TY - JOUR
T1 - Structural basis for xenobiotic extrusion by eukaryotic MATE transporter
AU - Miyauchi, Hirotake
AU - Moriyama, Satomi
AU - Kusakizako, Tsukasa
AU - Kumazaki, Kaoru
AU - Nakane, Takanori
AU - Yamashita, Keitaro
AU - Hirata, Kunio
AU - Dohmae, Naoshi
AU - Nishizawa, Tomohiro
AU - Ito, Koichi
AU - Miyaji, Takaaki
AU - Moriyama, Yoshinori
AU - Ishitani, Ryuichiro
AU - Nureki, Osamu
N1 - Funding Information:
We thank H. Nishimasu (University of Tokyo, Japan) for useful discussions, the beamline staff at BL32XU of SPring-8 (Hyogo, Japan) for technical support with data collection, and A. Kurabayashi for technical assistance. The X-ray diffraction experiments were performed at SPring-8 BL32XU (proposal Nos. 2015A1024, 2015B2024, 2016A2527, and 2016B2527) with the approval of RIKEN. This work was supported by the Platform for Drug Discovery, Informatics, and Structural Life Science, funded by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and by a Grant-in-Aid for Specially Promoted Research (16H06294), and a Grant-in-Aid for Scientific Research (B) (25291011) from the Japan Society for the Promotion of Science (JSPS) to O.N. and R.I., respectively.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85034621660&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85034621660&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-01541-0
DO - 10.1038/s41467-017-01541-0
M3 - Article
C2 - 29158478
AN - SCOPUS:85034621660
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1633
ER -