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, Osamu Nureki

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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.

Original languageEnglish
Article number1633
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Miyauchi, H., Moriyama, S., Kusakizako, T., Kumazaki, K., Nakane, T., Yamashita, K., Hirata, K., Dohmae, N., Nishizawa, T., Ito, K., Miyaji, T., Moriyama, Y., Ishitani, R., & Nureki, O. (2017). Structural basis for xenobiotic extrusion by eukaryotic MATE transporter. Nature Communications, 8(1), [1633]. https://doi.org/10.1038/s41467-017-01541-0