title: Charge is Major Determinant of Activation of the Ligand-Responsive Multidrug Resistance Gene Regulator, BmrR.
abstract: A medium-throughput approach (80+ compounds) to investigate allosteric transcriptional control in the multidrug resistance gene regulator BmrR, with cations, zwitterions, uncharged compounds and anions, is described. Even at the allosteric level, BmrR is quite promiscuous with regard to molecular shape and structure, but it is sensitive to molecular charge. A role for charge is further supported by differences in the activation properties of structurally similar ligands displaying variable charge properties as well as differences in activation by zwitterions and uncharged ligands, which show similar binding affinities. A comparison of allosteric selectivity with the distribution of differently charged ligands in bacterial cellular environments suggests that the selectivity of charge is a major factor in discrimination of xenobiotics, and native biological compounds and metabolites. Interestingly, in eukaryotic cells, the selectivity of cationic ligands might be a protective mechanism against chemical agents that act in a promiscuous fashion.
authors.affiliation: Laboratory of Biophysics & Cellular Physiology, Biochemistry & Biophysics Center, National Heart Lung and Blood Institute (NHLBI), 50 South Drive, MSC 8012, Bethesda, MD, 20892-8012, USA.
authors.forename: Sharrol
authors.initials: S
authors.lastname: Bachas
authors.affiliation: Department of Biophysics & Biophysical Chemistry, Johns Hopkins School of Medicine, 725 N. Wolfe Street, Baltimore, MD, 21205, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Kohrs
authors.affiliation: Department of Biophysics & Biophysical Chemistry, Johns Hopkins School of Medicine, 725 N. Wolfe Street, Baltimore, MD, 21205, USA. Herschel.wade@jhmi.edu.
authors.forename: Herschel
authors.identifier: 0000-0003-1095-7888
authors.initials: H
authors.lastname: Wade
mesh_terms: D000494:Allosteric Regulation; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001412:Bacillus subtilis / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D008024:Ligands; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008024:Ligands; D026901:Membrane Transport Proteins
keywords: allosterism; antibiotics; biosensors; molecular recognition; signal transduction