title: Structural contributions to multidrug recognition in the multidrug resistance (MDR) gene regulator, BmrR.
abstract: 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.
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Sharrol
authors.initials: S
authors.lastname: Bachas
authors.forename: Christopher
authors.initials: C
authors.lastname: Eginton
authors.forename: Drew
authors.initials: D
authors.lastname: Gunio
authors.forename: Herschel
authors.initials: H
authors.lastname: Wade
mesh_terms: D001412:Bacillus subtilis / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005798:Genes, Bacterial; D019450:Genes, MDR; D005809:Genes, Regulator; D006860:Hydrogen Bonding; D008024:Ligands; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D001426:Bacterial Proteins; D008024:Ligands; D026901:Membrane Transport Proteins; C075041:Bmr protein, Bacillus subtilis