Department of Chemistry , University College London , 20 Gordon Street , London WC1H 0AJ , U.K.
Institute of Structural and Molecular Biology, Division of Biosciences , University College London , Gower Street , London WC1E 6BT , U.K.
J Org Chem. 2019 Sep 20;84(18):11493-11512. doi: 10.1021/acs.joc.9b01253. Epub 2019 Aug 29.
In response to the growing threat posed by antibiotic-resistant bacterial strains, extensive research is currently focused on developing antimicrobial agents that target lipid II, a vital precursor in the biosynthesis of bacterial cell walls. The lantibiotic nisin and related peptides display unique and highly selective binding to lipid II. A key feature of the nisin-lipid II interaction is the formation of a cage-like complex between the pyrophosphate moiety of lipid II and the two thioether-bridged rings, rings A and B, at the N-terminus of nisin. To understand the important structural factors underlying this highly selective molecular recognition, we have used solid-phase peptide synthesis to prepare individual ring A and B structures from nisin, the related lantibiotic mutacin, and synthetic analogues. Through NMR studies of these rings, we have demonstrated that ring A is preorganized to adopt the correct conformation for binding lipid II in solution and that individual amino acid substitutions in ring A have little effect on the conformation. We have also analyzed the turn structures adopted by these thioether-bridged peptides and show that they do not adopt the tight α-turn or β-turn structures typically found in proteins.
针对抗生素耐药菌株构成的日益严重威胁，目前正在进行广泛的研究，以开发针对脂质 II 的抗菌剂，脂质 II 是细菌细胞壁生物合成中的重要前体。类尼生素乳链菌肽和相关肽显示出对脂质 II 的独特且高度选择性结合。乳链菌肽与脂质 II 相互作用的一个关键特征是脂质 II 的焦磷酸部分与乳链菌肽 N 端的两个硫醚桥环 A 和环 B 之间形成笼状复合物。为了了解这种高度选择性分子识别的重要结构因素，我们使用固相肽合成技术从乳链菌肽、相关的类尼生素 mutacin 和合成类似物中制备了单个环 A 和环 B 结构。通过对这些环的 NMR 研究，我们证明环 A 预先组织成在溶液中与脂质 II 结合的正确构象，并且环 A 中的单个氨基酸取代对构象几乎没有影响。我们还分析了这些硫醚桥接肽所采用的转角结构，并表明它们不采用通常在蛋白质中发现的紧密α-转角或β-转角结构。
