Structural analysis of endothelin receptors in complex with G-proteins

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K14634
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: The 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
• Keywords: GPCR / クライオ電子顕微鏡 / PACAP / G蛋白質

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.

Free Research Field

構造生物学

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。