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

Paul G. Leonard, Dasantila Golemi-Kotra, Ann M. Stock

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8525-8530
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number21
DOIs
StatePublished - May 21 2013

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Antimicrobial drug target
  • Methicillin-resistant Staphylococcus aureus
  • Transcription factor
  • Two-component system
  • Vancomycin resistance

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