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

Publication ,  Journal Article
Brooks, BE; Piro, KM; Brennan, RG
Published in: J Am Chem Soc
July 4, 2007

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.

Duke Scholars

Published In

J Am Chem Soc

DOI

ISSN

0002-7863

Publication Date

July 4, 2007

Volume

129

Issue

26

Start / End Page

8389 / 8395

Location

United States

Related Subject Headings

  • Repressor Proteins
  • Protein Binding
  • Mutagenesis
  • Molecular Structure
  • Models, Molecular
  • Genes, Bacterial
  • General Chemistry
  • Escherichia
  • Benzamidines
  • Bacterial Proteins
 

Citation

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Brooks, B. E., Piro, K. M., & Brennan, R. G. (2007). Multidrug-binding transcription factor QacR binds the bivalent aromatic diamidines DB75 and DB359 in multiple positions. J Am Chem Soc, 129(26), 8389–8395. https://doi.org/10.1021/ja072576v
Brooks, Benjamin E., Kevin M. Piro, and Richard G. Brennan. “Multidrug-binding transcription factor QacR binds the bivalent aromatic diamidines DB75 and DB359 in multiple positions.J Am Chem Soc 129, no. 26 (July 4, 2007): 8389–95. https://doi.org/10.1021/ja072576v.
Brooks, Benjamin E., et al. “Multidrug-binding transcription factor QacR binds the bivalent aromatic diamidines DB75 and DB359 in multiple positions.J Am Chem Soc, vol. 129, no. 26, July 2007, pp. 8389–95. Pubmed, doi:10.1021/ja072576v.
Journal cover image

Published In

J Am Chem Soc

DOI

ISSN

0002-7863

Publication Date

July 4, 2007

Volume

129

Issue

26

Start / End Page

8389 / 8395

Location

United States

Related Subject Headings

  • Repressor Proteins
  • Protein Binding
  • Mutagenesis
  • Molecular Structure
  • Models, Molecular
  • Genes, Bacterial
  • General Chemistry
  • Escherichia
  • Benzamidines
  • Bacterial Proteins