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PDBsum entry 5c6p
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Transport protein
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PDB id
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5c6p
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References listed in PDB file
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Key reference
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Title
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Structural basis for the blockade of mate multidrug efflux pumps.
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Authors
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M.Radchenko,
J.Symersky,
R.Nie,
M.Lu.
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Ref.
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Nat Commun, 2015,
6,
7995.
[DOI no: ]
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PubMed id
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Abstract
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Multidrug and toxic compound extrusion (MATE) transporters underpin multidrug
resistance by using the H(+) or Na(+) electrochemical gradient to extrude
different drugs across cell membranes. MATE transporters can be further parsed
into the DinF, NorM and eukaryotic subfamilies based on their amino-acid
sequence similarity. Here we report the 3.0 Å resolution X-ray structures of
a protonation-mimetic mutant of an H(+)-coupled DinF transporter, as well as of
an H(+)-coupled DinF and a Na(+)-coupled NorM transporters in complexes with
verapamil, a small-molecule pharmaceutical that inhibits MATE-mediated multidrug
extrusion. Combining structure-inspired mutational and functional studies, we
confirm the biological relevance of our crystal structures, reveal the
mechanistic differences among MATE transporters, and suggest how verapamil
inhibits MATE-mediated multidrug efflux. Our findings offer insights into how
MATE transporters extrude chemically and structurally dissimilar drugs and could
inform the design of new strategies for tackling multidrug resistance.
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