Structural highlights
FunctionLPXK_AQUAE Transfers the gamma-phosphate of ATP to the 4'-position of a tetraacyldisaccharide 1-phosphate intermediate (termed DS-1-P) to form tetraacyldisaccharide 1,4'-bis-phosphate (lipid IVA) (By similarity). Publication Abstract from PubMedThe membrane-bound tetraacyldisaccharide-1-phosphate 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. Structural basis of lipid binding for the membrane-embedded tetraacyldisaccharide-1-phosphate 4'-kinase LpxK.,Emptage RP, Tonthat NK, York JD, Schumacher MA, Zhou P J Biol Chem. 2014 Jul 14. pii: jbc.M114.589986. PMID:25023290[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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This page was last modified 11:07, 14 December 2022.