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Publication Abstract from PubMed

MdfA is a prototypical H(+)-coupled multidrug transporter that is characterized by extraordinarily broad substrate specificity. The involvement of specific H-bonds in MdfA-drug interactions and the simplicity of altering the substrate specificity of MdfA contradict the promiscuous nature of multidrug recognition, presenting a baffling conundrum. Here we show the X-ray structures of MdfA variant I239T/G354E in complexes with three electrically different ligands, determined at resolutions up to 2.2 A. Our structures reveal that I239T/G354E interacts with these compounds differently from MdfA and that I239T/G354E possesses two discrete, non-overlapping substrate-binding sites. Our results shed new light on the molecular design of multidrug-binding and protonation sites and highlight the importance of often-neglected, long-range charge-charge interactions in multidrug recognition. Beyond helping to solve the ostensible conundrum of multidrug recognition, our findings suggest the mechanistic difference between substrate and inhibitor for any H(+)-dependent multidrug transporter, which may open new vistas on curtailing efflux-mediated multidrug resistance.

Structure of an engineered multidrug transporter MdfA reveals the molecular basis for substrate recognition.,Wu HH, Symersky J, Lu M Commun Biol. 2019 Jun 17;2:210. doi: 10.1038/s42003-019-0446-y. eCollection 2019. PMID:31240248^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.