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Investigation of Allosteric Effect of 2,8-Dimethylation of A2503 in E. coli 23S rRNA by Molecular-Dynamics Simulations
Biochemistry (Moscow) ( IF 2.3 ) Pub Date : 2020-11-01 , DOI: 10.1134/s0006297920110139
T M Makarova 1 , G I Makarov 1
Affiliation  

Abstract Ribosome is a molecular machine that synthesizes all cellular proteins. It also is a target of about half of the clinically used antibiotics. Adaptive chemical modification of ribosomal RNAs residues is one of the ways to provide resistance to certain antibiotics. A curious example of such modification is 2,8-dimethylation of A2503 in 23S rRNA, which induces resistance to phenols, linkosamides, oxazolidinones, pleuromutilins, and certain macrolides. In this article the effect of 2,8-dimethylation of A2503 on conformation and mobility of RNA residues of the 70S E. coli ribosome was investigated employing molecular dynamics simulations method. Significant alterations were detected both in the immediate environment of the 2503 23S rRNA residue and in the nucleotides located deeper in the nascent peptide exit tunnel (NPET), which are known to be involved in signal transmission from the antibiotics bound in the NPET to the peptidyl transferase center. These alterations shift the ribosome towards the A/A, P/P-state from the conformationally different state – P/P, E/E one in our case. The obtained results allow us to conclude that the effect of m 2 m 8 A2503 modification involves additional stabilization of the A/A, P/P-state favoring the peptidyl transferase reaction (PTR) contrary to antibiotics that inhibit PTR.

中文翻译:

通过分子动力学模拟研究大肠杆菌 23S rRNA 中 A2503 2,8-二甲基化的变构效应

摘要 核糖体是一种合成所有细胞蛋白质的分子机器。它也是大约一半临床使用抗生素的目标。核糖体 RNA 残基的适应性化学修饰是提供对某些抗生素的抗性的方法之一。这种修饰的一个奇怪例子是 23S rRNA 中 A2503 的 2,8-二甲基化,这会诱导对酚类、链霉酰胺、恶唑烷酮、截短侧耳素和某些大环内酯类的抗性。在本文中,采用分子动力学模拟方法研究了 A2503 的 2,8-二甲基化对 70S 大肠杆菌核糖体的 RNA 残基的构象和迁移率的影响。在 2503 23S rRNA 残基的直接环境和位于新生肽出口隧道 (NPET) 深处的核苷酸中都检测到显着变化,已知它们参与从结合在 NPET 中的抗生素到肽基转移酶中心的信号传输。这些改变使核糖体从构象不同的状态转变为 A/A、P/P 状态——在我们的例子中是 P/P、E/E。获得的结果使我们能够得出结论,与抑制 PTR 的抗生素相反,m 2 m 8 A2503 修饰的效果涉及 A/A、P/P 状态的额外稳定化,有利于肽基转移酶反应 (PTR)。
更新日期:2020-11-01
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