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Structural biology of membrane transporters involved in the efflux mechanism of organic molecules

Research Project

Project/Area Number 17H03640
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Structural biochemistry
Research InstitutionThe University of Tokyo

Principal Investigator

Ishitani Ryuichiro  東京大学, 大学院理学系研究科(理学部), 特任教授 (90361568)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
KeywordsX線結晶構造解析 / 膜タンパク質 / 多剤耐性菌 / 薬物動態 / 結晶構造解析 / 膜蛋白質 / 輸送体 / 多剤耐性因子
Outline of Final Research Achievements

Living organisms are constantly exposed to toxic organic molecules, and cells have a mechanism to excrete them as a defensive measure. The molecular entity of this efflux mechanism is the membrane protein, the "efflux transporter". In this study, we analyzed the structure of MATE, a multidrug efflux transporter, focusing on the efflux mechanism of organic molecules. For eukaryotic MATE, we determined the structure of the outward opening state of the MATE transporter AtDTX14, from Arabidopsis, and verified the transport mechanism by structure-based mutational analysis. We also analyzed the structure of VcmN, a MATE from a pathogenic bacterium. The results of this structural analysis suggested that VcmN extrudes the substrate by H+-motive force-dependent TM1 bending.

Academic Significance and Societal Importance of the Research Achievements

生体は常に有毒な有機分子にさらされているが、細胞は防御策としてこれらを排出する機構を有している。これらの排出にかかわるMATE輸送体は細胞内外の物質の分布を制御する役割を担うため、その輸送機構を解明することは生命現象を理解するうえで必須であり、さらに医薬への応用などにおいても重要である。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (26 results)

All 2020 2019 2018 2017 2016 Other

All Int'l Joint Research (1 results) Journal Article (25 results) (of which Int'l Joint Research: 13 results,  Peer Reviewed: 25 results,  Open Access: 25 results,  Acknowledgement Compliant: 1 results)

  • [Int'l Joint Research] Vanderbilt University Medical Center/Nashville, TN 37232(米国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Crystal structure of Drosophila Piwi.2020

    • Author(s)
      Yamaguchi, S., Oe, A., Nishida, KM., Yamashita, K., Kajiya, A., Hirano, S., Matsumoto, N., Dohmae, N., Ishitani, R., Saito, K., Siomi, H., Nishimasu, H., Siomi, MC., and Nureki, O.
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 858-858

    • DOI

      10.1038/s41467-020-14687-1

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of Potent in Vivo Autotaxin Inhibitors that Bind to Both Hydrophobic Pockets and Channels in the Catalytic Domain2020

    • Author(s)
      Kawaguchi Mitsuyasu、Okabe Takayoshi、Okudaira Shinichi、Hama Kotaro、Kano Kuniyuki、Nishimasu Hiroshi、Nakagawa Hidehiko、Ishitani Ryuichiro、Kojima Hirotatsu、Nureki Osamu、Aoki Junken、Nagano Tetsuo
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 63 Issue: 6 Pages: 3188

    • DOI

      10.1021/acs.jmedchem.9b01967

    • URL

      https://pure.teikyo.jp/en/publications/c7eed15f-6a80-4a45-a51b-7d35115d5015

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cryo-EM structure of the volume-regulated anion channel LRRC8D isoform identifies features important for substrate permeation2020

    • Author(s)
      Nakamura Ryoki、Numata Tomohiro、Kasuya Go、Yokoyama Takeshi、Nishizawa Tomohiro、Kusakizako Tsukasa、Kato Takafumi、Hagino Tatsuya、Dohmae Naoshi、Inoue Masato、Watanabe Kengo、Ichijo Hidenori、Kikkawa Masahide、Shirouzu Mikako、Jentsch Thomas J.、Ishitani Ryuichiro、Okada Yasunobu、Nureki Osamu
    • Journal Title

      Communications Biology

      Volume: 3 Issue: 1 Pages: 240-240

    • DOI

      10.1038/s42003-020-0951-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc2019

    • Author(s)
      Lee Yongchan、Wiriyasermkul Pattama、Jin Chunhuan、Quan Lili、Ohgaki Ryuichi、Okuda Suguru、Kusakizako Tsukasa、Nishizawa Tomohiro、Oda Kazumasa、Ishitani Ryuichiro、Yokoyama Takeshi、Nakane Takanori、Shirouzu Mikako、Endou Hitoshi、Nagamori Shushi、Kanai Yoshikatsu、Nureki Osamu
    • Journal Title

      Nature Structural & Molecular Biology

      Volume: 26 Issue: 6 Pages: 510-517

    • DOI

      10.1038/s41594-019-0237-7

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structural biology of the multidrug and toxic compound extrusion superfamily transporters2019

    • Author(s)
      Kusakizako Tsukasa、Miyauchi Hirotake、Ishitani Ryuichiro、Nureki Osamu
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Biomembranes

      Volume: 1 Issue: 12 Pages: 183154-183154

    • DOI

      10.1016/j.bbamem.2019.183154

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural Basis of H+-Dependent Conformational Change in a Bacterial MATE Transporter2019

    • Author(s)
      Kusakizako Tsukasa、Claxton Derek P.、Tanaka Yoshiki、Maturana Andrs D.、Kuroda Teruo、Ishitani Ryuichiro、Mchaourab Hassane S.、Nureki Osamu
    • Journal Title

      Structure

      Volume: 27 Issue: 2 Pages: 293-301

    • DOI

      10.1016/j.str.2018.10.004

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Crystal structure of the Agrobacterium tumefaciens type VI effector-immunity complex.2018

    • Author(s)
      Fukuhara S, Nakane T, Yamashita K, Ishii R, Ishitani R, Nureki O
    • Journal Title

      Acta Crystallogr. F Struct. Biol. Commun.

