Phosphorylation-dependent conformational changes and domain rearrangements in Staphylococcus aureus VraR activation

Staphylococcus aureus VraR, a vancomycin-resistance-associated response regulator, activates a cell-wall-stress stimulon in response to antibiotics that inhibit cell wall formation. X-ray crystal structures of VraR in both unphosphorylated and beryllofluoride-activated states have been determined, r...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-05, Vol.110 (21), p.8525-8530
Main Authors: Leonard, Paul G., Golemi-Kotra, Dasantila, Stock, Ann M.
Format: Article
Language:English
Subjects:
Active sites
Antibiotics
Bacterial Proteins - chemistry
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Biological Sciences
Cells
Crystallography, X-Ray
Crystals
Deoxyribonucleic acid
Dimerization
Dimers
DNA
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Drug Resistance, Bacterial - physiology
Hydrogen bonds
Molecular structure
Phosphorylation
Phosphorylation - physiology
Protein Multimerization
Protein Structure, Quaternary
Protein Structure, Tertiary
Protein subunits
Regulator genes
Staphylococcus aureus
Staphylococcus aureus - chemistry
Staphylococcus aureus - genetics
Staphylococcus aureus - metabolism
Staphylococcus infections
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Summary:Staphylococcus aureus VraR, a vancomycin-resistance-associated response regulator, activates a cell-wall-stress stimulon in response to antibiotics that inhibit cell wall formation. X-ray crystal structures of VraR in both unphosphorylated and beryllofluoride-activated states have been determined, revealing a mechanism of phosphorylation-induced dimerization that features a deep hydrophobic pocket at the center of the receiver domain interface. Unphosphorylated VraR exists in a closed conformation that inhibits dimer formation. Phosphorylation at the active site promotes conformational changes that are propagated throughout the receiver domain, promoting the opening of a hydrophobic pocket that is essential for homodimer formation and enhanced DNA-binding activity. This prominent feature in the VraR dimer can potentially be exploited for the development of novel therapeutics to counteract antibiotic resistance in this important pathogen.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1302819110