On the ion coupling mechanism of the MATE transporter ClbM

Abstract

Bacteria use a number of mechanisms to defend themselves from antimicrobial drugs. One important defense strategy is the ability to export drugs by multidrug transporters. One class of multidrug transporter, the so-called multidrug and toxic compound extrusion (MATE) transporters, extrude a variety of antibiotic compounds from the bacterial cytoplasm. These MATE transporters are driven by a Na + , H + , or combined Na + /H + gradient, and act as antiporters to drive a conformational change in the transporter from the outward to the inward-facing conformation. In the inward-facing conformation, a chemical compound (drug) binds to the protein, resulting in a switch to the opposite conformation, thereby extruding the drug. Using molecular dynamics simulations, we now report the structural basis for Na + and H + binding in the dual ion coupled MATE transporter ClbM from Escherichia coli, which is connected to colibactin-induced genotoxicity, yielding novel insights into the ion/drug translocation mechanism of this bacterial transporter.

Conserved binding site in the N-lobe of prokaryotic MATE transporters suggests a role for Na+ in ion-coupled drug efflux

“…In our previous study we also presented bioinformatic evidence that this site is broadly conserved among prokaryotic MATEs and highlighted ClbM ( 33 ). A recent simulation study of ClbM has followed that prediction too ( 44 ).…”

A Novel MFS-MDR Transporter, MdrP, Employs D223 as a Key Determinant in the Na+ Translocation Coupled to Norfloxacin Efflux

“…A H + -coupled MATE transporter from Pyrococcus furiosus (PfMATE) has been shown to adopt two distinct conformations, a bent conformation and a straight conformation, in terms of the structure of TMH1 (Tanaka et al, 2013). A H + -and Na +coupled MATE transporter, E. coli ClbM, was also proposed using its X-ray structure via molecular dynamics simulations to share two similar conformations to those of PfMATE (Mousa et al, 2016;Mousa et al, 2017;Krah et al, 2020). This structural shift is proposed to satisfy the requirement for protonation of a conserved aspartate residue in TMH1 between H + -coupled MATE transporters (Lu et al, 2013a;Tanaka et al, 2013).…”

“…MATE transporters have been increasingly suggested or established to be able to achieve the extrusion of multiple antimicrobial drugs driven by either sodium motive force or/and proton motive force, such as Bacillus halodurans DinF (Lu et al, 2013a), NorM from Vibrio parahaemolyticus (Morita et al, 2000), Neissaeria gonorrhoeae (Lu et al, 2013b), and V. cholerae (Jin et al, 2014). The H + or/and Na + coupling mechanisms of the drug extrusion have been proposed in several MATE transporters (He et al, 2010;Lu et al, 2013a,b;Tanaka et al, 2013;Mousa et al, 2016;Nishima et al, 2016;Krah and Zachariae, 2017;Mousa et al, 2017;Krah et al, 2020).…”

The Molecular Basis for Purine Binding Selectivity in the Bacterial ATP Synthase ϵ Subunit

“…In contrast, molecular dynamics (MD) simulations provide a means to realistically describe biomolecular motion, and yield insights into the dynamics of proteins, the effects of mutations, and their interactions as a part of complexes. Example applications include investigations of ion binding, [47][48][49] energetic characterization of protonation states, [48] or the characterization of ligand binding to proteins (including, e. g., proteinÀ ion, [47,49] proteinÀ lipid, [50,51] or proteinÀ inhibitor interactions [52] ).…”