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Crystallographic study of multidrug efflux proteins coupled with outer membrane channel TolC

Research Project

Project/Area Number 24370045
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Structural biochemistry
Research InstitutionOsaka University

Principal Investigator

NAKASHIMA RYOSUKE  大阪大学, 産業科学研究所, 准教授 (20379100)

Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2014: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2013: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2012: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Keywords異物排出トランスポーター / 立体構造 / 多剤耐性 / 蛋白質 / 細菌 / 抗生物質 / 感染症
Outline of Final Research Achievements

Xenobiotic extruding pumps have recently been known to be widely distributed in living organisms from mammalian to bacteria as a host-defense mechanism in cellular level. These pumps confer multidrug resistance for cancer cells and pathogenic bacteria. We had reported the first inhibitor-bound structures of MexB which couples with TolC type outer membrane channel. Additionally, we succeeded in solving the crystal structure of new substrate binding MexB. These are result to lead to transporter-oriented structure based drug development.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (43 results)

All 2015 2014 2013 2012 Other

All Journal Article (6 results) (of which Peer Reviewed: 3 results,  Open Access: 1 results) Presentation (31 results) (of which Invited: 1 results) Book (1 results) Remarks (5 results)

  • [Journal Article] Structural basis of RND-type multidrug exporters2015

    • Author(s)
      Akihito Yamaguchi, Ryosuke Nakashima, Keisuke Sakurai
    • Journal Title

      Frontiers in Microbiology

      Volume: 6

    • DOI

      10.3389/fmicb.2015.00327

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 多剤耐性菌感染症の原因となる多剤排出タンパク質の阻害剤結合構造を決定2013

    • Author(s)
      山口明人、中島良介、櫻井啓介
    • Journal Title

      実験医学

      Volume: 31 Pages: 2272-2276

    • Related Report
      2013 Annual Research Report
  • [Journal Article] Structural basis for the inhibition of bacterial multidrug exporters2013

    • Author(s)
      Ryosuke Nakashima, Keisuke Sakurai, Seiii Yamasaki, Katsuhiko Hayashi, Chikahiro Nagata, Kazuki Hoshino, Yoshikuni Onodera, Kunihiko Nishino and Akihito Yamaguchi
    • Journal Title

      Nature

      Volume: 500 Issue: 7460 Pages: 102-106

    • DOI

      10.1038/nature12300

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The crystal structure of multidrug-resistance regulator RamR with multiple drugs2013

    • Author(s)
      Yamasaki S, Nikaido E, Nakashima R, Sakurai K, Fujiwara D, Fujii I, Nishino K
    • Journal Title

      Nature Comunications

      Volume: 4 Issue: 1 Pages: 1-7

    • DOI

      10.1038/ncomms3078

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 異物排出トランスポーターによる多剤認識機構2012

    • Author(s)
      中島良介、山口明人
    • Journal Title

      細胞工学

      Volume: 31 Pages: 529-534

    • Related Report
      2012 Annual Research Report
  • [Journal Article] 多剤耐性菌の薬剤排出機構を解明/阻害薬開発に期待2012

    • Author(s)
      山口明人、中島良介
    • Journal Title

      Medical Tribune

      Volume: 45 Pages: 50-50

    • Related Report
      2012 Annual Research Report
  • [Presentation] 異物排出の構造的基盤2014

    • Author(s)
      山口明人, 中島良介, 櫻井啓介
    • Organizer
      生体エネルギー研究会 第40回討論会
    • Place of Presentation
      愛媛
    • Year and Date
      2014-12-11 – 2014-12-13
    • Related Report
      2014 Annual Research Report
  • [Presentation] 多剤排出システム AcrAB-TolC 複合体には何分子の AcrA が必要か?2014

    • Author(s)
      林克彦, 中島良介, 山﨑聖司, 櫻井啓介, 西野邦彦, 山口明人
    • Organizer
      第36回 生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      徳島
    • Year and Date
      2014-11-20
    • Related Report
      2014 Annual Research Report
  • [Presentation] グラム陰性菌多剤排出トランスポーターの阻害剤結合構造2014

