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Allosteric modulators that recognize the transition-states of receptor channels

Research Project

Project/Area Number 18K06945
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionThe University of Tokyo (2020-2021)
National Institute of Advanced Industrial Science and Technology (2018-2019)

Principal Investigator

Kubo Tai  東京大学, 大学院新領域創成科学研究科, 特任研究員 (10178030)

Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsアロステリック / アセチルコリン受容体 / 進化工学 / 分子動態 / 遷移状態
Outline of Final Research Achievements

To establish the new drug development platform for the allosteric modulators, in vitro evolution (IVE) technology and a single molecular dynamic study were applied to the neuronal nicotinic acetylcholine receptor (nAChR) alpha 7. The nAChR alpha 7 molecules undergo molecular dynamic motions with/without ligands. In our previous study, both the agonistic and antagonistic receptor ligands were successfully identified by IVE technology from the three-finger (3-F) scaffold-based library. Thus, the alpha 7 binder peptides that recognize the various dynamic states were screened from the library. The candidate peptides were under investigation to characterize the positive/negative allostericity of the nAChR alpha 7. Diffracted X-ray Tracking method was applied to study the transition states of alpha 7 receptor, and ivermectine, one of the Positive Allosteric Modulators (PAMs), showed to induce molecular motions to the receptor distinct from the ligand acetylcholine.

Academic Significance and Societal Importance of the Research Achievements

現在進められている創薬研究の多くは、標的となるタンパク質の活性中心やリガンドポケットを狙う、所謂「オルソステリック創薬」が中心となっている。一方この方法では、リガンド結合領域を含む機能領域の配列や構造が類似するファミリータンパク質において広く作用することが多く、これに起因する副作用問題が重大な課題となっている。本研究では、タンパク質が生体機能を発揮する過程で分子がダイナミックに分子内運動をすることに着目し、その遷移状態を特異的に認識するペプチドを創製することにより、従来の問題を回避する新たな創薬「アロステリック創薬」のプラットフォームを確立するための基盤となる。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (15 results)

All 2021 2020 2019 2018

All Journal Article (7 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (6 results) (of which Int'l Joint Research: 3 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] Living-Cell Diffracted X-ray Tracking Analysis Confirmed Internal Salt Bridge Is Critical for Ligand-Induced Twisting Motion of Serotonin Receptors2021

    • Author(s)
      Mio Kazuhiro、Fujimura Shoko、Ishihara Masaki、Kuramochi Masahiro、Sekiguchi Hiroshi、Kubo Tai、Sasaki Yuji C.
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 10 Pages: 5285-5285

    • DOI

      10.3390/ijms22105285

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] X-ray-based living-cell motion analysis of individual serotonin receptors2020

    • Author(s)
      Mio Kazuhiro、Ishihara Masaki、Fujimura Shoko、Sasaki Daisuke、Nozawa Shunsuke、Ichiyanagi Kohei、Fukaya Ryo、Adachi Shin-ichi、Kuramochi Masahiro、Sekiguchi Hiroshi、Kubo Tai、Sasaki Yuji C.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 529 Issue: 2 Pages: 306-313

    • DOI

      10.1016/j.bbrc.2020.05.200

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Agonist and Antagonist-Diverted Twisting Motions of a Single TRPV1 Channel2020

    • Author(s)
      Fujimura Shoko、Mio Kazuhiro、Kuramochi Masahiro、Sekiguchi Hiroshi、Ikezaki Keigo、Mio Muneyo、Hengphasatporn Kowit、Shigeta Yasuteru、Kubo Tai、Sasaki Yuji C.
    • Journal Title

      The Journal of Physical Chemistry B

      Volume: 124 Issue: 51 Pages: 11617-11624

    • DOI

      10.1021/acs.jpcb.0c08250

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] cDNA Display of Disulfide-containing Peptide Library and in vitro Evolution2020

    • Author(s)
      Kubo, T., & Naimuddin, M.
    • Journal Title

      Methods in Molecular Biology

      Volume: 2070 Pages: 57-67

    • DOI

      10.1007/978-1-4939-9853-1_4

    • ISBN
      9781493998524, 9781493998531
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Toward understanding of internal motion measurement with quantum probe and cryo-EM2019

