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Asymmetric dynamics of hetero dimeric ABC transporters explored by molecular simulations

Research Project

Project/Area Number 15K00400
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Life / Health / Medical informatics
Research InstitutionTokyo Institute of Technology

Principal Investigator

Furuta Tadaomi  東京工業大学, 生命理工学院, 助教 (10431834)

Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsABCトランスポーター / ATP / 基質 / 輸送 / 変異 / 構造機能相関 / 疎水性クラスター / 分子シミュレーション / CFTR / ホモ・ヘテロ / 構造ダイナミクス
Outline of Final Research Achievements

ATP-binding cassette (ABC) transporters constitute a large superfamily of membrane proteins that transport various substrates through membranes utilizing the energy of ATP. In this study, we investigated asymmetric dynamics of ABC transporters TM287/288 and CFTR induced by the binding of ATP and substrate using molecular simulations. It was revealed that substrate binding induced allosteric interdomain communication in TM287 / 288 and that the most frequent mutation in CFTR caused the disruption of a hydrophobic cluster at the domain interface, leading to dysfunction. These findings would provide important insights into the structure-function relationship of ABC transporters.

Academic Significance and Societal Importance of the Research Achievements

ABCトランスポーターおよびその変異は、多剤耐性や様々な疾患に関連している。本研究で得られたABCトランスポーターの構造ダイナミクスに関する重要な知見は、今後の創薬において揺らぎといった観点からも大変有益であると思われる。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (33 results)

All 2019 2018 2017 2016 2015

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 3 results,  Acknowledgement Compliant: 2 results) Presentation (22 results) (of which Int'l Joint Research: 5 results,  Invited: 2 results) Book (1 results)

  • [Journal Article] Development of an ATP force field for coarse‐grained simulation of ATPases and its application to the maltose transporter2019

    • Author(s)
      Ryosuke Hirano, Tsubasa Yabuchi, Minoru Sakurai, Tadaomi Furuta
    • Journal Title

      J. Comput. Chem.

      Volume: - Issue: 24 Pages: 2096-2102

    • DOI

      10.1002/jcc.25861

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The mechanism of nucleotide‐binding domain dimerization in the intact maltose transporter as studied by all‐atom molecular dynamics simulations2018

    • Author(s)
      Wei‐Lin Hsu Tadaomi Furuta Minoru Sakurai
    • Journal Title

      Proteins

      Volume: 86 Issue: 2 Pages: 237-247

    • DOI

      10.1002/prot.25433

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Molecular dynamics simulation study on the structural instability of the most common cystic fibrosis-associated mutant ΔF508-CFTR2018

    • Author(s)
      Mitsuhiko Odera, Tadaomi Furuta, Yoshiro Sohma, Minoru Sakurai
    • Journal Title

      Biophysics and Physicobiology

      Volume: 15 Issue: 0 Pages: 33-44

    • DOI

      10.2142/biophysico.15.0_33

    • NAID

      130006337976

    • ISSN
      2189-4779
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Probing native metal ion association sites through quenching of fluorophores in the nucleotide-binding domains of the ABC transporter MsbA2017

    • Author(s)
      Daiki Tatsumi, Kei Nanatani, Yuto Koike, Kiyoto Kamagata, Satoshi Takahashi, Ayumu Konno, Tadaomi Furuta, Minoru Sakurai, Nobuyuki Uozumi
    • Journal Title

      Biochem. J.

      Volume: 474 Issue: 12 Pages: 1993-2007

    • DOI

      10.1042/bcj20161051

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Analysis of an ATP-induced conformational transition of ABC transporter MsbA using a coarse-grained model2017

    • Author(s)
      Naoki Arai, Tadaomi Furuta, Minoru Sakurai
    • Journal Title

      Biophysics and Physicobiology

      Volume: 14 Issue: 0 Pages: 161-171

    • DOI

      10.2142/biophysico.14.0_161

    • NAID

      130006243558

    • ISSN
      2189-4779
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ATP Hydrolysis Mechanism in a Maltose Transporter Explored by QM/MM Metadynamics Simulation2016

    • Author(s)
      W.-L. Hsu, T. Furuta, and M. Sakurai
    • Journal Title

      J. Phys. Chem. B

      Volume: 120 Issue: 43 Pages: 11102-11112

    • DOI

      10.1021/acs.jpcb.6b07332

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Structural Dynamics of the Heterodimeric ABC Transporter TM287/ 288 Induced by ATP and Substrate Binding2016

    • Author(s)
      T. Furuta, Y. Sato, M. Sakurai
    • Journal Title

      Biochemistry

      Volume: 55 Issue: 48 Pages: 6730-6738

    • DOI

      10.1021/acs.biochem.6b00947

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Thermal fluctuations enable rapid protein-protein associations inaqueous solution by lowering the reaction barrier2016

    • Author(s)
      Honami Sakaizawa, Hiroshi C. Watanabe, Tadaomi Furuta, Minoru Sakurai
    • Journal Title

      Chem. Phys. Lett.

