对50S前体识别和向由抗红红素甲基转移酶的机制性见解
Sombuddha Sengupta1, Rajat Mukherjee1, Michael Pilsl2
1Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, Maharashtra, India.
Science advances
|November 26, 2025
概括
抗红素耐药性甲基转移酶 (Erms) 向前体核糖体,以赋予抗生素耐药性. 这项研究揭示了Erms.
科学领域:
- 结构生物学 结构生物学
- 分子生物学分子生物学
- 微生物学 微生物学
背景情况:
- 抗红素的甲基转移酶 (EA) 是一种酶,可以对宏酸,林科萨米德和链路蛋白B型抗生素产生抗药性.
- 埃尔姆蛋白通过在50S核糖体子单元的23S核糖体RNA (rRNA) 组成部分内甲基化特定的腺基 (A2058) 来起作用.
- 这种甲基化发生在一个短暂的,难以捉摸的前体核糖体状态,使得目标难以研究.
研究的目的:
- 阐明Erm蛋白识别和甲基化23SrRNA前体的结构机制.
- 了解Erm的辅助C端域在实现动态核糖体基质特异性的作用.
- 确定开发新型抗生素的潜在目标,以对抗抗菌素耐药性.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来捕捉50S核糖体前体-Erm复合物的结构.
- 用单分子弗斯特共振能量转移 (smFRET) 研究来研究催化过程中Erm的动态形状变化.
- 结构分析的重点是确定甲基化过程中所涉及的关键相互作用和结构动态.
主要成果:
- 化EM揭示了核糖体前体中的一个短暂的口袋,作为Erm C-终端域的,对特异性至关重要.
- 观察到Erm的催化罗斯曼折叠会发生摇摆运动,从而促进基质的识别.
- smFRET数据表明,Erm在多个构造之间进行过渡,以确保甲基化目标螺旋的正确方向.
结论:
- 埃尔姆蛋白利用一种独特的向机制,包括一个短暂的核糖体口袋和结构灵活性,以实现特异性.
- 这些发现为了解ERM如何产生抗生素耐药性的结构性基础.
- 这种知识可以指导所有菌抑制剂的合理设计,以克服宏化物,林科萨米德和链路蛋白B抗性.
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