Studies of prerequisites for ETB agonists to accelerate anti-cancer therapy

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K07172
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Kyoto University
• Principal Investigator: Doi Tomoko 京都大学, 理学研究科, 准教授 (00397580)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: ペプチドGPCR / シグナル伝搬

Outline of Final Research Achievements

The peptide hormone endothelin regulates vascular tone and humoral homeostasis. The endothelin type B receptor (ETB), a G-protein coupled receptor (GPCR) was thermostabilized by introducing 4~5 mutations, which allowed crystallization of ET-1-bound and an antagonist, bosentan-bound ETB structures. Based on these structures, structure-function studies of ETB were carried out biochemically and pharmacologically. The results showed that the C-terminal 5 residues of ET-1 bound to the ETB transmembrane core tightly, responsible for high-affinity binding and high potency, whereas Y13 and F14 in the helical region of ET-1 were prerequisites for the full activation of ETB via interactions near the extracellular side. Furthermore, the hydrogen-bond networks observed in the transmembrane region of ETB changed from the bosentan-bound to the ET-1 bound structures and the interactions formed among these residues were essential for the full activation of ETB receptor.

Free Research Field

機能生物化学

Academic Significance and Societal Importance of the Research Achievements

ETB経路は、その血管弛緩作用から抗がん剤の効果を高め副作用を低減させる作用が、がん治療において期待されている。しかしながら未だにETB作用薬の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ETB構造を利用してリガンド認識、活性化機構を検証することは、独自のより選択的なETB作動薬の開発を加速して、がん治療法の進歩に寄与できると考えられる。