通过tigecycline对真核核糖核酶体的差异抑制的结构基础
Xiang Li1, Mengjiao Wang1, Timo Denk2
1Minhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan University, Shanghai, China.
Nature communications
|June 28, 2024
概括
提格环素在临床度上向人类的线粒体,抑制蛋白质翻译. 它在高度下与人类和酵母菌的核糖体结合,可能引导新的药物设计.
科学领域:
- 结构生物学 结构生物学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 提格环素是复杂细菌感染的关键抗生素.
- 它抑制人类细胞细胞毒性的机制尚未完全理解.
- 提格环素通过阻断核糖体A位点来向细菌蛋白质合成.
研究的目的:
- 阐明tigecycline对人类核糖体作用的分子机制.
- 为了确定tigecycline细胞毒性的结构基础.
- 调查tigecycline与人类线粒体 (55S) 和细胞质 (80S) 核糖体的结合.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于确定高分辨率结构.
- 对tigecycline与人类55S,人类80S和酵母80S核糖体的结合的分析.
- 在临床相关和高度下结合的比较.
主要成果:
- 提格环素在临床度下与人类55S线粒体结合,阻碍tRNA适应并阻断基转移中心.
- 在生理学度下,tigecycline不会结合人类80S核糖体.
- 在高度下,tigecycline在A位点和L1茎限制位点结合了人类和酵母80S核糖体.
结论:
- 蒂格环素对人类的线粒体和80S线粒体具有独特的结合特性.
- 这些发现为tigecycline的作用机制和细胞毒性提供了结构性的见解.
- 这种独特的结合方式可能有助于开发新型抗生素和治疗策略.
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