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Structural Basis for drug transport by ABC transporters

Research Project

Project/Area Number 17K07306
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Structural biochemistry
Research InstitutionKyoto University

Principal Investigator

Kodan Atsushi  京都大学, 高等研究院, 特定助教 (80360543)

Co-Investigator(Kenkyū-buntansha) HIPOLITO CHRIS  筑波大学, 医学医療系, 助教 (20759914)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
KeywordsABC輸送体 / P糖蛋白質 / 膜蛋白質 / 分子メカニズム / 機能-構造相関 / ATP / 生体分子 / タンパク質 / 膜タンパク質 / 立体構造 / 機能 / 蛋白質 / 構造変化 / バイオテクノロジー / 薬理学 / 癌
Outline of Final Research Achievements

P-glycoprotein, a member of the ATP-binding cassette (ABC) transporter family, extrudes a large variety of lipophilic compounds from cells, but the underlying molecular mechanism of how the transporter performs multidrug pumping using ATP as fuel remains unknown. We have solved two structures of a eukaryotic P-glycoprotein ortholog: an outward-open state with bound nucleotide, and an inward-open state. The detailed structural differences between the two conformations of the same molecule allowed us to propose a rational model for the molecular mechanism. To evaluate the validity of the model, we generated more than 100 mutants and test their functions by biochemical analyses. These results supported the validity of the proposed model, indicating that this transporter squeezes various lipophilic compounds to the extracellular space and that the squeeze movement is driven by local conformational changes of nucleotide binding domains upon ATP binding.

Academic Significance and Societal Importance of the Research Achievements

これまでに異なる二状態(内向型と外向型)の結晶構造を同一のP糖蛋白質で明らかにした例はなかった。代表者らは、ヒトP糖蛋白質と基質特性が良く似たP糖蛋白質オーソログを見いだし、その両状態の結晶構造を世界に先駆けて高分解能で決定することに成功した。両者の原子レベルでの厳密な比較、および、機能-構造相関解析により、当輸送体の分子メカニズムの理解を飛躍的に向上させることに成功した。本研究で得られた成果は、ABC蛋白質全般の機能を考える上で重要であり、新たな治療方針や創薬アイデアの策定に多大な貢献ができると期待される。

Report

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

    (6 results)

All 2020 2019 Other

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Book (1 results) Remarks (3 results)

  • [Journal Article] In vivo FRET analyses reveal a role of ATP hydrolysis?associated conformational changes in human P-glycoprotein2020

    • Author(s)
      Futamata Ryota、Ogasawara Fumihiko、Ichikawa Takafumi、Kodan Atsushi、Kimura Yasuhisa、Kioka Noriyuki、Ueda Kazumitsu
    • Journal Title

      Journal of Biological Chemistry

      Volume: in press Issue: 15 Pages: 5002-5011

    • DOI

      10.1074/jbc.ra119.012042

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inward- and outward-facing X-ray crystal structures of homodimeric P-glycoprotein CmABCB12019

    • Author(s)
      Kodan Atsushi、Yamaguchi Tomohiro、Nakatsu Toru、Matsuoka Keita、Kimura Yasuhisa、Ueda Kazumitsu、Kato Hiroaki
    • Journal Title

      Nature Communications

      Volume: 10 Issue: 1 Pages: 1-12

    • DOI

      10.1038/s41467-018-08007-x

    • NAID

      120006547405

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Book] 「膜タンパク質工学ハンドブック」第2編 膜タンパク質 ― 医学・薬学への展開、第3章 トランスポーター 、第1節 多剤輸送体MDR1(ABCB1)p. 211-2162020

    • Author(s)
      木村 泰久、小段 篤史、植田 和光
    • Total Pages
      624
    • Publisher
      (株)エヌ・ティー・エス
    • Related Report
      2019 Annual Research Report
  • [Remarks] 京都大学ホームページ

    • URL

      http://www.kyoto-u.ac.jp/ja/research/research_results/2018/190108_2.html

    • Related Report
      2018 Research-status Report
  • [Remarks] SPring-8大型放射光施設ホームページ

    • URL

      http://www.spring8.or.jp/ja/news_publications/press_release/2019/190108/

    • Related Report
      2018 Research-status Report
  • [Remarks] 日本経済新聞

    • URL

      https://www.nikkei.com/article/DGXLRSP499732_Q9A110C1000000/

    • Related Report
      2018 Research-status Report

URL: 

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

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