Haloduracin α Binds the Peptidoglycan Precursor Lipid II with 2:1 Stoichiometry
Journal of the American Chemical Society2011Vol. 133(44), pp. 17544–17547
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Trent J. Oman, Tania J. Lupoli, Tsung‐Shing Andrew Wang, Daniel Kahne, Suzanne Walker, Wilfred A. van der Donk
Abstract
The two-peptide lantibiotic haloduracin is composed of two post-translationally modified polycyclic peptides that synergistically act on gram-positive bacteria. We show here that Halα inhibits the transglycosylation reaction catalyzed by PBP1b by binding in a 2:1 stoichiometry to its substrate lipid II. Halβ and the mutant Halα-E22Q were not able to inhibit this step in peptidoglycan biosynthesis, but Halα with its leader peptide still attached was a potent inhibitor. Combined with previous findings, the data support a model in which a 1:2:2 lipid II:Halα:Halβ complex inhibits cell wall biosynthesis and mediates pore formation, resulting in loss of membrane potential and potassium efflux.
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