Gagnon Matthieu G, Roy Raktim N, Lomakin Ivan B, Florin Tanja, Mankin Alexander S, Steitz Thomas A
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA Howard Hughes Medical Institute, Yale University, New Haven, CT 06520-8114, USA
Howard Hughes Medical Institute, Yale University, New Haven, CT 06520-8114, USA Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
Nucleic Acids Res. 2016 Mar 18;44(5):2439-50. doi: 10.1093/nar/gkw018. Epub 2016 Jan 24.
With bacterial resistance becoming a serious threat to global public health, antimicrobial peptides (AMPs) have become a promising area of focus in antibiotic research. AMPs are derived from a diverse range of species, from prokaryotes to humans, with a mechanism of action that often involves disruption of the bacterial cell membrane. Proline-rich antimicrobial peptides (PrAMPs) are instead actively transported inside the bacterial cell where they bind and inactivate specific targets. Recently, it was reported that some PrAMPs, such as Bac71 -35, oncocins and apidaecins, bind and inactivate the bacterial ribosome. Here we report the crystal structures of Bac71 -35, Pyrrhocoricin, Metalnikowin and two oncocin derivatives, bound to the Thermus thermophilus 70S ribosome. Each of the PrAMPs blocks the peptide exit tunnel of the ribosome by simultaneously occupying three well characterized antibiotic-binding sites and interferes with the initiation step of translation, thereby revealing a common mechanism of action used by these PrAMPs to inactivate protein synthesis. Our study expands the repertoire of PrAMPs and provides a framework for designing new-generation therapeutics.
随着细菌耐药性对全球公共卫生构成严重威胁，抗菌肽已成为抗生素研究中一个有前景的重点领域。抗菌肽来源于从原核生物到人类的多种物种，其作用机制通常涉及破坏细菌细胞膜。富含脯氨酸的抗菌肽（PrAMPs）则相反，它们被主动转运到细菌细胞内，在那里结合并使特定靶点失活。最近，有报道称一些PrAMPs，如Bac71 - 35、癌菌素和蜜蜂抗菌肽，能结合并使细菌核糖体失活。在此，我们报道了Bac71 - 35、红蝽菌素、Metalnikowin和两种癌菌素衍生物与嗜热栖热菌70S核糖体结合的晶体结构。每种PrAMP通过同时占据三个特征明确的抗生素结合位点来阻断核糖体的肽出口通道，并干扰翻译起始步骤，从而揭示了这些PrAMPs使蛋白质合成失活的共同作用机制。我们的研究扩展了PrAMPs的种类，并为设计新一代治疗药物提供了框架。