    • Author(s)
      林克彦, 中島良介, 櫻井啓介, 山﨑聖司, 西野邦彦, 山口明人
    • Organizer
      第12回次世代を担う若手のためのフィジカル・ファーマフォーラム
    • Place of Presentation
      神奈川
    • Year and Date
      2014-07-14 – 2014-07-15
    • Related Report
      2014 Annual Research Report
  • [Presentation] 大腸菌多剤排出トランスポーターAcrABの機能複合体の構成比2014

    • Author(s)
      林 克彦、中島 良介、山崎 聖司、櫻井 啓介、北川 公惠、西野 邦彦、山口 明人
    • Organizer
      第14回 蛋白質科学会年会
    • Place of Presentation
      大阪
    • Year and Date
      2014-06-25 – 2014-06-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] RND型異物排出タンパクのユニバーサル阻害剤開発2014

    • Author(s)
      櫻井啓介, 中島良介, 山崎聖司, 林克彦, 西野邦彦, 山口明人
    • Organizer
      第9回トランスポーター研究会
    • Place of Presentation
      愛知
    • Year and Date
      2014-06-14 – 2014-06-15
    • Related Report
      2014 Annual Research Report
  • [Presentation] 多剤排出トランスポーターの阻害剤結合様式と阻害メカニズムの解明2014

    • Author(s)
      山﨑聖司、中島良介、櫻井啓介、林克彦、長田親弘、星野一樹、小野寺宜郷、西野邦彦、山口明人
    • Organizer
      第87回日本細菌学会総会
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] Structural Basis of Bacterial Major Multidrug Efflux Transporter Inhibition2014

    • Author(s)
      Hayashi K, Nakashima R, Sakurai K, Yamasaki S, Nishino K, Yamaguchi A
    • Organizer
      The 17th SANKEN International Symposium / The 2nd International Symposium of Nano-Macro Materials, Devices, and System Research Alliance Project
    • Place of Presentation
      大阪
    • Related Report
      2013 Annual Research Report
  • [Presentation] Structures of the Multidrug Exporter AcrB Reveal a Proximal Multisite Drug-binding Pocket2014

    • Author(s)
      Yamasaki, S., Nishino K, Nakashima R, Sakurai K, Yamaguchi A
    • Organizer
      The 17th SANKEN International Symposium / The 2nd International Symposium of Nano-Macro Materials, Devices, and System Research Alliance Project
    • Place of Presentation
      大阪
    • Related Report
      2013 Annual Research Report
  • [Presentation] サルモネラの薬剤排出ポンプAcrABの転写調節因子RamRのX線結晶構造解析及び機能解析2013

    • Author(s)
      山崎優、二階堂英司、中島良介、櫻井啓介、山口明人、西野邦彦
    • Organizer
      第85回 日本生化学大会
    • Place of Presentation
      福岡
    • Year and Date
      2013-12-15
    • Related Report
      2012 Annual Research Report
  • [Presentation] 異物排出輸送の構造的基盤2013

    • Author(s)
      山口明人、中島良介
    • Organizer
      第85回 日本生化学大会
    • Place of Presentation
      福岡
    • Year and Date
      2013-12-15
    • Related Report
      2012 Annual Research Report
  • [Presentation] RND型多剤排出ポンプ阻害剤開発の基本概念2013

    • Author(s)
      林克彦、中島良介、櫻井啓介、山崎聖司、長田親弘、小野寺宜郷、西野邦彦、山口明人
    • Organizer
      日本薬学会第133年会
    • Place of Presentation
      横浜
    • Year and Date
      2013-03-28
    • Related Report
      2012 Annual Research Report
  • [Presentation] 細菌多剤耐性化に関与する転写制御因子RamRと多剤との共結晶構造解析2013

    • Author(s)
      山崎優、二階堂英司、中島良介、櫻井啓介、西野邦彦
    • Organizer
      日本薬学会第133年会
    • Place of Presentation
      横浜
    • Year and Date
      2013-03-28
    • Related Report
      2012 Annual Research Report
  • [Presentation] The crystal structures of Bacterial multidrug efflux pumps with a specific inhibitor in the common inhibitory narrow pit2013

    • Author(s)
      K. Hayashi, R. Nakashima, K. Sakurai, S. Yamasaki, C. Nagata, K. Hoshino, Y. Onodera, K. Nishino and A. Yamaguchi
    • Organizer
      Gordon Research Conference, "Multi-Drug Emux Systems"
    • Place of Presentation
      CA, U.S.A.
    • Year and Date
      2013-03-20
    • Related Report
      2012 Annual Research Report
  • [Presentation] The crystal structures of Bacterial multidrug efflux pumps with a specific inhibitor in the common inhibitory narrow pit.2013

