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Structure-based mechanism of lipoteichoic acid synthesis by Staphylococcus aureus LtaS

DOI: 10.1073/pnas.0809020106 DOI Help
PMID: 19168632 PMID Help

Authors: Duo Lu (Imperial College London) , Mirka Wormann (Imperial College London) , Xiaodong Zhang (Imperial College London) , O. Schneewind (Imperial College London) , A. Grundling (Imperial College London) , A. Freemont (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 106 (5) , PAGES 1584-9

State: Published (Approved)
Published: February 2009

Abstract: Staphylococcus aureus synthesizes polyglycerol-phosphate lipoteichoic acid (LTA) from phosphatidylglycerol. LtaS, a predicted membrane protein with 5 N-terminal transmembrane helices followed by a large extracellular part (eLtaS), is required for staphylococcal growth and LTA synthesis. Here, we report the first crystal structure of the eLtaS domain at 1.2-angstrom resolution and show that it assumes a sulfatase-like fold with an alpha/beta core and a C-terminal part composed of 4 anti-parallel beta-strands and a long alpha-helix. Overlaying eLtaS with sulfatase structures identified active site residues, which were confirmed by alanine substitution mutagenesis and in vivo enzyme function assays. The cocrystal structure with glycerolphosphate and the coordination of a Mn(2+) cation allowed us to propose a reaction mechanism, whereby the active site threonine of LtaS functions as nucleophile for phosphatidylglycerol hydrolysis and formation of a covalent threonine-glycerolphosphate intermediate. These results will aid in the development of LtaS-specific inhibitors for S. aureus and many other Gram-positive pathogens.

Journal Keywords: Catalytic; Hydrolysis; Lipopolysaccharides; Manganese; Models; Molecular; Mutagenesis; Site-Directed; Protein; Staphylococcus; Teichoic Acids

Subject Areas: Biology and Bio-materials

Instruments: I04-Macromolecular Crystallography

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