Abstract
The multidrug transporter AcrB transports a broad range of drugs out of the cell by means of the proton-motive force. The asymmetric crystal structure of trimeric AcrB suggests a functionally rotating mechanism for drug transport. Despite various supportive forms of evidence from biochemical and simulation studies for this mechanism, the link between the functional rotation and proton translocation across the membrane remains elusive. Here, calculating the minimum free energy pathway of the functional rotation for the complete AcrB trimer, we describe the structural and energetic basis behind the coupling between the functional rotation and the proton translocation at atomic resolution. Free energy calculations show that protonation of Asp408 in the transmembrane portion of the drug-bound protomer drives the functional rotation. The conformational pathway identifies vertical shear motions among several transmembrane helices, which regulate alternate access of water in the transmembrane as well as peristaltic motions that pump drugs in the periplasm.
Highlights
Bacterial multidrug resistance (MDR) is an increasing threat to current antibiotic therapy (Li et al, 2015)
In Escherichia coli, the AcrA-AcrB-TolC complex is largely responsible for MDR against many lipophilic antibiotics (Du et al, 2015)
A drug was explicitly included in both systems. It is bound in protomer I at first, and transported to the exit pore during the functional rotation
Summary
Bacterial multidrug resistance (MDR) is an increasing threat to current antibiotic therapy (Li et al, 2015). Resistance nodulation cell division (RND) transporters are one of the main causes of MDR in Gram-negative bacteria. These transporters pump a wide spectrum of antibiotics out of the cell by means of proton- or sodium-motive forces, conferring MDR to the bacterium when overexpressed. In Escherichia coli, the AcrA-AcrB-TolC complex is largely responsible for MDR against many lipophilic antibiotics (Du et al, 2015). This tripartite assembly spans the periplasmic space between the inner and the outer membranes of the cell, transporting drugs from the cell to the medium. AcrA acts as an adaptor that bridges TolC and AcrB (Du et al, 2014; Wang et al, 2017)
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