      Volume: 74 Issue: 3 Pages: 810-816

    • DOI

      10.1038/s41477-019-0367-2

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cap-specific terminal N6-methylation of RNA by an RNA polymerase II?associated methyltransferase2018

    • Author(s)
      Akichika Shinichiro、Hirano Seiichi、Shichino Yuichi、Suzuki Takeo、Nishimasu Hiroshi、Ishitani Ryuichiro、Sugita Ai、Hirose Yutaka、Iwasaki Shintaro、Nureki Osamu、Suzuki Tsutomu
    • Journal Title

      Science

      Volume: 363 Issue: 363 Pages: 1-7

    • DOI

      10.1126/science.aav0080

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural insights into cGAMP degradation by Ecto-nucleotide pyrophosphatase phosphodiesterase 12018

    • Author(s)
      Kato Kazuki、Nishimasu Hiroshi、Oikawa Daisuke、Hirano Seiichi、Hirano Hisato、Kasuya Go、Ishitani Ryuichiro、Tokunaga Fuminori、Nureki Osamu
    • Journal Title

      Nature Communications

      Volume: 9 Issue: 1 Pages: 4424-4424

    • DOI

      10.1038/s41467-018-06922-7

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Vibrational and Molecular Properties of Mg2+ Binding and Ion Selectivity in the Magnesium Channel MgtE2018

    • Author(s)
      Kimura Tetsunari、Lorenz-Fonfria Victor A.、Douki Shintaro、Motoki Hideyoshi、Ishitani Ryuichiro、Nureki Osamu、Higashi Masahiro、Furutani Yuji
    • Journal Title

      The Journal of Physical Chemistry B

      Volume: 122 Issue: 42 Pages: 9681-9696

    • DOI

      10.1021/acs.jpcb.8b07967

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] An Atomistic Model of a Precursor State of Light-Induced Channel Opening of Channelrhodopsin2018

    • Author(s)
      Cheng Cheng, Motoshi Kamiya, Mizuki Takemoto, Ryuichiro Ishitani, Osamu Nureki, *Norio Yoshida, and *Shigehiko Hayashi
    • Journal Title

      Biophysical Journal

      Volume: 115 Issue: 7 Pages: 1281-1291

    • DOI

      10.1016/j.bpj.2018.08.024

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Free Energy Landscape for the Entire Transport Cycle of Triose-Phosphate/Phosphate Translocator2018

    • Author(s)
      Takemoto M, Lee Y, Ishitani R, Nureki O
    • Journal Title

      Structure

      Volume: 26 Issue: 9 Pages: 1284-1296

    • DOI

      10.1016/j.str.2018.05.012

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Engineered CRISPR-Cas9 nuclease with expanded targeting space2018

    • Author(s)
      Nishimasu Hiroshi、Shi Xi、Ishiguro Soh、Gao Linyi、Hirano Seiichi、Okazaki Sae、Noda Taichi、Abudayyeh Omar O.、Gootenberg Jonathan S.、Mori Hideto、Oura Seiya、Holmes Benjamin、Tanaka Mamoru、Seki Motoaki、Hirano Hisato、Aburatani Hiroyuki、Ishitani Ryuichiro、Ikawa Masahito、Yachie Nozomu、Zhang Feng、Nureki Osamu
    • Journal Title

      Science

      Volume: 361 Issue: 6408 Pages: 1259-1262

    • DOI

      10.1126/science.aas9129

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cryo-EM structures of the human volume-regulated anion channel LRRC82018

    • Author(s)
      Kasuya G, Nakane T, Yokoyama T, Jia Y, Inoue M, Watanabe K, Nakamura R, Nishizawa T, Kusakizako T, Tsutsumi A, Yanagisawa H, Dohmae N, Hattori M, Ichijo H, Yan Z, Kikkawa M, Shirouzu M, Ishitani R, Nureki O
    • Journal Title

      Nat Struct Mol Biol.

