Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA.
EMBO Rep. 2024 Nov;25(11):5194-5211. doi: 10.1038/s44319-024-00277-5. Epub 2024 Oct 16.
Apidaecin 1b (Api), the first characterized Type II Proline-rich antimicrobial peptide (PrAMP), is encoded in the honey bee genome. It inhibits bacterial growth by binding in the nascent peptide exit tunnel of the ribosome after the release of the completed protein and trapping the release factors. By genome mining, we have identified 71 PrAMPs encoded in insect genomes as pre-pro-polyproteins. Having chemically synthesized and tested the activity of 26 peptides, we demonstrate that despite significant sequence variation in the N-terminal sequence, the majority of the PrAMPs that retain the conserved C-terminal sequence of Api are able to trap the ribosome at the stop codons and induce stop codon readthrough-all hallmarks of Type II PrAMP mode of action. Some of the characterized PrAMPs exhibit superior antibacterial activity in comparison with Api. The newly solved crystallographic structures of the ribosome complexed with Api and with the more active peptide Fva1 from the stingless bee demonstrate the universal placement of the PrAMPs' C-terminal pharmacophore in the post-release ribosome despite variations in their N-terminal sequence.
蜂肽 1b（Api）是第一个被描述的 II 型富含脯氨酸的抗菌肽（PrAMP），它被编码在蜜蜂基因组中。它通过在核糖体新生肽出口隧道中结合完成蛋白释放后的释放因子，并捕获释放因子，从而抑制细菌生长。通过基因组挖掘，我们在昆虫基因组中鉴定出 71 个编码 PrAMP 的前原多肽。通过化学合成和测试 26 个肽的活性，我们证明尽管 N 端序列存在显著的序列变异，但保留 Api 保守 C 端序列的大多数 PrAMP 能够在核糖体上捕获终止密码子并诱导终止密码子通读——这都是 II 型 PrAMP 作用模式的标志。一些已鉴定的 PrAMP 与 Api 相比具有更高的抗菌活性。新解决的核糖体与 Api 以及来自无刺蜜蜂的更活跃肽 Fva1 的晶体结构复合物证明了尽管 N 端序列存在差异，但 PrAMP 的 C 端药效团在核糖体释放后仍然具有普遍性。
