4LKV

Determinants of lipid substrate and membrane binding for the tetraacyldisaccharide-1-phosphate 4 -kinase LpxK

Summary for 4LKV

• Entry DOI: 10.2210/pdb4lkv/pdb
• Related: 4ehw 4ehx 4ehy 4itl 4itm 4itn
• Descriptor: Tetraacyldisaccharide 4'-kinase, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, 2-deoxy-3-O-[(3R)-3-hydroxytetradecanoyl]-2-{[(3R)-3-hydroxytetradecanoyl]amino}-4-O-phosphono-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: p-loop containing nucleotide triphosphate hydrolase, kinase, membrane protein, transferase
• Biological source: Aquifex aeolicus
• Total number of polymer chains: 4
• Total formula weight: 149476.67

Authors

Emptage, R.P.,Tonthat, N.K.,York, J.D.,Schumacher, M.A.,Zhou, P. (deposition date: 2013-07-08, release date: 2014-07-09, Last modification date: 2024-02-28)

Primary citation

Emptage, R.P.,Tonthat, N.K.,York, J.D.,Schumacher, M.A.,Zhou, P.
Structural Basis of Lipid Binding for the Membrane-embedded Tetraacyldisaccharide-1-phosphate 4'-Kinase LpxK.
J.Biol.Chem., 289:24059-24068, 2014

PubMed Abstract: 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.

PubMed: 25023290
DOI: 10.1074/jbc.M114.589986

Experimental method

X-RAY DIFFRACTION (3.5109 Å)