The proline-rich antimicrobial peptide (PrAMP) Drosocin (Dro) from fruit flies shows sequence similarity to other PrAMPs that bind to the ribosome and inhibit protein synthesis by varying mechanisms. The target and mechanism of action of Dro, however, remain unknown. Here we show that Dro arrests ribosomes at stop codons, probably sequestering class 1 release factors associated with the ribosome. This mode of action is comparable to that of apidaecin (Api) from honeybees, making Dro the second member of the type II PrAMP class. Nonetheless, analysis of a comprehensive library of endogenously expressed Dro mutants shows that the interactions of Dro and Api with the target are markedly distinct. While only a few C-terminal amino acids of Api are critical for binding, the interaction of Dro with the ribosome relies on multiple amino acid residues distributed throughout the PrAMP. Single-residue substitutions can substantially enhance the on-target activity of Dro.

来自果蝇的富含脯氨酸的抗菌肽 (PrAMP) Drosocin (Dro) 与其他 PrAMP 具有序列相似性，后者与核糖体结合并通过不同机制抑制蛋白质合成。然而，Dro 的作用靶点和机制仍不清楚。在这里，我们表明 Dro 在终止密码子处捕获核糖体，可能隔离与核糖体相关的 1 类释放因子。这种作用方式与蜜蜂的阿哌达星 (Api) 相当，使 Dro 成为 II 型 PrAMP 类的第二个成员。尽管如此，对内源表达 Dro 突变体的综合文库的分析表明，Dro 和 Api 与靶标的相互作用明显不同。虽然 Api 只有几个 C 端氨基酸对于结合至关重要，但 Dro 与核糖体的相互作用依赖于分布在 PrAMP 中的多个氨基酸残基。单残基取代可以显着增强 Dro 的靶向活性。