Hsu Shang-Te D, Breukink Eefjan, Tischenko Eugene, Lutters Mandy A G, de Kruijff Ben, Kaptein Robert, Bonvin Alexandre M J J, van Nuland Nico A J
Department of NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands.
Nat Struct Mol Biol. 2004 Oct;11(10):963-7. doi: 10.1038/nsmb830. Epub 2004 Sep 12.
The emerging antibiotics-resistance problem has underlined the urgent need for novel antimicrobial agents. Lantibiotics (lanthionine-containing antibiotics) are promising candidates to alleviate this problem. Nisin, a member of this family, has a unique pore-forming activity against bacteria. It binds to lipid II, the essential precursor of cell wall synthesis. As a result, the membrane permeabilization activity of nisin is increased by three orders of magnitude. Here we report the solution structure of the complex of nisin and lipid II. The structure shows a novel lipid II-binding motif in which the pyrophosphate moiety of lipid II is primarily coordinated by the N-terminal backbone amides of nisin via intermolecular hydrogen bonds. This cage structure provides a rationale for the conservation of the lanthionine rings among several lipid II-binding lantibiotics. The structure of the pyrophosphate cage offers a template for structure-based design of novel antibiotics.
新出现的抗生素耐药性问题凸显了对新型抗菌剂的迫切需求。羊毛硫抗生素(含羊毛硫氨酸的抗生素)是缓解这一问题的有希望的候选药物。乳酸链球菌素是这个家族的一员,对细菌具有独特的成孔活性。它与细胞壁合成的必需前体脂质II结合。结果,乳酸链球菌素的膜通透活性提高了三个数量级。在此,我们报告了乳酸链球菌素与脂质II复合物的溶液结构。该结构显示了一种新的脂质II结合基序,其中脂质II的焦磷酸部分主要通过分子间氢键由乳酸链球菌素的N端主链酰胺配位。这种笼状结构为几种脂质II结合羊毛硫抗生素中羊毛硫氨酸环的保守性提供了理论依据。焦磷酸笼的结构为新型抗生素的基于结构的设计提供了模板。