPCRs) - - GPR4,GPR65和GPR68 - - 能够感知细胞外pH值并影响各种生理过程.
- 质子激活这些受体的精确机制在很大程度上是未知的.
研究的目的:
- 阐明GPR4,GPR65和GPR68中质子激活的结构和功能基础.
- 确定参与质子识别和信号传导的关键残留物和网络.
主要方法:
- 电子显微镜 (cryo-EM) 来确定三种质子感应GPCR的结构.
- 深度突变扫描 (DMS) 以功能性地评估单个残留物在GPR68激活中的重要性.
- 恒定pH分子动力学模拟以探索形态动力学和质子化状态.
主要成果:
- 化电磁结构揭示了受体内的质子感应残留物的空间排列.
- DMS发现没有任何一个残留物仅仅负责GPR68中的质子识别.
- 从细胞外表面延伸到膜外域的可定位残留物分布网络被发现是激活的关键.
- 模拟提供了对动态质子化模式和形态状态的见解.
结论:
- 这些GPCR中的质子传感是由复杂的可定位残留物网络介导而不是单个质子结合点.
- 这项研究为了解质子感应GPCR的激活机制提供了全面的框架.
- 这些发现为调节pH敏感信号通路的治疗干预提供了潜在的目标.
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