A Chemical Biology Approach to Understanding Molecular Recognition of Lipid II by Nisin(1-12): Synthesis and NMR Ensemble Analysis of Nisin(1-12) and Analogues
A Chemical Biology Approach to Understanding Molecular Recognition of Lipid II by Nisin(1-12): Synthesis and NMR Ensemble Analysis of Nisin(1-12) and Analogues
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DOI：
10.1002/chem.201902814
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发表时间：
2019-10-10
影响因子：
4.3
通讯作者：
Tabor, Alethea B.
中科院分区：
文献类型：
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作者：
Dickman, Rachael;Danelius, Emma;Tabor, Alethea B.
靶向脂质II的天然产物，如lantibiotic nisin，在开发新的抗菌剂以对抗抗菌素耐药性的上升方面具有战略重要性。了解的结构因素，管理的高度选择性的分子识别的脂质II的N-末端区域的乳链菌肽，乳链菌肽（1-12），是一个关键的一步，在利用这些化合物的潜力。为了阐明该双环肽片段的氨基酸序列与构象之间的关系，我们使用固相肽合成法制备了两种新的Nisin类似物（1-12），其中Nisin（1-12）的Nisin残基被取代。我们已经进行了一个NMR系综分析这些类似物和野生型乳链菌肽（1-12）的肽，以比较这两个双环肽的构象。我们的分析表明，残基突变对环构象的影响。我们还证明了乳酸链球菌素（1-12）的各个环在一定程度上是预先组织好的，可以与脂质II的焦磷酸基团结合，在连接两个环的中心酰胺键中表现出高度的灵活性。
Natural products that target lipid II, such as the lantibiotic nisin, are strategically important in the development of new antibacterial agents to combat the rise of antimicrobial resistance. Understanding the structural factors that govern the highly selective molecular recognition of lipid II by the N-terminal region of nisin, nisin(1-12), is a crucial step in exploiting the potential of such compounds. In order to elucidate the relationships between amino acid sequence and conformation of this bicyclic peptide fragment, we have used solid-phase peptide synthesis to prepare two novel analogues of nisin(1-12) in which the dehydro residues have been replaced. We have carried out an NMR ensemble analysis of one of these analogues and of the wild-type nisin(1-12) peptide in order to compare the conformations of these two bicyclic peptides. Our analysis has shown the effects of residue mutation on ring conformation. We have also demonstrated that the individual rings of nisin(1-12) are pre-organised to an extent for binding to the pyrophosphate group of lipid II, with a high degree of flexibility exhibited in the central amide bond joining the two rings.