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Structural analysis of G protein/Arrestin-GPCR complex for development of biased ligands

Research Project

Project/Area Number 19H03428
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionKansai Medical University

Principal Investigator

SUNO Ryoji  関西医科大学, 医学部, 准教授 (60447521)

Co-Investigator(Kenkyū-buntansha) 斉藤 毅  筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80609933)
Project Period (FY) 2019-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2023: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2022: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2021: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2020: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
KeywordsGPCR / クライオ電子顕微鏡単粒子解析 / シグナル伝達 / SBDD / 膜タンパク質 / 創薬 / バイアスドリガンド / X線結晶構造解析 / クライオ電子顕微鏡 / 薬剤開発 / バイアスリガンド / ナルコレプシー
Outline of Research at the Start

創薬ターゲットとして知られているGPCRは細胞外からの生理活性物質と結合すると細胞内の種々のシグナル伝達因子と結合し、それらを活性化する。G蛋白質とアレスチンの2つの異なるシグナル伝達経路の一方を選択的に活性化するリガンド(バイアスリガンド)が知られており、副作用のない治療薬として期待されている。本研究では、GPCRとG蛋白質あるいはアレスチンとの複合体のX線結晶構造解析およびクライオ電子顕微鏡単粒子解析を行い、その構造情報からGPCRのG蛋白質およびアレスチンを介したシグナル伝達機構および作動薬結合様式を解明する。さらに構造情報をもとにした迅速で合理的なバイアスリガンドの開発とその技術の発展に貢献する。

Outline of Final Research Achievements

Among several types of G proteins, we select the conditions that form the most stable complexes with OX2R and EP3, respectively, and have found stable complex conditions for the EP3-Gi and Go,G13 complexes and the OX2R-Gi/o complex, and for EP3-Gi, the structure was determined at 3.4 A resolution by Cryo-EM SPA The structure of EP3-Gi was determined at 3.4 A resolution by Cryo-EM SPA. Our group has also determined the complex structure with another subtype of EP4-G protein and published a paper discussing the structural basis of G-protein selectivity of prostaglandin receptors based on different G-protein types with pharmacological analysis (Suno R., Cell Reports, 2022).

Academic Significance and Societal Importance of the Research Achievements

Gタンパク質共役受容体(GPCR)は創薬ターゲットとして知られており、その構造情報は副作用のない薬剤の合理的な開発に有用な情報となる。一つのGPCRに対してGタンパク質やアレスチンなどのシグナル伝達因子を活性化することで生体内に異なるシグナルを伝達する。これらを制御することで目的の薬剤効果を発揮し、副作用を軽減することが期待される。本研究では異なるGタンパク質を活性化する2種のプロスタグランジン受容体の構造を決定し、これらのシグナル伝達の選択性に重要なアミノ酸を発見した。この研究技術は構造情報の有用性を示しており、他のGPCRにも応用できる。

Report

(6 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (25 results)

All 2024 2023 2022 2021 2020 2019

All Journal Article (10 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 10 results,  Open Access: 6 results) Presentation (14 results) (of which Int'l Joint Research: 2 results,  Invited: 10 results) Book (1 results)

  • [Journal Article] Interaction modes of human orexin 2 receptor with selective and nonselective antagonists studied by NMR spectroscopy2024

    • Author(s)
      Imamura Kayo、Akagi Ken-Ichi、Miyanoiri Yohei、Tsujimoto Hirokazu、Hirokawa Takatsugu、Ashida Hideo、Murakami Kaori、Inoue Asuka、Suno Ryoji、Ikegami Takahisa、Sekiyama Naotaka、Iwata So、Kobayashi Takuya、Tochio Hidehito
    • Journal Title

      Structure

      Volume: 32 Issue: 3 Pages: 352-361

    • DOI

      10.1016/j.str.2023.12.008

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural insights into the G protein selectivity revealed by the human EP3-Gi signaling complex2022

    • Author(s)
      Ryoji Suno, Yukihiko Sugita, Kazushi Morimoto, Hiroko Takazaki, Hirokazu Tsujimoto, Mika Hirose, Chiyo Suno-Ikeda, Norimichi Nomura, Tomoya Hino, Asuka Inoue, Kenji Iwasaki, Takayuki Kato, So Iwata, Takuya Kobayashi
    • Journal Title

      Cell Rep.

      Volume: 40(11) Issue: 11 Pages: 111323-111323

    • DOI

      10.1016/j.celrep.2022.111323

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor2022

    • Author(s)
      Asada Hidetsugu、Im Dohyun、Hotta Yunhon、Yasuda Satoshi、Murata Takeshi、Suno Ryoji、Iwata So
    • Journal Title

      Structure

      Volume: 30 Issue: 12 Pages: 1582-1589.e4

    • DOI

      10.1016/j.str.2022.11.001

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Liquid Chromatography-Mass Spectrometry Method to Study the Interaction between Membrane Proteins and Low-Molecular-Weight Compound Mixtures2022

    • Author(s)
      Hideo Ogiso, Ryoji Suno, Takuya Kobayashi, Masashi Kawami, Mikihisa Takano, Masaru Ogasawara
    • Journal Title

      Molecules

      Volume: 27(15) Issue: 15 Pages: 4889-4889

    • DOI

      10.3390/molecules27154889

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Vibrational spectroscopy analysis of ligand efficacy in human M2 muscarinic acetylcholine receptor (M2R)2021

    • Author(s)
      Katayama Kota、Suzuki Kohei、Suno Ryoji、Kise Ryoji、Tsujimoto Hirokazu、Iwata So、Inoue Asuka、Kobayashi Takuya、Kandori Hideki
    • Journal Title

      Communications Biology

      Volume: 4 Issue: 1 Pages: 1-10

    • DOI

      10.1038/s42003-021-02836-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cryo-EM structure of the human MT1-Gi signaling complex.2021

    • Author(s)
      Okamoto, H. H., Miyauchi, H., Inoue, A., Raimondi, F., Tsujimoto, H., Kusakizako, T., Shihoya, W., Yamashita, K., Suno, R., Nomura, N., Kobayashi, T., Iwata, S., Nishizawa, T. and Nureki, O.
    • Journal Title

      Nat. Struct. Mol. Biol.

