Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, IL, USA.
Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA.
Nat Commun. 2021 May 14;12(1):2803. doi: 10.1038/s41467-021-23068-1.
Macrolide antibiotics bind in the nascent peptide exit tunnel of the bacterial ribosome and prevent polymerization of specific amino acid sequences, selectively inhibiting translation of a subset of proteins. Because preventing translation of individual proteins could be beneficial for the treatment of human diseases, we asked whether macrolides, if bound to the eukaryotic ribosome, would retain their context- and protein-specific action. By introducing a single mutation in rRNA, we rendered yeast Saccharomyces cerevisiae cells sensitive to macrolides. Cryo-EM structural analysis showed that the macrolide telithromycin binds in the tunnel of the engineered eukaryotic ribosome. Genome-wide analysis of cellular translation and biochemical studies demonstrated that the drug inhibits eukaryotic translation by preferentially stalling ribosomes at distinct sequence motifs. Context-specific action markedly depends on the macrolide structure. Eliminating macrolide-arrest motifs from a protein renders its translation macrolide-tolerant. Our data illuminate the prospects of adapting macrolides for protein-selective translation inhibition in eukaryotic cells.
大环内酯类抗生素结合在细菌核糖体的新生肽出口隧道中，阻止特定氨基酸序列的聚合，从而选择性地抑制一组蛋白质的翻译。因为阻止特定蛋白质的翻译可能对人类疾病的治疗有益，所以我们想知道如果大环内酯类药物与真核核糖体结合，它们是否会保留其上下文和蛋白质特异性作用。通过在 rRNA 中引入单个突变，我们使酵母酿酒酵母细胞对大环内酯类药物敏感。低温电子显微镜结构分析表明，大环内酯类药物泰利霉素结合在工程化的真核核糖体隧道中。对细胞翻译的全基因组分析和生化研究表明，该药物通过优先在不同的序列基序处使核糖体停滞来抑制真核翻译。上下文特异性作用显著取决于大环内酯类药物的结构。从蛋白质中消除大环内酯类药物的停滞基序可使其对大环内酯类药物具有耐受性。我们的数据阐明了在真核细胞中适应大环内酯类药物以进行蛋白质选择性翻译抑制的前景。
