Charge is Major Determinant of Activation of the Ligand-Responsive Multidrug Resistance Gene Regulator, BmrR

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. Charged allostery: A medium-throughput in vitro transcription approach has been used to elucidate ligand structural requirements for allosteric control in BmrR, a multidrug resistance gene regulator in Bacillus subtilis. Results obtained for cationic, zwitterionic, charge-neutral and anionic probes highlight a central importance for charge in ligand-activated transcription. An analysis of ligand-charge distribution of the E. coli metabolome suggests that charge may be an importance factor in identifying xenobiotics.