      Volume: 25 Issue: 9 Pages: 797-804

    • DOI

      10.1038/s41594-018-0109-6

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Functional roles of Mg2+ binding sites in ion-dependent gating of a Mg2+ channel, MgtE, revealed by solution NMR2018

    • Author(s)
      Maruyama Tatsuro、Imai Shunsuke、Kusakizako Tsukasa、Hattori Motoyuki、Ishitani Ryuichiro、Nureki Osamu、Ito Koichi、Maturana Andr?s D、Shimada Ichio、Osawa Masanori
    • Journal Title

      eLife

      Volume: 7

    • DOI

      10.7554/elife.31596

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structural basis for xenobiotics extrusion by eukaryotic MATE transporter.2017

    • Author(s)
      Miyauchi H., Moriyama S., Kusakizako T., Kumazaki K., Ito K., Dohmae N., Nishizawa T., Miyaji T., Moriyama Y., Ishitani R., Nureki O.
    • Journal Title

      Nature Commun.

      Volume: 8 Issue: 1 Pages: 1633-1633

    • DOI

      10.1038/s41467-017-01541-0

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel2017

    • Author(s)
      Kasuya G, Yamaura T, Ma XB, Nakamura R, Takemoto M, Nagumo H, Tanaka E, Dohmae N, Nakane T, Yu Y, Ishitani R, Matsuzaki O, Hattori M, Nureki O
    • Journal Title

      Nat Commun.

      Volume: 8 Issue: 1 Pages: 876-876

    • DOI

      10.1038/s41467-017-00887-9

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structure of the triose-phosphate/phosphate translocator reveals the basis of substrate specificity.2017

    • Author(s)
      Lee Y, Nishizawa T, Takemoto M, Kumazaki K, Yamashita K, Hirata K, Minoda A, Nagatoishi S, Tsumoto K, Ishitani R and Nureki O.
    • Journal Title

      Nature Plants.

      Volume: 3 Issue: 10 Pages: 825-832

    • DOI

      10.1038/s41477-017-0022-8

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA62017

    • Author(s)
      Taniguchi Reiya、Inoue Asuka、Sayama Misa、Uwamizu Akiharu、Yamashita Keitaro、Hirata Kunio、Yoshida Masahito、Tanaka Yoshiki、Kato Hideaki E.、Nakada-Nakura Yoshiko、Otani Yuko、Nishizawa Tomohiro、Doi Takayuki、Ohwada Tomohiko、Ishitani Ryuichiro、Aoki Junken、Nureki Osamu
    • Journal Title

      Nature

      Volume: 548 Issue: 7667 Pages: 356-360

    • DOI

      10.1038/nature23448

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural Basis for the Canonical and Non-canonical PAM Recognition by CRISPR-Cpf12017

    • Author(s)
      Yamano Takashi、Zetsche Bernd、Ishitani Ryuichiro、Zhang Feng、Nishimasu Hiroshi、Nureki Osamu
    • Journal Title

      Molecular Cell

      Volume: 67 Issue: 4 Pages: 633-645

    • DOI

      10.1016/j.molcel.2017.06.035

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ATP-dependent modulation of MgtE in Mg2+ homeostasis2017

    • Author(s)
      Tomita Atsuhiro、Zhang Mingfeng、Jin Fei、Zhuang Wenhui、Takeda Hironori、Maruyama Tatsuro、Osawa Masanori、Hashimoto Ken-ichi、Kawasaki Hisashi、Ito Koichi、Dohmae Naoshi、Ishitani Ryuichiro、Shimada Ichio、Yan Zhiqiang、Hattori Motoyuki、Nureki Osamu
    • Journal Title

      Nature Communications

      Volume: 8 Issue: 1 Pages: 148-148

    • DOI

      10.1038/s41467-017-00082-w

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structural Basis for the Altered PAM Recognition by Engineered CRISPR-Cpf12017

    • Author(s)
      Nishimasu Hiroshi、Yamano Takashi、Gao Linyi、Zhang Feng、Ishitani Ryuichiro、Nureki Osamu
    • Journal Title

      Molecular Cell

      Volume: 67 Issue: 1 Pages: 139-147

    • DOI

      10.1016/j.molcel.2017.04.019

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cyclic GMP-AMP as an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA2017

    • Author(s)
      Kato K, Omura H, Ishitani R, Nureki O
    • Journal Title

      Annu Rev Biochem

      Volume: 86 Issue: 1 Pages: 541-566

    • DOI

      10.1146/annurev-biochem-061516-044813

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural insights into the nucleotide base specificity of P2X receptors.2017

    • Author(s)
      Kasuya G, Fujiwara Y, Tsukamoto H, Morinaga S, Ryu S, Touhara K, Ishitani R, Furutani Y, Hattori M, Nureki O.
    • Journal Title

      Sci Rep.

      Volume: 7 Issue: 1 Pages: 45208-45208

    • DOI

      10.1038/srep45208

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Crystal Structure of the Minimal Cas9 from Campylobacter jejuni Reveals the Molecular Diversity in the CRISPR-Cas9 Systems2016

    • Author(s)
      Yamada M, Watanabe Y, Gootenberg JS, Hirano H, Ran FA, Nakane T, Ishitani R, Zhang F, Nishimasu H, Nureki O
    • Journal Title

      Mol Cell

      Volume: 65 Issue: 6 Pages: 1109-1121

    • DOI

      10.1016/j.molcel.2017.02.007

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant

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Published: 2017-04-28   Modified: 2021-02-19  

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