Dissecting Signal Control in the Multidrug Sensor, BMRR

Abstract

Multidrug (MD) (or xenobiotic) e□ux actively removes cytotoxic chemicals from the interiors of normal-functioning cells. However, high levels of e□ux can render drug-targeted cells resistant to a broad-range of therapeutic agents, including those to which cells were never exposed. Key multidrug resistance (MDR) contributors include allosteric e□ux pumps, gene regulators and other sensory systems that mediate the detection and extrusion of diverse drugs from cellular environments. To date, MDR functions remain only partially understood. Ligand-dependent allosteric control in BmrR has been quantitatively addressed using in vitro transcription experiments, dose-response curves and thermodynamic models that relate the observed transcriptional responses to ligand binding and changes in BmrR conformation. Preliminary results indicate that allosteric control in BmrR is sensitive to both energetic and structural aspects of ligand recognition. Importantly, increased cooperativity in signal control relative to recognition implicates a major allosteric role for the RNA polymerase.