Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 5, Pages 1584-1589Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0809020106
Keywords
Gram-positive; cell wall; enzyme
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Funding
- U.S. Public Health Service [AI073511A]
- National Institute of Allergy and Infectious Diseases
- Medical Research Council [G0701212, MRC76791]
- MRC [G0501723, G0701212] Funding Source: UKRI
- Medical Research Council [G0501723, G0701212] Funding Source: researchfish
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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 Mn2+ 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.
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