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Clarification of GPCR signaling regulation mechanism by NMR

Research Project

Project/Area Number 20H03375
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
Research InstitutionThe University of Tokyo

Principal Investigator

Ueda Takumi  東京大学, 大学院薬学系研究科(薬学部), 准教授 (20451859)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
KeywordsNMR / GPCR / 膜タンパク質 / 動的構造平衡 / Gタンパク質 / アレスチン / システム生物学 / G蛋白質 / アドレナリン受容体 / オピオイド受容体
Outline of Research at the Start

GPCRでは、異なるシグナル強度を示すリガンドの存在(薬効度)や、G蛋白質とアレスチンの一方をより強く活性化するバイアスリガンドの存在(シグナル選択性)が、創薬上重要です。本研究課題では、GPCR であるb2 アドレナリン受容体(b2AR) およびmオピオイド受容体(mOR)が、どのような構造の間を、どの程度の速度および量比で交換しているか、またそれらが薬剤の結合や活性を変化させる変異の導入に伴いどのように変化するかを明らかにして、薬効度やシグナル選択性の制御機構を解明することを目的とします。

Outline of Final Research Achievements

BMR-96122 is reportedly non-competitively bound to mu opioid receptor (mOR) and increase the signaling activity of mOR bound to the full agonist. In this study, we observed resonances from methionine residues of mOR in the presence of BMS-986122 and various ligands. Our study revealed that BMS-987122 enhances the signaling activity of mOR bound to the full agonist by perturbing the interaction between TM3 and TM6, in which signaling atctivity-related conformational dynamics was observed, and stabilizing the fully active state, in which the intraceller region adopts open conforation,

Academic Significance and Societal Importance of the Research Achievements

GPCRを標的とする医薬品は、GPCRの細胞外側に存在するポケットに結合してGPCRを活性化する。しかし、既存薬はGPCRの活性を十分に引き出すことができないことから、このポケット以外の場所に結合して作用するアロステリック薬剤の実用化が期待されている。本研究の成果により、アロステリック薬剤がGPCRに対してその構造平衡状態を変え、既存薬の限界を超えて活性を上昇させることができる可能性が示された。したがって、本研究の成果は、これまで十分な薬効を持つ医薬品が見つかっていないGPCR関連疾病に対し、十分な薬効を示す新しい医薬品開発に貢献することが期待できる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (16 results)

All 2023 2022 2021 2020 Other

All Journal Article (11 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 10 results,  Open Access: 5 results) Presentation (2 results) (of which Invited: 1 results) Remarks (3 results)

  • [Journal Article] Amide-to-ester substitution as a stable alternative to N-methylation for increasing membrane permeability in cyclic peptides.2023

    • Author(s)
      Hosono Y, Uchida S, Shinkai M, Townsend CE, Kelly CN, Naylor MR, Lee HW, Kanamitsu K, Ishii M, Ueki R, Ueda T, Takeuchi K, Sugita M, Akiyama Y, Lokey SR, Morimoto J, Sando S.
    • Journal Title

      Nat. Commun.

      Volume: 14 Issue: 1 Pages: 1416-1416

    • DOI

      10.1038/s41467-023-36978-z

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Function-Related Conformational Dynamics of GPCRs Revealed by Solution NMR2022

    • Author(s)
      UEDA Takumi、KOFUKU Yutaka、TAKEUCHI Koh、IMAI Shunsuke、SHIRAISHI Yutaro、SHIMADA Ichio
    • Journal Title

      Nihon Kessho Gakkaishi

      Volume: 64 Issue: 4 Pages: 279-284

    • DOI

      10.5940/jcrsj.64.279

    • ISSN
      0369-4585, 1884-5576
    • Year and Date
      2022-12-15
    • Related Report
      2022 Annual Research Report
  • [Journal Article] Residue-based program of a β-peptoid twisted strand shape via a cyclopentane constraint2022

    • Author(s)
      Kim J, Kobayashi H, Yokomine M, Shiratori Y, Ueda T, Takeuchi K, Umezawa K, Kuroda D, Tsumoto K, Morimoto J, Sando S.
    • Journal Title

      Org. Biomol. Chem.