      Volume: 643 Pages: 114-118

    • DOI

      10.1016/j.cplett.2015.11.014

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Mechanism for the Transport of ABC Transporters by Experimental and Simulation Studies2016

    • Author(s)
      古田忠臣、山口知宏、加藤博章、櫻井実
    • Journal Title

      Seibutsu Butsuri

      Volume: 56 Issue: 1 Pages: 005-008

    • DOI

      10.2142/biophys.56.005

    • NAID

      130005121652

    • ISSN
      0582-4052, 1347-4219
    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Analysis of the free energy landscapes for the opening-closing dynamics of the maltose transporter ATPase MalK2 using enhanced-sampling molecular dynamics simulation2015

    • Author(s)
      Wei-Lin Hsu, Tadaomi Furuta, Minoru Sakurai
    • Journal Title

      J. Phys. Chem. B

      Volume: 119 Issue: 30 Pages: 9717-9725

    • DOI

      10.1021/acs.jpcb.5b05432

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] Development of an ATP force field for coarse-grained simulation of ATPases and its application to the maltose transporter2019

    • Author(s)
      Ryosuke Hirano, Tsubasa Yabuchi, Minoru Sakurai, Tadaomi Furuta
    • Organizer
      The 63rd Annual Meeting of the Biophysical Society
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 粗視化MDシミュレーションを用いたATP結合により誘起されるマルトーストランスポーターの構造変化の解析2018

    • Author(s)
      平野諒輔, 古田忠臣, 櫻井実
    • Organizer
      第18回日本蛋白質科学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ABCトランスポーターにおけるヌクレオチドドメイン2量体化の駆動力に関する計算化学的解析2018

    • Author(s)
      境澤穂波, 許維麟, 古田忠臣, 櫻井実
    • Organizer
      第18回日本蛋白質科学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ABCトランスポーターCFTRの構造変化及び基質輸送機構の計算化学的解析2018

    • Author(s)
      千葉一輝, 古田忠臣, 櫻井実
    • Organizer
      第18回日本蛋白質科学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] MDシミュレーションを用いたグルコーストランスポーター8(GLUT8)の膜貫通ヘリックス7(TM7)に関する解析2018

    • Author(s)
      中田康太, 古田忠臣, 櫻井実
    • Organizer
      第18回日本蛋白質科学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 転写制御因子LmrRおよびQacRにおける多剤認識メカニズムに関する分子シミュレーション研究2018

    • Author(s)
      クライヤー篠塚一穂, 古田忠臣, 櫻井実
    • Organizer
      第56回日本生物物理学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Structural and Functional dynamics of ABC transporters explored by molecular simulations2018

    • Author(s)
      Tadaomi Furuta
    • Organizer
      第56回日本生物物理学会年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Martini 力場を用いた粗視化シミュレーションによるCl-チャネルCFTRのダイナミクスの解析2017

    • Author(s)
      矢渕翼, 南條舜, 古田忠臣, 櫻井実
    • Organizer
      第17回日本蛋白質科学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 親水性タンパク質ータンパク質間会合の駆動力に関するMD及び3D-RISM計算2017

    • Author(s)
      境澤穂波, 古田忠臣, 櫻井実
    • Organizer
      第55回日本生物物理学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] Molecular dynamics investigation of the full maltose transporter with and without the maltose binding protein MalE2016

    • Author(s)
      許維麟、古田忠臣、櫻井実
    • Organizer
      第54回日本生物物理学会年会
    • Place of Presentation
      つくば国際会議場(茨城県つくば市)
    • Year and Date
      2016-11-26
    • Related Report
      2016 Research-status Report
  • [Presentation] 多剤認識転写因子LmrRにおける薬剤分子認識機構の計算化学的解析2016

    • Author(s)
      クライヤー篠塚一帆、古田忠臣、櫻井実
    • Organizer
      第54回日本生物物理学会年会
    • Place of Presentation
      つくば国際会議場(茨城県つくば市)
    • Year and Date
      2016-11-25
    • Related Report
      2016 Research-status Report
  • [Presentation] MDシミュレーションによるCFTRチャネルの基質輸送機構及び変異による影響の解析2016

    • Author(s)
      古田忠臣、南條舜、相馬義朗、櫻井実
    • Organizer
      第16回日本蛋白質科学会年会
    • Place of Presentation
      福岡国際会議場(福岡県福岡市)
    • Year and Date
      2016-06-08
    • Related Report
      2016 Research-status Report
  • [Presentation] QM/MM Metadynamicsで探るマルトーストランスポーターのATP加水分解メカニズム2016