      Volume: 28 Issue: 8 Pages: 694-701

    • DOI

      10.1038/s41594-021-00634-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Vibrational analysis of acetylcholine binding to the M2 receptor2021

    • Author(s)
      Suzuki K, Katayama K, Sumii Y, Nakagita T, Suno R, Tsujimoto H, Iwata S, Kobayashi T, Shibata N and Kandori H
    • Journal Title

      RSC. Adv.

      Volume: 11 Issue: 21 Pages: 12559-12567

    • DOI

      10.1039/d1ra01030a

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cryo-EM Structure of the Prostaglandin E Receptor EP4 Coupled to G Protein.2021

    • Author(s)
      Nojima S, Fujita Y, Kimura KT, Nomura N, Suno R, Morimoto K, Yamamoto M, Noda T, Iwata S, Shigematsu H, Kobayashi T.
    • Journal Title

      Structure

      Volume: 29 Issue: 3 Pages: 252-260

    • DOI

      10.1016/j.str.2020.11.007

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Biophysical Society of Japan (BSJ) ? Miyazaki Meeting, September 2019 Session 1SHP?frontier of structure-function studies to unveil diverse GPCR signaling2020

    • Author(s)
      Katayama Kota、Suno Ryoji
    • Journal Title

      Biophysical Reviews

      Volume: 12 Issue: 2 Pages: 271-272

    • DOI

      10.1007/s12551-020-00689-2

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ligand Binding-Induced Structural Changes in the M2 Muscarinic Acetylcholine Receptor Revealed by Vibrational Spectroscopy.2019

    • Author(s)
      K.Katayama, K. Suzuki, R. Suno, H. Tsujimoto, S. Iwata, T. Kobayashi, H. Kandori*
    • Journal Title

      J Phys Chem Lett.

      Volume: 10(22) Issue: 22 Pages: 7270-7276

    • DOI

      10.1021/acs.jpclett.9b02942

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] バイアスドリガンドによるヒトκオピオイド受容体シグナル伝達の構造的洞察2023

    • Author(s)
      寿野 良二
    • Organizer
      第46回日本分子生物学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Structural and dynamic insights into the biased signaling mechanism of the kappa opioid receptor2023

    • Author(s)
      寿野 良二
    • Organizer
      生理学研究会2023
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Structural insights into human kappa opioid receptor signaling by biased ligand2023

    • Author(s)
      寿野 良二
    • Organizer
      第61回日本生物物理学会(名古屋)
    • Related Report
      2023 Annual Research Report
  • [Presentation] G蛋白質共役受容体の多様な機能発現機構の構造生物学的解明2023

    • Author(s)
      寿野 良二
    • Organizer
      東京理科大学 研究推進機構 総合研究院 2023年度 生物環境イノベーション研究部門・公開シンポジウム
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Structural insights into the human Prostaglandin E receptor EP3-Gi signaling complex.2023

    • Author(s)
      Ryoji Suno
    • Organizer
      GPCR workshop
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] プロスタグランジン受容体の構造解析によるシグナル伝達機構の解明2023

    • Author(s)
      寿野 良二
    • Organizer
      日本薬学会第143年会(札幌)
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 創薬に資するGPCRの構造生物学2022

    • Author(s)
      寿野 良二
    • Organizer
      Neuro2022
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 構造生物学的技術によるGPCRの多様なシグナル伝達機構の解明2022

    • Author(s)
      寿野 良二
    • Organizer
      第95回 日本生化学会(名古屋)
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] ヒトプロスタグランジン受容体EP3-Gタンパク質複合体の構造解析2021

    • Author(s)
      寿野 良二
    • Organizer
      第59回日本生物物理学会年会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ヒトプロスタグランジンE2受容体EP3-Gタンパク質複合体のクライオ電子顕微鏡単粒子解析2021

    • Author(s)
      寿野 良二
    • Organizer
      第21回日本蛋白質科学会年会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 構造情報から読み解くGPCR活性化機構 -創薬に貢献するヒトGPCRの構造解析-2020

    • Author(s)
      寿野 良二
    • Organizer
      第93回日本生化学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Structural insights into the subtype-selective antagonist binding to the M2 muscarinic receptor.2019

    • Author(s)
      Ryoji Suno
    • Organizer
      Cold Spring Harbor laboratory Asia Meeting, Membrane Proteins: from Physiology to Pharmacology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 理論的予測法を用いた熱安定化GPCRの構造解析2019

    • Author(s)
      寿野 良二
    • Organizer
      第92回日本生化学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 理論計算による熱安定化ムスカリンM2受容体の選択的アンタゴニストAF-DX 384結合型構造2019

    • Author(s)
      寿野 良二
    • Organizer
      第57回日本生物物理学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Book] クライオ電子顕微鏡ハンドブック2023

    • Author(s)
      寿野 良二、清水(小林)拓也
    • Total Pages
      460
    • Publisher
      NTS
    • Related Report
      2023 Annual Research Report 2022 Annual Research Report

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Published: 2019-04-18   Modified: 2025-01-30  

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