对连接体识别和酸盐受体 SUCNR1 的激活的结构洞察
Aijun Liu1, Yezhou Liu2, Weijia Zhang3
1Dongguan Songshan Lake Central Hospital, Dongguan Third People's Hospital, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, Guangdong 523326, China; Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong 518000, China.
对酸盐受体 (SUCNR1) 激活的结构洞察力揭示了酸盐和cis-epoxysuccinate结合的关键相互作用. 这些发现有助于我们更好地理解关联信号传递和对受体的潜在治疗开发.
科学领域:
- 生物化学 生物化学
- 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:
- 酸是一种酸循环中间体,在能量恒温和代谢调节中起着至关重要的作用.
- 细胞外酸盐通过酸盐受体 (SUCNR1) 作为压力信号,它是一种A类G蛋白结合受体.
- 对抗激素结合的SUCNR1的有限的高分辨率结构阻碍了对基信号的研究.
研究的目的:
- 为了确定结晶电子显微镜 (cryo-EM) 结构的 SUCNR1-Gi 复合物绑定到 succinate 和 cis-epoxysuccinate.
- 阐明关键的分子决定因素,涉及到苏酸和cis-epoxysuccinate的识别通过SUCNR1.1.
- 了解SUCNR1激活和下游Gi信号的结构基础.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于解析高分辨率结构.
- 对受体-连接体相互作用的生物化学分析.
- 分子建模以确定关键的结合残留物和信号通路.
主要成果:
- 获得了SUCNR1-Gi复合物的高分辨率冷-EM结构,其中含有苏酸盐和cis-epoxysuccinate.
- 确定了关键残留物 (R281,Y83,Y30,R99),对酸盐和cis-epoxysuccinate结合至关重要.
- 揭示了细胞外循环2 (F175) 在封闭结合口袋中的作用.
- 在激动剂结合时观察到受体-Gi接口 (TM5,TM6) 的重新排列,启动TM信号 (TM3,TM7).
结论:
- 这项研究提供了关键的结构洞察力,了解酸盐受体 (SUCNR1) 对酸盐的识别和结合.
- 了解这些相互作用有助于设计针对 SUCNR1 的新疗法,以治疗代谢和与压力相关的疾病.
- 这些发现显著提升了对G蛋白结合受体信号传递机制的知识,其中包括糖酸盐.
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