结构基础的CXC化学因受体1带结合和激活的结构基础
Naito Ishimoto1, Jae-Hyun Park1, Kouki Kawakami2
1Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, Tsurumi, Yokohama, 230-0045, Japan.
Nature communications
|July 11, 2023
概括
研究人员解决了与CXCL8 (IL-8) 和G蛋白结合的CXCR1受体结构. 这揭示了CXCR1的存在.
科学领域:
- 免疫学 免疫学 免疫学
- 结构生物学 结构生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 中性粒细胞对天生的免疫至关重要,通过CXCL8 (IL-8) 等化学基因迁移到感染部位.
- CXCL8及其受体CXCR1和CXCR2与免疫和癌症有关,这使得它们成为关键的药物标.
- 了解GPCR - 配体相互作用对于开发向疗法至关重要.
研究的目的:
- 阐明CXCR1受体与CXCL8和Gαi蛋白质复合的高分辨率结构.
- 详细说明控制CXCL8与CXCR1结合的分子相互作用.
- 研究CXCR1对单体CXCL8.8的选择性的结构基础.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来确定CXCR1-CXCL8-Gαi复合物的结构.
- 使用结构建模来分析连接体-受体相互作用.
- 进行了涉及CXCR1细胞外循环2 (ECL2) 的突变性研究,以评估化学激素的选择性.
主要成果:
- 冷-EM结构揭示了CXCR1,单体CXCL8和Gαi蛋白之间的详细相互作用.
- 由于CXCR1与其细胞外循环2 (ECL2) 的固态碰撞,CXCR1对单体CXCL8表现出强烈的偏好,而不是二维形式.
- 修改CXCR1的ECL2以与CXCR2的ECL2相似,取消了对单质CXCL8的偏好.
结论:
- 确定的结构为CXCL8.8对CXCR1激活提供了关键的见解.
- 这些发现突出了ECL2在决定化基因单体/二元体选择性的作用.
- 这种结构和功能理解将有助于基于结构的CXCR1和相关受体的药物设计.
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