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Structural analysis of endothelin receptors in complex with G-proteins

Research Project

Project/Area Number 18K14634
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 43020:Structural biochemistry-related
Research InstitutionThe University of Tokyo

Principal Investigator

Shihoya Wataru  東京大学, 大学院理学系研究科(理学部), 特別研究員 (30809421)

Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
KeywordsGPCR / クライオ電子顕微鏡 / PACAP / G蛋白質 / Cryo-EM / エンドセリン / エンドセリン受容体 / 構造生物学 / 単粒子解析 / Gタンパク質共役受容体
Outline of Final Research Achievements

We determined the structure of the human ETB receptor in complex with ETB selective drugs.These structures elucidated the structural basis for the ETB-selective binding of the compounds. We have successfully formed a complex between the ETB receptor and Gi protein. PAC1R is a neural GPCR and is activated by the endogenous peptide PACAP. PAC1R plays an important role in feeding control, psychiatric disorders, and lacrimal fluid secretion and is a promising drug target. In this study, we determined the structure of the signaling complex consisting of PACAP, human PAC1 receptor, and Gs protein by single-particle analysis using cryo-electron microscopy. This structure revealed the detail of the PACAP recognition mechanism.

Academic Significance and Societal Importance of the Research Achievements

PAC1受容体は類似受容体VPAC1やVPAC2が存在するため、PAC1受容体選択的な薬剤の創出が困難だった。本研究により、PAC1受容体は細胞外ドメインによりリガンドの親和性を高める一方で、その受容体膜貫通部位との相互作用のみにより受容体可能であることが明らかになった。今後は、本構造情報を活用した、PAC1受容体の膜貫通部位と選択的に相互作用できる低分子薬剤の開発が期待される。

Report

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

    (3 results)

All 2020 2019 2018

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 3 results)

  • [Journal Article] Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein2020

    • Author(s)
      Kobayashi Kazuhiro、Shihoya Wataru、Nishizawa Tomohiro、Kadji Francois Marie Ngako、Aoki Junken、Inoue Asuka、Nureki Osamu
    • Journal Title

      Nature Structural & Molecular Biology

      Volume: 27 Issue: 3 Pages: 274-280

    • DOI

      10.1038/s41594-020-0386-8

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL25002019

    • Author(s)
      Nagiri Chisae、Shihoya Wataru、Inoue Asuka、Kadji Francois Marie Ngako、Aoki Junken、Nureki Osamu
    • Journal Title

      Communications Biology

      Volume: 2 Issue: 1 Pages: 1-11

    • DOI

      10.1038/s42003-019-0482-7

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Crystal structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation2018

    • Author(s)
      Shihoya Wataru、Izume Tamaki、Inoue Asuka、Yamashita Keitaro、Kadji Francois Marie Ngako、Hirata Kunio、Aoki Junken、Nishizawa Tomohiro、Nureki Osamu
    • Journal Title

      Nature Communications

      Volume: 9 Issue: 1 Pages: 1-11

    • DOI

      10.1038/s41467-018-07094-0

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access

URL: 

Published: 2018-04-23   Modified: 2021-02-19  

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