    • Author(s)
      許維麟、古田忠臣、櫻井実
    • Organizer
      第16回日本蛋白質科学会年会
    • Place of Presentation
      福岡国際会議場(福岡県福岡市)
    • Year and Date
      2016-06-07
    • Related Report
      2016 Research-status Report
  • [Presentation] 多剤認識転写因子LmrRにおける薬剤分子認識機構の計算化学的解析2016

    • Author(s)
      クライヤー篠塚一帆、古田忠臣、櫻井実
    • Organizer
      第16回日本蛋白質科学会年会
    • Place of Presentation
      福岡国際会議場(福岡県福岡市)
    • Year and Date
      2016-06-07
    • Related Report
      2016 Research-status Report
  • [Presentation] 分子シミュレーションで探るABCトランスポーターの機能的ダイナミクス2016

    • Author(s)
      古田忠臣
    • Organizer
      大阪大学蛋白質研究所セミナー「膜タンパク質の構造ダイナミクス」
    • Place of Presentation
      大阪大学蛋白質研究所(大阪府吹田市)
    • Year and Date
      2016-05-12
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] Free energy calculation for the ATP-induced dimerization of the nucleotide-binding domains in a maltose transporter: Importance of the water-mediated entropic force2015

    • Author(s)
      Tomohiko Hayashi, Shuntaro Chiba, Tadaomi Furuta, Minoru Sakurai
    • Organizer
      The International Chemical Congress of Pacific Basin Societies 2015 (Pacifichem 2015)
    • Place of Presentation
      Hawaii Convention Center, Honolulu, Hawaii, U.S.A.(ホノルル)
    • Year and Date
      2015-12-17
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] 3D-RISM study of water-meditated forces between the nucleotide binding domains responsible for the power stroke in an ABC transporter2015

    • Author(s)
      Tomoka Furukawa-Hagiya, Norio Yoshida, Shuntaro Chiba, Tomohiko Hayashi, Tadaomi Furuta, Minoru Sakurai
    • Organizer
      The International Chemical Congress of Pacific Basin Societies 2015 (Pacifichem 2015)
    • Place of Presentation
      Hawaii Convention Center, Honolulu, Hawaii, U.S.A.(ホノルル)
    • Year and Date
      2015-12-17
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Structural and functional roles of coupling helices in ABC transporter MsbA: Experimental and computational studies2015

    • Author(s)
      Tadaomi Furuta, Tomohiro Yamaguchi, Hiroaki Kato, Minoru Sakurai
    • Organizer
      The International Chemical Congress of Pacific Basin Societies 2015 (Pacifichem 2015)
    • Place of Presentation
      Hawaii Convention Center, Honolulu, Hawaii, U.S.A.(ホノルル)
    • Year and Date
      2015-12-17
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Analysis of the free energy landscape for the open-close dynamics of maltose transporter ATPase, MalK, using enhanced sampling MD simulation2015

    • Author(s)
      Wei-Lin Hsu, Tadaomi Furuta, Minoru Sakurai
    • Organizer
      The International Chemical Congress of Pacific Basin Societies 2015 (Pacifichem 2015)
    • Place of Presentation
      Hawaii Convention Center, Honolulu, Hawaii, U.S.A.(ホノルル)
    • Year and Date
      2015-12-17
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] 熱ゆらぎと水和効果に着目したABCトランスポーターのNBD二量体化過程の統計熱力学的解析2015

    • Author(s)
      境澤穂波、渡邉宙志、古田忠臣、櫻井実
    • Organizer
      第53回日本生物物理学会年会
    • Place of Presentation
      金沢大学角間キャンパス自然科学本館(金沢市)
    • Year and Date
      2015-09-14
    • Related Report
      2015 Research-status Report
  • [Presentation] Analysis of the Free Energy Landscapes for the Open-Closing Dynamics of MalK2 Using Enhanced Sampling MD Simulation2015

    • Author(s)
      許維麟, 古田忠臣, 櫻井実
    • Organizer
      第53回日本生物物理学会年会
    • Place of Presentation
      金沢大学角間キャンパス自然科学本館(金沢市)
    • Year and Date
      2015-09-13
    • Related Report
      2015 Research-status Report
  • [Presentation] 熱ゆらぎと水和効果に着目したABCトランスポーターのNBD二量体化過程の統計熱力学的解析2015

    • Author(s)
      境澤穂波, 渡邉宙志, 古田忠臣, 櫻井実
    • Organizer
      第15回日本蛋白質科学会年会
    • Place of Presentation
      あわぎんホール(徳島市)
    • Year and Date
      2015-06-25
    • Related Report
      2015 Research-status Report
  • [Book] The Role of Water in ATP Hydrolysis Energy Transduction by Protein Machinery2018

    • Author(s)
      Tadaomi Furuta, Minoru Sakurai
    • Total Pages
      353
    • Publisher
      Springer
    • ISBN
      9789811084591
    • Related Report
      2018 Annual Research Report

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Published: 2015-04-16   Modified: 2020-03-30  

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