Journal
CELL RESEARCH
Volume 25, Issue 9, Pages 1060-1073Publisher
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2015.94
Keywords
multidrug resistance; MFS transporter; antiporters
Categories
Funding
- National Basic Research Program of China (973 Program) [2011CB910301, 2014CB910104, 2014CB910400]
- Chinese Academy of Sciences [XDB08020301]
- National Natural Science Foundation of China [31470745, 31200560]
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Multidrug resistance is a serious threat to public health. Proton motive force-driven antiporters from the major facilitator superfamily (MFS) constitute a major group of multidrug-resistance transporters. Currently, no reports on crystal structures of MFS antiporters in complex with their substrates exist. The E. coli MdfA transporter is a well-studied model system for biochemical analyses of multidrug-resistance MFS antiporters. Here, we report three crystal structures of MdfA-ligand complexes at resolutions up to 2.0 angstrom, all in the inward-facing conformation. The substrate-binding site sits proximal to the conserved acidic residue, D34. Our mutagenesis studies support the structural observations of the substrate-binding mode and the notion that D34 responds to substrate binding by adjusting its protonation status. Taken together, our data unveil the substrate-binding mode of MFS antiporters and suggest a mechanism of transport via this group of transporters.
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