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J Biol Chem. 2014 Aug 29;289(35):24059-68. doi: 10.1074/jbc.M114.589986. Epub 2014 Jul 14.

Structural basis of lipid binding for the membrane-embedded tetraacyldisaccharide-1-phosphate 4'-kinase LpxK.

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From the Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710 and.
the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37205.
From the Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710 and


The membrane-bound tetraacyldisaccharide-1-phosphate 4'-kinase, LpxK, catalyzes the sixth step of the lipid A (Raetz) biosynthetic pathway and is a viable antibiotic target against emerging Gram-negative pathogens. We report the crystal structure of lipid IVA, the LpxK product, bound to the enzyme, providing a rare glimpse into interfacial catalysis and the surface scanning strategy by which many poorly understood lipid modification enzymes operate. Unlike the few previously structurally characterized proteins that bind lipid A or its precursors, LpxK binds almost exclusively to the glucosamine/phosphate moieties of the lipid molecule. Steady-state kinetic analysis of multiple point mutants of the lipid-binding pocket pinpoints critical residues involved in substrate binding, and characterization of N-terminal helix truncation mutants uncovers the role of this substructure as a hydrophobic membrane anchor. These studies make critical contributions to the limited knowledge surrounding membrane-bound enzymes that act upon lipid substrates and provide a structural template for designing small molecule inhibitors targeting this essential kinase.


Antibiotic; Crystal Structure; Enzyme; Lipid A; Lipid Kinase; Lipid-binding Protein; Lipopolysaccharide (LPS); Membrane Protein

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