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PDBsum entry 4hul
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Transport protein
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PDB id
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4hul
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References listed in PDB file
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Key reference
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Title
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Structures of a na+-Coupled, Substrate-Bound mate multidrug transporter.
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Authors
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M.Lu,
J.Symersky,
M.Radchenko,
A.Koide,
Y.Guo,
R.Nie,
S.Koide.
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Ref.
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Proc Natl Acad Sci U S A, 2013,
110,
2099-2104.
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PubMed id
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Abstract
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Multidrug transporters belonging to the multidrug and toxic compound extrusion
(MATE) family expel dissimilar lipophilic and cationic drugs across cell
membranes by dissipating a preexisting Na(+) or H(+) gradient. Despite its
clinical relevance, the transport mechanism of MATE proteins remains poorly
understood, largely owing to a lack of structural information on the
substrate-bound transporter. Here we report crystal structures of a
Na(+)-coupled MATE transporter NorM from Neisseria gonorrheae in complexes with
three distinct translocation substrates (ethidium, rhodamine 6G, and
tetraphenylphosphonium), as well as Cs(+) (a Na(+) congener), all captured in
extracellular-facing and drug-bound states. The structures revealed a
multidrug-binding cavity festooned with four negatively charged amino acids and
surprisingly limited hydrophobic moieties, in stark contrast to the general
belief that aromatic amino acids play a prominent role in multidrug recognition.
Furthermore, we discovered an uncommon cation-π interaction in the
Na(+)-binding site located outside the drug-binding cavity and validated the
biological relevance of both the substrate- and cation-binding sites by
conducting drug resistance and transport assays. Additionally, we uncovered
potential rearrangement of at least two transmembrane helices upon Na(+)-induced
drug export. Based on our structural and functional analyses, we suggest that
Na(+) triggers multidrug extrusion by inducing protein conformational changes
rather than by directly competing for the substrate-binding amino acids. This
scenario is distinct from the canonical antiport mechanism, in which both
substrate and counterion compete for a shared binding site in the transporter.
Collectively, our findings provide an important step toward a detailed and
mechanistic understanding of multidrug transport.
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