在活性状态下,单质CXCL12结合的CXCR4的冷-EM结构
Yezhou Liu1, Aijun Liu2, Xinyu Li3
1Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China.
Cell reports
|August 2, 2024
概括
CXCL12-CXCR4复合体的第一个结构揭示了化学如何激活细胞保留和转移的关键受体. 这一发现为了解CXCR4信号提供了结构基础.
科学领域:
- 结构生物学 结构生物学
- 分子和细胞生物学分子和细胞生物学
- 生物化学 生化学
背景情况:
- 通过其连接体CXCL12激活CXCR4受体,可以调解关键的细胞功能,包括血液生成原始细胞的保留和癌症转移.
- 虽然存在对抗剂结合的CXCR4结构,但活性CXCL12结合的CXCR4复合物的结构仍然难以捉摸.
研究的目的:
- 为了确定CXCL12-CXCR4-Gi复合体的高分辨率冷电子显微镜 (cryo-EM) 结构.
- 阐明CXCR4被其内源性激素CXCL12激活的基础结构机制.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 解析了CXCL12-CXCR4-Gi复合物的结构.
- 功能测试和计算分析与结构数据相结合.
主要成果:
- 测定了CXCL12-CXCR4-Gi复合体的冷-EM结构,分辨率为2.65 Å,显示了1:1的静电学.
- CXCL12的N端8氨基酸对CXCR4激活至关重要,与跨膜子口袋残留物进行接触.
- 在CXCR4中CXCL12的深入插入,由与W6.48切换开关的3.2 Å距离证明,诱导G蛋白激活所需的形状变化.
结论:
- 这项研究提供了关于CXCR4通过其天然配体CXCL12激活CXCR4的第一个结构见解.
- 这些发现阐明了调节化学因子受体激活的分子相互作用和结构动力学.
- 通过CXCL12激活CXCR4的结构基础为涉及该途径的疾病的治疗干预提供了潜在的目标.
关键词:
科普:分子生物学 分子生物学在CXCL12中,CXCL12是最重要的.在CXCR4中,CXCR4是最常见的.在GPCRs中,GPCRs是指GPCR.化学物质 (chemokines) 是一种化学物质.化-EM结构的结构.更多相关视频
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