Structure-based mechanism of lipoteichoic acid synthesis by Staphylococcus aureus LtaS.
Proc Natl Acad Sci U S A
; 106(5): 1584-9, 2009 Feb 03.
Article
em En
| MEDLINE
| ID: mdl-19168632
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-A 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 glycerol-phosphate 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Staphylococcus aureus
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Ácidos Teicoicos
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Proteínas de Bactérias
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Lipopolissacarídeos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Reino Unido