      Volume: 20 Issue: 35 Pages: 6994-7000

    • DOI

      10.1039/d2ob01300b

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activation mechanism of the μ-opioid receptor by an allosteric modulator.2022

    • Author(s)
      Kaneko S, Imai S, Asao N, Kofuku Y, Ueda T, Shimada I.
    • Journal Title

      Proc. Natl. Acad. Sci. U. S. A.

      Volume: 119 Issue: 16

    • DOI

      10.1073/pnas.2121918119

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ultrafast water permeation through nanochannels with a densely fluorous interior surface.2022

    • Author(s)
      Itoh Y, Chen S, Hirahara R, Konda T, Aoki T, Ueda T, Shimada I, Cannon JJ, Shao C, Shiomi J, Tabata KV, Noji H, Sato K, Aida T.
    • Journal Title

      Science

      Volume: 376 Issue: 6594 Pages: 738-743

    • DOI

      10.1126/science.abd0966

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Function-related dynamics of GPCRs2022

    • Author(s)
      Ueda Takumi、Imai Shunsuke、Shimada Ichio
    • Journal Title

      Journal of Magnetic Resonance

      Volume: 336 Pages: 107164-107164

    • DOI

      10.1016/j.jmr.2022.107164

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Oligo(N‐methylalanine) as a Peptide‐Based Molecular Scaffold with a Minimal Structure and High Density of Functionalizable Sites2022

    • Author(s)
      Yokomine Marin、Morimoto Jumpei、Fukuda Yasuhiro、Shiratori Yota、Kuroda Daisuke、Ueda Takumi、Takeuchi Koh、Tsumoto Kouhei、Sando Shinsuke
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 61 Issue: 14 Pages: 6994-7000

    • DOI

      10.1002/anie.202200119

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biphasic activation of β-arrestin 1 upon interaction with a GPCR revealed by methyl-TROSY NMR2021

    • Author(s)
      Shiraishi Yutaro、Kofuku Yutaka、Ueda Takumi、Pandey Shubhi、Dwivedi-Agnihotri Hemlata、Shukla Arun K.、Shimada Ichio
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 7158-7158

    • DOI

      10.1038/s41467-021-27482-3

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Function-Related Dynamics in Multi-Spanning Helical Membrane Proteins Revealed by Solution NMR2021

    • Author(s)
      Takeuchi Koh、Kofuku Yutaka、Imai Shunsuke、Ueda Takumi、Tokunaga Yuji、Toyama Yuki、Shiraishi Yutaro、Shimada Ichio
    • Journal Title

      Membranes

      Volume: 11 Issue: 8 Pages: 604-604

    • DOI

      10.3390/membranes11080604

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural equilibrium underlying ligand-dependent activation of b2-adrenoreceptor2020

    • Author(s)
      Shunsuke Imai, Tomoki Yokomizo, Yutaka Kofuku, Yutaro Shiraishi, Takumi Ueda, Ichio Shimada
    • Journal Title

      Nature Chemical Biology

      Volume: 16 Issue: 4 Pages: 430-439

    • DOI

      10.1038/s41589-019-0457-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activation of adenosine A2A receptor by lipids from docosahexaenoic acid revealed by NMR2020

    • Author(s)
      Takuya Mizumura, Keita Kondo, Masatoshi Kurita, Yutaka Kofuku, Mei Natsume, Shunsuke Imai, Yutaro Shiraishi, Takumi Ueda, Ichio Shimada
    • Journal Title

      Science Advances

      Volume: 6 Issue: 12

    • DOI

      10.1126/sciadv.aay8544

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] アデノシンA2A受容体とリガンドの滞在時間を規定する構造基盤の解明2022

    • Author(s)
      上田 卓見
    • Organizer
      第61回NMR討論会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Clarification of the GPCR signaling mechanism based on the function-related conformational dynamics2022

    • Author(s)
      上田 卓見
    • Organizer
      第61回NMR討論会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Remarks]

    • URL

      https://biophys.f.u-tokyo.ac.jp/

    • Related Report
      2022 Annual Research Report
  • [Remarks]

    • URL

      https://biophys.f.u-tokyo.ac.jp/

    • Related Report
      2021 Annual Research Report
  • [Remarks]

    • URL

      http://ishimada.f.u-tokyo.ac.jp/public_html/index_j.html

    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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