    • Author(s)
      K. Hayashi, R. Nakashima, K. Sakurai, S. Yamasaki, C. Nagata, K. Hoshino, Y. Onodera, K. Nishino, A. Yamaguchi
    • Organizer
      The 16th SANKEN International Symposium 2013/The 11th SANKEN Nanotechnology Symposium2013
    • Place of Presentation
      大阪
    • Year and Date
      2013-01-22
    • Related Report
      2012 Annual Research Report
  • [Presentation] Structures of AcrB Multidrug Emux Pump Reveal the Peristaltic Drug Export Mechanism2013

    • Author(s)
      S. Yamasaki, K. Nishino, R. Nakashima, K, Sakurai, A. Yamaguchi
    • Organizer
      The 16th SANKEN International Symposium 2013/The 11th SANKEN Nanotechnology Symposium2013
    • Place of Presentation
      大阪
    • Year and Date
      2013-01-22
    • Related Report
      2012 Annual Research Report
  • [Presentation] The crystal structure of multidrug resistance regulator RamR reveal the mechanism of multiple drugs recognition2013

    • Author(s)
      S. Yamasaki, E. Nikaido, R. Nakashima, K. Sakurai, A. Yamaguchi, K. Nishino
    • Organizer
      The 16th SANKEN International Symposium 2013/The 11th SANKEN Nanotechnology Symposium2013
    • Place of Presentation
      大阪
    • Year and Date
      2013-01-22
    • Related Report
      2012 Annual Research Report
  • [Presentation] 多剤排出タンパクの阻害剤結合構造2013

    • Author(s)
      中島良介、櫻井啓介、山崎聖司、林克彦、西野邦彦、山口明人
    • Organizer
      第35回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] 細菌の異物認識機構と排出制御2013

    • Author(s)
      山崎優、二階堂英司、中島良介、櫻井啓介、藤原大佑、藤井郁雄、西野邦彦
    • Organizer
      第35回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] 異物排出トランスポーターの阻害剤結合様式と阻害メカニズムの解明2013

    • Author(s)
      山﨑聖司、中島良介、櫻井啓介、林克彦、長田親弘、星野一樹、小野寺宜郷、西野邦彦、山口明人
    • Organizer
      第66回日本細菌学会関西支部総会
    • Place of Presentation
      大阪
    • Related Report
      2013 Annual Research Report
  • [Presentation] RND 型薬剤排出トランスポーターの阻害活性の構造的基礎2013

    • Author(s)
      櫻井啓介、中島良介、山崎聖司、林克彦、西野邦彦、山口明人
    • Organizer
      第51回日本生物物理学会年会
    • Place of Presentation
      京都
    • Related Report
      2013 Annual Research Report
  • [Presentation] 大腸菌多剤排出トランスポーター複合体AcrAB の結合比決定2013

    • Author(s)
      林克彦、中島良介、櫻井啓介、山崎聖司、西野邦彦、山口明人
    • Organizer
      第51回日本生物物理学会年会
    • Place of Presentation
      京都
    • Related Report
      2013 Annual Research Report
  • [Presentation] Crystal structures of the inhibitor-bound multi-drug efflux transporters, AcrB and MexB2013

    • Author(s)
      Hayashi K, Nakashima R, Sakurai K, Yamasaki S, Nishino K, Yamaguchi A
    • Organizer
      第86回 日本生化学会大会
    • Place of Presentation
      神奈川
    • Related Report
      2013 Annual Research Report
  • [Presentation] Inhibitor-bound structures of bacterial major multidrug efflux transporters, AcrB and MexB2013

    • Author(s)
      Hayashi K, Nakashima R, Sakurai K, Yamasaki S, Nishino K, Yamaguchi A
    • Organizer
      5th Symposium on Antimicrobial Resistance in Animals and the Environment
    • Place of Presentation
      Belgium
    • Related Report
      2013 Annual Research Report
  • [Presentation] Peristaltic drug export mechanism of the multidrug exporter AcrB2013

