Structural contributions to multidrug recognition in the multidrug resistance (MDR) gene regulator, BmrR

Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2011; 108(27):11046-51. DOI: 10.1073/pnas.1104850108
Source: PubMed


Current views of multidrug (MD) recognition focus on large drug-binding cavities with flexible elements. However, MD recognition in BmrR is supported by a small, rigid drug-binding pocket. Here, a detailed description of MD binding by the noncanonical BmrR protein is offered through the combined use of X-ray and solution studies. Low shape complementarity, suboptimal packing, and efficient burial of a diverse set of ligands is facilitated by an aromatic docking platform formed by a set of conformationally fixed aromatic residues, hydrophobic pincer pair that locks the different drug structures on the adaptable platform surface, and a trio of acidic residues that enables cation selectivity without much regard to ligand structure. Within the binding pocket is a set of BmrR-derived H-bonding donor and acceptors that solvate a wide range of ligand polar substituent arrangements in a manner analogous to aqueous solvent. Energetic analyses of MD binding by BmrR are consistent with structural data. A common binding orientation for the different BmrR ligands is in line with promiscuous allosteric regulation.

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    • "Multidrug recognition in this type of small binding pocket has been already conferred in BmrR multidrug-resistant (MDR) transcription factor [11]. In case of BmrR, the same residues of active site interact with different ligand molecules in a highly rigid binding pocket [11]. This is different from the canonical concept of multidrug recognition [12] [13], which postulates a key role of flexibility in placing diverse ligands in a specific site. "
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