A motor mechanism for MtrD

JA Mitchell and M O'Mara

The Australian National University

With over 106 million cases reported yearly, gonorrhoea is a major sexually transmitted infection for which no vaccine is available. Multidrug antimicrobial resistance in the gram-negative bacterium Neisseria gonorrhoeae is mediated in large part by the three-part MtrCDE efflux system. Molecular recognition and drug efflux in this system are powered by the RND membrane transporter MtrD. MtrD is a homologue of the well-characterised AcrB from E. coli. Crystallographic studies of AcrB suggest that drug binding and export is coupled to the import of protons across the inner membrane via a charge relay in the transmembrane region. In this way, the entropic cost of pumping drugs against the concentration gradient and out of the cell is paid by importing protons along the electrochemical gradient from the periplasm to the cytoplasm. By altering the charge state of the residues implicated in proton transfer, this coupling can be observed via molecular dynamics simulation of MtrD, allowing the structure-function mechanism of this motor protein to be elucidated. Here we link key proton-generated changes in the motor domain to transporter function, suggesting that a similar mechanism is in play in N. gonorrhoeae as hypothesized in the E. coli AcrB.