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

Publication ,  Journal Article
Emptage, RP; Tonthat, NK; York, JD; Schumacher, MA; Zhou, P
Published in: J Biol Chem
August 29, 2014

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.

Duke Scholars

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

August 29, 2014

Volume

289

Issue

35

Start / End Page

24059 / 24068

Location

United States

Related Subject Headings

  • Protein Conformation
  • Protein Binding
  • Point Mutation
  • Phosphotransferases (Alcohol Group Acceptor)
  • Models, Molecular
  • Membrane Proteins
  • Lipids
  • Kinetics
  • Genetic Complementation Test
  • Gene Knockdown Techniques
 

Citation

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Emptage, R. P., Tonthat, N. K., York, J. D., Schumacher, M. A., & Zhou, P. (2014). Structural basis of lipid binding for the membrane-embedded tetraacyldisaccharide-1-phosphate 4'-kinase LpxK. J Biol Chem, 289(35), 24059–24068. https://doi.org/10.1074/jbc.M114.589986
Emptage, Ryan P., Nam K. Tonthat, John D. York, Maria A. Schumacher, and Pei Zhou. “Structural basis of lipid binding for the membrane-embedded tetraacyldisaccharide-1-phosphate 4'-kinase LpxK.J Biol Chem 289, no. 35 (August 29, 2014): 24059–68. https://doi.org/10.1074/jbc.M114.589986.
Emptage RP, Tonthat NK, York JD, Schumacher MA, Zhou P. Structural basis of lipid binding for the membrane-embedded tetraacyldisaccharide-1-phosphate 4'-kinase LpxK. J Biol Chem. 2014 Aug 29;289(35):24059–68.
Emptage, Ryan P., et al. “Structural basis of lipid binding for the membrane-embedded tetraacyldisaccharide-1-phosphate 4'-kinase LpxK.J Biol Chem, vol. 289, no. 35, Aug. 2014, pp. 24059–68. Pubmed, doi:10.1074/jbc.M114.589986.
Emptage RP, Tonthat NK, York JD, Schumacher MA, Zhou P. Structural basis of lipid binding for the membrane-embedded tetraacyldisaccharide-1-phosphate 4'-kinase LpxK. J Biol Chem. 2014 Aug 29;289(35):24059–24068.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

August 29, 2014

Volume

289

Issue

35

Start / End Page

24059 / 24068

Location

United States

Related Subject Headings

  • Protein Conformation
  • Protein Binding
  • Point Mutation
  • Phosphotransferases (Alcohol Group Acceptor)
  • Models, Molecular
  • Membrane Proteins
  • Lipids
  • Kinetics
  • Genetic Complementation Test
  • Gene Knockdown Techniques