Structural basis for xenobiotic extrusion by eukaryotic MATE transporter

Hirotake Miyauchi, Satomi Moriyama, Tsukasa Kusakizako, Kaoru Kumazaki, Takanori Nakane, Keitaro Yamashita, Kunio Hirata, Naoshi Dohmae, Tomohiro Nishizawa, Koichi Ito, Takaaki Miyaji, Yoshinori Moriyama, Ryuichiro Ishitani () and Osamu Nureki ()
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Hirotake Miyauchi: Graduate School of Science, The University of Tokyo
Satomi Moriyama: Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Tsukasa Kusakizako: Graduate School of Science, The University of Tokyo
Kaoru Kumazaki: Graduate School of Science, The University of Tokyo
Takanori Nakane: Graduate School of Science, The University of Tokyo
Keitaro Yamashita: RIKEN SPring-8 Center, Sayo-gun
Kunio Hirata: RIKEN SPring-8 Center, Sayo-gun
Naoshi Dohmae: RIKEN Center for Sustainable Resource Science, Wako
Tomohiro Nishizawa: Graduate School of Science, The University of Tokyo
Koichi Ito: Graduate School of Frontier Sciences, The University of Tokyo
Takaaki Miyaji: Okayama University
Yoshinori Moriyama: Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Ryuichiro Ishitani: Graduate School of Science, The University of Tokyo
Osamu Nureki: Graduate School of Science, The University of Tokyo

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Mulitidrug and toxic compound extrusion (MATE) family transporters export xenobiotics to maintain cellular homeostasis. The human MATE transporters mediate the excretion of xenobiotics and cationic clinical drugs, whereas some plant MATE transporters are responsible for aluminum tolerance and secondary metabolite transport. Here we report the crystal structure of the eukaryotic MATE transporter from Arabidopsis thaliana, at 2.6 Å resolution. The structure reveals that its carboxy-terminal lobe (C-lobe) contains an extensive hydrogen-bonding network with well-conserved acidic residues, and their importance is demonstrated by the structure-based mutational analysis. The structural and functional analyses suggest that the transport mechanism involves the structural change of transmembrane helix 7, induced by the formation of a hydrogen-bonding network upon the protonation of the conserved acidic residue in the C-lobe. Our findings provide insights into the transport mechanism of eukaryotic MATE transporters, which is important for the improvement of the pharmacokinetics of the clinical drugs.

Date: 2017
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DOI: 10.1038/s41467-017-01541-0

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