Outward open conformation of a Major Facilitator Superfamily multidrug/H+ antiporter provides insights into switching mechanism

Kumar Nagarathinam, Yoshiko Nakada-Nakura, Christoph Parthier, Tohru Terada, Narinobu Juge, Frank Jaenecke, Kehong Liu, Yunhon Hotta, Takaaki Miyaji, Hiroshi Omote, So Iwata, Norimichi Nomura, Milton T. Stubbs () and Mikio Tanabe ()
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Kumar Nagarathinam: ZIK HALOmem
Yoshiko Nakada-Nakura: Kyoto University
Christoph Parthier: Martin-Luther Universität Halle-Wittenberg
Tohru Terada: The University of Tokyo
Narinobu Juge: Okayama University
Frank Jaenecke: ZIK HALOmem
Kehong Liu: Kyoto University
Yunhon Hotta: Kyoto University
Takaaki Miyaji: Okayama University
Hiroshi Omote: Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
So Iwata: Kyoto University
Norimichi Nomura: Kyoto University
Milton T. Stubbs: ZIK HALOmem
Mikio Tanabe: ZIK HALOmem

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract 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 coli 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.

Date: 2018
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DOI: 10.1038/s41467-018-06306-x

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