Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17152-7. doi: 10.1073/pnas.1007988107. Epub 2010 Sep 27.
Differences between the structures of bacterial, archaeal, and eukaryotic ribosomes account for the selective action of antibiotics. Even minor variations in the structure of ribosomes of different bacterial species may lead to idiosyncratic, species-specific interactions of the drugs with their targets. Although crystallographic structures of antibiotics bound to the peptidyl transferase center or the exit tunnel of archaeal (Haloarcula marismortui) and bacterial (Deinococcus radiodurans) large ribosomal subunits have been reported, it remains unclear whether the interactions of antibiotics with these ribosomes accurately reflect those with the ribosomes of pathogenic bacteria. Here we report X-ray crystal structures of the Escherichia coli ribosome in complexes with clinically important antibiotics of four major classes, including the macrolide erythromycin, the ketolide telithromycin, the lincosamide clindamycin, and a phenicol, chloramphenicol, at resolutions of ∼3.3 Å-3.4 Å. Binding modes of three of these antibiotics show important variations compared to the previously determined structures. Biochemical and structural evidence also indicates that interactions of telithromycin with the E. coli ribosome more closely resembles drug binding to ribosomes of bacterial pathogens. The present data further argue that the identity of nucleotides 752, 2609, and 2055 of 23S ribosomal RNA explain in part the spectrum and selectivity of antibiotic action.
细菌、古菌和真核生物核糖体结构的差异解释了抗生素的选择性作用。即使不同细菌种类的核糖体结构存在微小差异，也可能导致药物与其靶标之间出现特殊的、特定于物种的相互作用。尽管已经报道了抗生素与古菌（盐沼盐球菌）和细菌（抗辐射球菌）大亚基的肽基转移酶中心或出口隧道结合的晶体结构，但仍不清楚抗生素与这些核糖体的相互作用是否准确反映了与致病性细菌核糖体的相互作用。在这里，我们报告了大肠杆菌核糖体与四种主要类别的临床重要抗生素复合物的 X 射线晶体结构，包括大环内酯类红霉素、酮内酯类泰利霉素、林可酰胺类克林霉素和氯霉素，分辨率约为 3.3 Å-3.4 Å。与之前确定的结构相比，这三种抗生素的结合模式显示出重要的差异。生化和结构证据还表明，泰利霉素与大肠杆菌核糖体的相互作用更类似于药物与细菌病原体核糖体的结合。目前的数据进一步表明，23S 核糖体 RNA 的核苷酸 752、2609 和 2055 的身份部分解释了抗生素作用的范围和选择性。
