生物
核糖体
嗜热菌
翻译(生物学)
肽
抗菌肽
蛋白质生物合成
内部核糖体进入位点
核糖体RNA
真核核糖体
核糖体蛋白
细胞生物学
生物化学
核糖核酸
大肠杆菌
基因
信使核糖核酸
作者
A. Carolin Seefeldt,Michael Graf,Natacha Pérébaskine,Fabian Nguyen,Stefan Arenz,Mario Mardirossian,Marco Scocchi,Daniel N. Wilson,C. Axel Innis
摘要
Proline-rich antimicrobial peptides (PrAMPs) produced as part of the innate immune response of animals, insects and plants represent a vast, untapped resource for the treatment of multidrug-resistant bacterial infections. PrAMPs such as oncocin or bactenecin-7 (Bac7) interact with the bacterial ribosome to inhibit translation, but their supposed specificity as inhibitors of bacterial rather than mammalian protein synthesis remains unclear, despite being key to developing drugs with low toxicity. Here, we present crystal structures of the Thermus thermophilus 70S ribosome in complex with the first 16 residues of mammalian Bac7, as well as the insect-derived PrAMPs metalnikowin I and pyrrhocoricin. The structures reveal that the mammalian Bac7 interacts with a similar region of the ribosome as insect-derived PrAMPs. Consistently, Bac7 and the oncocin derivative Onc112 compete effectively with antibiotics, such as erythromycin, which target the ribosomal exit tunnel. Moreover, we demonstrate that Bac7 allows initiation complex formation but prevents entry into the elongation phase of translation, and show that it inhibits translation on both mammalian and bacterial ribosomes, explaining why this peptide needs to be stored as an inactive pro-peptide. These findings highlight the need to consider the specificity of PrAMP derivatives for the bacterial ribosome in future drug development efforts.
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