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Elucidation of the ion transport mechanism of the rotary molecular motor

Research Project

Project/Area Number 21H02409
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 43020:Structural biochemistry-related
Research InstitutionChiba University

Principal Investigator

Murata Takeshi  千葉大学, 大学院理学研究院, 教授 (80415322)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
KeywordsV-ATPase / 分子モーター / 構造解析 / イオン輸送 / 分子メカニズム
Outline of Research at the Start

腸球菌V-ATPaseはATPのエネルギーを使って回転しながらイオンを輸送する膜たんぱく質で、腸球菌の生育に重要な役割を担っています。最近我々は薬剤耐性腸球菌の抗菌剤が結合した腸球菌V-ATPaseの詳細な立体構造マップを得ることに成功しました。そこで本研究では、腸球菌V-ATPaseの詳細な立体構造を決定します。そして、得られた構造情報からイオン輸送や抗菌剤結合に重要と考えられる箇所を詳細に解析し、V-ATPaseがどのようにイオンを輸送するのか、抗菌剤がどのようにV-ATPaseを阻害するのかを明らかにします。

Outline of Final Research Achievements

Enterococcal V-ATPase is a membrane protein that utilizes energy from ATP to transport Na+ while rotating, playing an essential role in the growth of enterococci. We discovered an inhibitor of V-ATPase and identified its potential as an antimicrobial agent against multidrug-resistant enterococci. In this study, we used cryo-electron microscopy to elucidate the detailed structure of the V-ATPase complex bound to the inhibitor. By integrating the obtained structural and functional analysis information, we clarified (i) the Na+ transport mechanism of this enzyme, (ii) the mechanism by which the inhibitor blocks Na+ transport, and (iii) the molecular differences between Na+ and H+ transport mechanisms. Currently, we are advancing the development of antimicrobial agents based on the obtained information.

Academic Significance and Societal Importance of the Research Achievements

腸球菌V-ATPaseは、ATPのエネルギーを利用して回転しながらイオンを輸送する膜タンパク質であり、腸球菌の生育に重要な役割を果たしています。我々は、腸球菌V-ATPaseの阻害剤を発見し、多剤耐性腸球菌に対する抗菌薬としての可能性を見出しました。本研究では、阻害剤が結合した腸球菌V-ATPaseの詳細な立体構造を決定しました。そして、V-ATPaseがどのようにイオンを輸送するのか、阻害剤がどのようにV-ATPaseを阻害するのかを明らかにしました。現在、得られた情報を基に抗菌薬の開発を進めています。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (19 results)

All 2024 2023 2022 Other

All Int'l Joint Research (8 results) Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (7 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] Arizona State University/University of Illinois(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University de Lorraine(フランス)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Arizona State University/University of Illinois(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Medical Research Council/Imperial College London(英国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] University de Lorraine(フランス)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Arizona State University/University of Illinois(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Medical Research Council/Imperial College London(英国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] University de Lorraine(フランス)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Six states of Enterococcus hirae V-type ATPase reveals non-uniform rotor rotation during turnover2023

    • Author(s)
      Burton-Smith Raymond N.、Song Chihong、Ueno Hiroshi、Murata Takeshi、Iino Ryota、Murata Kazuyoshi
    • Journal Title

      Communications Biology

      Volume: 6 Issue: 1 Pages: 755-755

    • DOI

      10.1038/s42003-023-05110-8

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Physical pictures of rotation mechanisms of F1- and V1-ATPases: Leading roles of translational, configurational entropy of water2023

    • Author(s)
      Yasuda Satoshi、Hayashi Tomohiko、Murata Takeshi、Kinoshita Masahiro
    • Journal Title

      Frontiers in Molecular Biosciences

      Volume: 10 Pages: 1-23

    • DOI

      10.3389/fmolb.2023.1159603

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Revealing a Hidden Intermediate of Rotatory Catalysis with X-ray Crystallography and Molecular Simulations2022

    • Author(s)
      Shekhar Mrinal、Gupta Chitrak、Suzuki Kano、Chan Chun Kit、Murata Takeshi、Singharoy Abhishek
    • Journal Title

      ACS Central Science

      Volume: 8 Issue: 7 Pages: 915-925

    • DOI

      10.1021/acscentsci.1c01599

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Discovery of a novel inhibitor for Na+-transporting V-ATPase enables suppression of VRE colonization in mice and reveals high-resolution structure of the Na+ transport pathway2023

    • Author(s)
      Takeshi Murata
    • Organizer
      Gordon Research Conference on Bioenergetics
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Na+-Transporting V-ATPase Inhibitor Suppresses VRE Growth in Mice and Unveils Na+ Pathway Structure2023

    • Author(s)
      Takeshi Murata
    • Organizer
      21th IPR Retreat
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Physical pictures of rotation mechanisms of F1- and V1-ATPases: Leading roles of translational, configurational entropy of water2023

    • Author(s)
      Satoshi Yasuda, Tomohiko Hayashi, Takeshi Murata and Masahiro Kinoshita
    • Organizer
      第61回日本生物物理学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 腸球菌V-ATPase阻害剤はウェルシュ菌の増殖をpH依存的に阻害する2022

    • Author(s)
      阿部 晶平、清水 康輝、金沢 達志、宮城 侑弥、清木 一生、森山 克彦、宮田 茂、村田 武士
    • Organizer
      第26回腸内細菌学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] The Off-Axis Rotor of Enterococcus hirae V-type ATPase by Volta Phase Contrast and Conventional Phase Cryo-EM2022

    • Author(s)
      Raymond N. Burton-Smith, Jun Tsunoda, Chihong Song, Hiroshi Ueno, Takeshi Murata, Ryota Iino, Kazuyoshi Murata
    • Organizer
      第60回日本生物物理学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Single-molecule analysis and engineering of rotary V-ATPase2022

    • Author(s)
      大友 章裕、飯田 龍也、上野 博史、村田 武士、飯野 亮太
    • Organizer
      第60回日本生物物理学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 腸球菌V-ATPase阻害剤はウェルシュ菌の増殖を阻害する2022

    • Author(s)
      阿部晶平、清水康輝、金沢達志、清木一生、森山克彦、村田武士
    • Organizer
      第95回日本細菌学会
    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 抗菌組成物及び医薬並びに抗菌方法2024

    • Inventor(s)
      村田武士、阿部晶平、鈴木花野、後藤義幸
    • Industrial Property Rights Holder
      村田武士、阿部晶平、鈴木花野、後藤義幸
    • Industrial Property Rights Type
      特許
    • Filing Date
      2024
    • Related Report
      2023 Annual Research Report
    • Overseas

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Published: 2021-04-28   Modified: 2025-01-30  

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