    • Author(s)
      Yamasaki S, Nishino K, Nakashima R, Sakurai K, Yamaguchi A
    • Organizer
      5th Symposium on Antimicrobial Resistance in Animals and the Environment
    • Place of Presentation
      Belgium
    • Related Report
      2013 Annual Research Report
  • [Presentation] 多剤排出タンパクAcrB, MexBの阻害剤結合構造2013

    • Author(s)
      中島良介、櫻井啓介、山崎聖司、林克彦、西野邦彦、山口明人
    • Organizer
      第8回トランスポーター研究会
    • Place of Presentation
      熊本
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 多剤耐性制御因子RamRによる抗菌薬認識機構の解明2012

    • Author(s)
      山崎優、二階堂英司、城阪郁江、櫻井啓介、中島良介、山口明人、西野邦彦
    • Organizer
      大阪大学 産業科学研究所 第68回学術講演会
    • Place of Presentation
      大阪
    • Year and Date
      2012-11-22
    • Related Report
      2012 Annual Research Report
  • [Presentation] サルモネラ薬剤排出ポンプAcrABの制御機構の解析2012

    • Author(s)
      山崎優、二階堂英司、櫻井啓介、中島良介、山口明人、西野邦彦
    • Organizer
      第62回 日本薬学会近畿支部総会・大会
    • Place of Presentation
      兵庫
    • Year and Date
      2012-10-20
    • Related Report
      2012 Annual Research Report
  • [Presentation] サルモネラの薬剤排出ポンプAcrABの転写制御因子RamRと基質の相互作用及びX線結晶構造解析2012

    • Author(s)
      山崎優、二階堂英司、城坂郁江、中島良介、櫻井啓介、山口明人、西野邦彦
    • Organizer
      第10回 次世代を担う若手のためのフィジカル・ファーマフォーラム
    • Place of Presentation
      京都
    • Year and Date
      2012-08-07
    • Related Report
      2012 Annual Research Report
  • [Presentation] サルモネラの薬剤排出ポンプAcrABの制御因子RamRと基質の相互作用及びX線結晶構造2012

    • Author(s)
      山崎優、櫻井啓介、中島良介、山口明人、西野邦彦
    • Organizer
      BIA Symposium 2012
    • Place of Presentation
      東京
    • Year and Date
      2012-07-20
    • Related Report
      2012 Annual Research Report
  • [Presentation] 多剤排出トランスポーターの基質認識と排出機構2012

    • Author(s)
      中島良介、櫻井啓介、山崎聖司、西野邦彦、山口明人
    • Organizer
      第12回 日本蛋白質科学会年会
    • Place of Presentation
      名古屋(招待講演)
    • Year and Date
      2012-06-22
    • Related Report
      2012 Annual Research Report
  • [Presentation] Peristaltic Drug Export Mechanism of the AcrB Multidrug Emux Pump2012

    • Author(s)
      S. Yamasaki, K. Nishino, R.Nakashima, K. Sakurai and A. Yamaguchi
    • Organizer
      ASM American Society for Microbiology 112th General Meeting
    • Place of Presentation
      San Francisco, U. S. A.
    • Year and Date
      2012-06-18
    • Related Report
      2012 Annual Research Report
  • [Book] 実験医学増刊号 構造生命科学で何がわかるのか,何ができるのか2014

    • Author(s)
      中島良介、櫻井啓介、山口明人
    • Total Pages
      230
    • Publisher
      羊土社
    • Related Report
      2014 Annual Research Report
  • [Remarks] 研究室紹介ページ

    • URL

      http://www.sanken.osaka-u.ac.jp/labs/cmb/

    • Related Report
      2014 Annual Research Report
  • [Remarks] 多剤排出タンパク質の阻害剤結合構造決定に初めて成功

    • URL

      http://www.sanken.osaka-u.ac.jp/jp/operation/press_release.html

    • Related Report
      2013 Annual Research Report
  • [Remarks] 多剤排出タンパク質の発現にブレーキを掛ける機構を解明!

    • URL

      http://www.sanken.osaka-u.ac.jp/jp/operation/press_release.html

    • Related Report
      2013 Annual Research Report
  • [Remarks]

    • URL

      http://www.sanken.osaka-u.ac.jp/labs/cmb/

    • Related Report
      2012 Annual Research Report
  • [Remarks]

    • URL

      http://www.sanken.osaka-u.ac.jp/operation/report.html

    • Related Report
      2012 Annual Research Report

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Published: 2012-04-24   Modified: 2019-07-29  

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