Multidrug-binding transcription factor QacR binds the bivalent aromatic diamidines DB75 and DB359 in multiple positions.

Journal Article (Journal Article)

Staphylococcus aureus QacR is a multidrug-binding transcription repressor. Crystal structures of multiple QacR-drug complexes reveal that these toxins bind in a large pocket, which is composed of smaller overlapping "minipockets". Stacking, van der Waals, and ionic interactions are common features of binding, whereas hydrogen bonds are limited. Pentamidine, a bivalent aromatic diamidine, interacts with QacR differently as one positively charged benzamidine moiety is neutralized by the dipoles of side-chain and peptide backbone oxygens rather than a formal negative charge from proximal acidic residues. To understand the binding mechanisms of other bivalent benzamidines, we determined the crystal structures of the QacR-DB75 and QacR-DB359 complexes and measured their binding affinities. Although these rigid aromatic diamidines bind with low-micromolar affinities, they do not use single, discrete binding modes. Such promiscuous binding underscores the intrinsic chemical redundancy of the QacR multidrug-binding pocket. Chemical redundancy is likely a hallmark of all multidrug-binding pockets, yet it is utilized by only a subset of drugs, which, for QacR, so far appears to be limited to chemically rigid, bivalent compounds.

Full Text

Duke Authors

Cited Authors

  • Brooks, BE; Piro, KM; Brennan, RG

Published Date

  • July 4, 2007

Published In

Volume / Issue

  • 129 / 26

Start / End Page

  • 8389 - 8395

PubMed ID

  • 17567017

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja072576v


  • eng

Conference Location

  • United States