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PDBsum entry 6oop
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Transport protein
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PDB id
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6oop
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References listed in PDB file
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Key reference
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Title
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Structure of an engineered multidrug transporter mdfa reveals the molecular basis for substrate recognition.
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Authors
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H.H.Wu,
J.Symersky,
M.Lu.
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Ref.
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Commun Biol, 2019,
2,
210.
[DOI no: ]
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PubMed id
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Abstract
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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 Å. 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.
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