Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-06306-x
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Funding
- Bundesministerium fur Bildung und Forschung (BMBF) program ZIK HALOmem [FKZ 03Z2HN21]
- European Regional Development Fund ERDF [1241090001]
- Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics and Structural Life Science (PDIS) from the Japan Agency for Medical Research and Development (AMED) [JP18am0101107, JP18am0101079, JP18am0101071]
- Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from the Japan Agency for Medical Research and Development (AMED) [JP18am0101107, JP18am0101079, JP18am0101071]
- ERATO Human Receptor Crystallography Project of the Japan Science and Technology Agency (JST)
- Strategic Basic Research Program, JST
- Targeted Proteins Research Program of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan
- MEXT [22570114]
- European Community's 7th Framework Programme (FP7/2007-2013) under BioStruct-X [283570, BioStructx_5450]
- Grants-in-Aid for Scientific Research [22570114] Funding Source: KAKEN
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Multidrug resistance (MDR) poses a major challenge to medicine. A principle cause of MDR is through active efflux by MDR transporters situated in the bacterial membrane. Here we present the crystal structure of the major facilitator superfamily (MFS) drug/H+ antiporter MdfA from Escherichia coil in an outward open conformation. Comparison with the inward facing (drug binding) state shows that, in addition to the expected change in relative orientations of the N- and C-terminal lobes of the antiporter, the conformation of TM5 is kinked and twisted. In vitro reconstitution experiments demonstrate the importance of selected residues for transport and molecular dynamics simulations are used to gain insights into antiporter switching. With the availability of structures of alternative conformational states, we anticipate that MdfA will serve as a model system for understanding drug efflux in MFS MDR antiporters.
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