A novel site of antibiotic action in the ribosome: Interaction of evernimicin with the large ribosomal subunit
A novel site of antibiotic action in the ribosome: Interaction of evernimicin with the large ribosomal subunit
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DOI：
10.1073/pnas.071527498
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发表时间：
2001-03-27
影响因子：
11.1
通讯作者：
Mankin, AS
中科院分区：
文献类型：
--
作者：
Belova, L;Tenson, T;Mankin, AS
依维米星（Evn）是一种寡糖抗生素，与核糖体大亚基相互作用并抑制细菌蛋白质合成。RNA探测表明，该药物保护细菌和古细菌核糖体中23S rRNA发夹89和91环中的一组特定核苷酸。盐生盐杆菌的自发Evn抗性突变体包含23S rRNA的发夹89和91突变。在核糖体三级结构中，参与与药物相互作用的rRNA残基形成紧密簇，描绘药物结合位点。细菌核糖体蛋白L16中的抗性突变与古细菌蛋白L10e同源，与rRNA突变聚集在同一区域。Evn结合位点与起始因子2的结合位点重叠。Evn在体外抑制起始因子2的活性，表明该药物干扰70S起始复合物的形成。Evn结合位点及其作用模式与其他核糖体靶向抗生素不同。该抗生素靶位点可潜在地用于开发新的抗菌药物。
Evernimicin (Evn), an oligosaccharide antibiotic, interacts with the large ribosomal subunit and inhibits bacterial protein synthesis. RNA probing demonstrated that the drug protects a specific set of nucleotides in the loops of hairpins 89 and 91 of 23S rRNA in bacterial and archaeal ribosomes. Spontaneous Evn-resistant mutants of Halobacterium halobium contained mutations in hairpins 89 and 91 of 23S rRNA, In the ribosome tertiary structure, rRNA residues involved in interaction with the drug form a tight cluster that delineates the drug-binding site. Resistance mutations in the bacterial ribosomal protein L16, which is shown to be homologous to archaeal protein L10e, cluster to the same region as the rRNA mutations. The Evn-binding site overlaps with the binding site of initiation factor 2. Evn inhibits activity of initiation factor 2 in vitro, suggesting that the drug interferes with formation of the 70S initiation complex. The site of Evn binding and its mode of action are distinct from other ribosome-targeted antibiotics. This antibiotic target site can potentially be used for the development of new antibacterial drugs.