Multidrug-Binding Transcription Factor QacR Binds the Bivalent Aromatic Diamidines DB75 and DB359 in Multiple Positions

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• 作者：Benjamin E. Brooks ; Kevin M. Piro ; Richard G. Brennan
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：July 4, 2007
• 年：2007
• 卷：129
• 期：26
• 页码：8389 - 8395
• 全文大小：582K
• 年卷期：v.129,no.26(July 4, 2007)
• ISSN：1520-5126

文摘

Staphylococcus aureus QacR is a multidrug-binding transcription repressor. Crystal structuresof multiple QacR-drug complexes reveal that these toxins bind in a large pocket, which is composed ofsmaller overlapping "minipockets". Stacking, van der Waals, and ionic interactions are common featuresof binding, whereas hydrogen bonds are limited. Pentamidine, a bivalent aromatic diamidine, interactswith 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 structuresof the QacR-DB75 and QacR-DB359 complexes and measured their binding affinities. Although theserigid 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-bindingpocket. Chemical redundancy is likely a hallmark of all multidrug-binding pockets, yet it is utilized by onlya subset of drugs, which, for QacR, so far appears to be limited to chemically rigid, bivalent compounds.