title: The nisin-lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics.
abstract: 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.
authors.affiliation: Department of NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands.
authors.forename: Shang-Te D
authors.initials: ST
authors.lastname: Hsu
authors.forename: Eefjan
authors.initials: E
authors.lastname: Breukink
authors.forename: Eugene
authors.initials: E
authors.lastname: Tischenko
authors.forename: Mandy A G
authors.initials: MA
authors.lastname: Lutters
authors.forename: Ben
authors.initials: B
authors.lastname: de Kruijff
authors.forename: Robert
authors.initials: R
authors.lastname: Kaptein
authors.forename: Alexandre M J J
authors.initials: AM
authors.lastname: Bonvin
authors.forename: Nico A J
authors.initials: NA
authors.lastname: van Nuland
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D011756:Diphosphates / Q000378:metabolism*; D050356:Lipid Metabolism; D009561:Nisin / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D011756:Diphosphates; D009561:Nisin