4MYO : Crystal structure of streptogramin group A antibiotic acetyltransferase VatA from Staphylococcus aureus

  • Peter J. Stogios (Contributor)
  • Elena Evdokimova (Contributor)
  • Patrice Courvalin (Contributor)
  • Wayne F Anderson (Contributor)
  • Alexei Savchenko (Contributor)



Experimental Technique/Method:X-RAY DIFFRACTION
Release Date:2013-10-16
Deposition Date:2013-09-27
Revision Date:2014-09-24#2014-12-24
Molecular Weight:73650.44
Macromolecule Type:Protein
Residue Count:642
Atom Site Count:5121

Combinations of group A and B streptogramins (i.e., dalfopristin and quinupristin) are "last-resort" antibiotics for the treatment of infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Resistance to streptogramins has arisen via multiple mechanisms, including the deactivation of the group A component by the large family of virginiamycin O-acetyltransferase (Vat) enzymes. Despite the structural elucidation performed for the VatD acetyltransferase, which provided a general molecular framework for activity, a detailed characterization of the essential catalytic and antibiotic substrate-binding determinants in Vat enzymes is still lacking. We have determined the crystal structure of S. aureus VatA in apo, virginiamycin M1- and acetyl-coenzyme A (CoA)-bound forms and provide an extensive mutagenesis and functional analysis of the structural determinants required for catalysis and streptogramin A recognition. Based on an updated genomic survey across the Vat enzyme family, we identified key conserved residues critical for VatA activity that are not part of the O-acetylation catalytic apparatus. Exploiting such constraints of the Vat active site may lead to the development of streptogramin A compounds that evade inactivation by Vat enzymes while retaining binding to their ribosomal target.
Date made available2013

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