Broadly conserved Na ⁺ -binding site in the N-lobe of prokaryotic multidrug MATE transporters

Abstract

Significance MATE transporters deplete the bacterial cytosol of natural and human-made antibiotics and contribute to confer multidrug resistance to a wide range of human pathogens. Despite being a compelling pharmacological target, little is known about their molecular mechanism. Based upon crystallographic and computational data, we gain insights into the mechanism by which drug efflux is energized by transmembrane electrochemical gradients of ions by identifying a Na + -binding site in the N-terminal domain of the transporter. This site can be clearly discerned in two different high-resolution structures and is broadly conserved within the MATE superfamily. Our structural analysis also provides a plausible rationale for the observation of H + -coupled drug transport and other pH-dependent effects.