固醇结合的光滑化GPCR-Gi蛋白质复合物的完全激活的结构
Amy-Doan P Vo1, Soo-Kyung Kim1, Moon Young Yang1
1Materials and Process Simulation Center, Division of Chemistry & Chemical Engineering, California Institute of Technology, Pasadena, CA 91125.
概括
我们揭示了与Gi蛋白和固醇连接体相互作用的激活滑化 (SMO) 的分子结构. 这提供了对子通路激活和平滑的关键见解.
科学领域:
- 结构生物学 结构生物学
- 分子药理学分子药理学
- 生物化学 生物化学
背景情况:
- 滑化 (SMO) 是刺信号通路中的关键信号传感器,调节细胞分化和胚胎发生.
- SMO是一种F类G蛋白结合受体 (GPCR),与Gi蛋白相互作用,但其完全激活的结构尚不清楚.
- 了解SMO激活对于开发针对性治疗发育障碍和癌症至关重要.
研究的目的:
- 为了确定激活的人类SMO与Gi蛋白和醇连接体复合的原子结构.
- 阐明SMO激活和Gi蛋白合背后的分子机制.
- 确定与SMO过渡到完全活跃状态相关的关键结构变化.
主要方法:
- 激活人类SMO的原子分子动力学模拟.
- 在生理条件下 (310 K,pH,盐度) 在完全的脂质双层中进行了模拟.
- 分析结构变化,包括皮相互作用断裂,Gi蛋白合,CRD倾斜和固醇连接体迁移.
主要成果:
- 平衡的SMO-Gi复合体结构显示了R451-W535皮相互作用的完全破坏,这是F类受体激活的标志.
- 基蛋白通过七个强点与SMO结合,类似于A类GPCRs,涉及细胞内环和跨膜螺旋.
- 细胞外囊丰富的域 (CRD) 经历了显著的倾斜,并且一个固醇连接体迁移到激活SMO的深袋特征.
结论:
- 在完全激活之前,SMO与Gi蛋白相互作用,破坏非活性构造并建立Gi合.
- 在SMO的激活过程中,CRD倾斜和固醇连接体迁移是关键事件.
- 这项研究提供了激活SMO的详细分子模型,提供了对Hedgehog路径调节和治疗向的见解.
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