Multidrug-binding transcription factor QacR binds the bivalent aromatic diamidines DB75 and DB359 in multiple positions.
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.
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- Repressor Proteins
- Protein Binding
- Mutagenesis
- Molecular Structure
- Models, Molecular
- Genes, Bacterial
- General Chemistry
- Escherichia
- Benzamidines
- Bacterial Proteins
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Repressor Proteins
- Protein Binding
- Mutagenesis
- Molecular Structure
- Models, Molecular
- Genes, Bacterial
- General Chemistry
- Escherichia
- Benzamidines
- Bacterial Proteins