Studies of activation mechanism of vascular-constricting hormone receptor

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03210
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Kyoto University
• Principal Investigator: Doi Tomoko 京都大学, 理学研究科, 准教授 (00397580)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ペプチドGPCR / シグナル伝達 / 三量体Gタンパク質

Outline of Final Research Achievements

The peptide hormone endothelin (ET-1) regulates vascular tone and humoral homeostasis. Y13 and F14 in the helical region of ET-1 interact with the N-terminal tail and extracellular side of TM7 in the endothelin type B receptor (ETB) and start signal propagation in the ETBR. The structure of ETBR bound to ET-1, a G-protein coupled receptor (GPCR) complexed with Gi1 and scFv16, a complex stabilizer was analyzed by cryo-EM and single-particle analysis. The interactions observed in the complex were analyzed by cell-based G-protein coupling assays, showing that the tip of C-terminal alpha-5 helix engages with the cytoplasmic end of TM7 and TM8, and that ETBR employs an original stabilization mechanism of the active conformation, while it utilizes the conserved common surface area to interact with Gi, Gq, and Gs.

Free Research Field

機能生物化学

Academic Significance and Societal Importance of the Research Achievements

ETBRは創薬における標的受容体であり、心臓血管疾患、脳神経系疾患、がんなどの疾病と深くかかわる。しかしながら未だに非ペプチド性アゴニストが開発されていない。我々の研究が明らかにしたET-1結合型や阻害薬Bosentan結合型ETBR構造、ETBR－Gi複合体構造を利用してETBRのリガンド認識、活性化機構を解明することは、副作用が少ない、より選択的な作用薬の開発を加速するとともに、GPCRの活性化における新たな分子機構を提案できると考えられる。