    • Author(s)
      Mio, K.,Fujimura, A.,Kuramochi, M.,Ishihara, M.,Honda, M.,Kubo, T.,Sekiguchi, H.,Sasaki, Y.C.
    • Journal Title

      Japanese Journal of Pesticide Science

      Volume: 44 Issue: 2 Pages: 210-215

    • DOI

      10.1584/jpestics.W19-40

    • NAID

      130007843643

    • ISSN
      2187-0365, 2187-8692
    • Year and Date
      2019-08-20
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] cDNA Display of Disulfide-containing Peptide Library and in vitro Evolution2019

    • Author(s)
      Kubo, T., & Naimuddin, M
    • Journal Title

      Methods in Molecular Biology

      Volume: 印刷中

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Diffracted X-ray blinking tracks single protein motions2018

    • Author(s)
      Sekiguchi, H., Kuramochi, M., Ikesaki, K., Okamura, Y., Yoshimura, K., Matsubara, K., Chang, J. W., Ohta, N., Kubo, T., Mio, K., Suzuki, Y., Chavas, L. M., & Sasaki, Y.
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 1709-1709

    • DOI

      10.1038/s41598-018-35468-3

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] ANTAGONIST-INDUCED CLOCKWISE ROTATION IN THE TRPV12019

    • Author(s)
      Shoko Fujimura, Kazuhiro Mio, Masahiro Kuramochi, Hiroshi Sekiguchi, Muneyo Mio, Tai Kubo, Yuji C. Sasaki
    • Organizer
      63rd annual meeting Biophysical Society (BPS19)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] TRPV1 チャネルの 1 分子内回転動態の決定 Rotational Motions of Single TRPV1 Channel upon Gating2019

    • Author(s)
      三尾 和弘、藤村 章子、倉持 昌弘、関口 博史、三尾 宗代、久保 泰、佐々木 裕次
    • Organizer
      第19回日本蛋白質科学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Screening and characterization of allosteric modulators for nAChR α7 from structurally constrained pept ide librarie2018

    • Author(s)
      久保 泰、伊藤 弘幸、大橋 澄子、齋藤 光義
    • Organizer
      10th International Peptide Symposium
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Rotational Brownian Motion of TRPV1 Channel observed by Synchrotron Diffracted X-ray Tracking and Labora tory X-ray blinking analysi2018

    • Author(s)
      三尾 和弘、倉持 昌弘、松原賢、池﨑 圭吾、関口 博史、三尾 宗代、久保 泰、佐々木 裕次
    • Organizer
      62th Annual Meeting Biophysical Society
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] X線1分子追跡法によるTRPV1チャネルの3次元運動2018

    • Author(s)
      藤村 章子、三尾 和弘、倉持 昌弘、関口博史、池﨑 圭吾、三尾 宗代、久保 泰、佐々木 裕次
    • Organizer
      第27回 日本バイオイメージング学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 3D motion of TRPV1 cation channel depicted by diffracted X-ray tracking method2018

    • Author(s)
      藤村 章子、三尾 和弘、倉 持 昌弘、関口博史、池﨑 圭吾、三尾 宗代、久保 泰、佐々木 裕次
    • Organizer
      日本生物物理 学会第56回年会
    • Related Report
      2018 Research-status Report
  • [Patent(Industrial Property Rights)] 生理活性を持つ中分子の薬物動態を改善する方法、薬物動態の改善を利用した中分子ライブラリの製造法2019

    • Inventor(s)
      竹内恒、夏目徹、久保泰
    • Industrial Property Rights Holder
      産業技術総合研究所
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2018 Research-status Report
    • Overseas
  • [Patent(Industrial Property Rights)] 核酸リンカー2018

    • Inventor(s)
      久保泰、M.ナイムディン
    • Industrial Property Rights Holder
      産業技術総合研究所
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Acquisition Date
      2019
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2023-01-30  

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