Structural analysis of in vivo protein-ligand interactions by 19F-NMR and PRE

2022 Fiscal Year Final Research Report

• Project/Area Number: 17K07298
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: Tohoku University
• Principal Investigator: Koshiba Seizo 東北大学, 未来型医療創成センター, 教授 (70332301)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Keywords: NMR / クライオ電子顕微鏡 / 動的構造 / Keap1 / PAH

Outline of Final Research Achievements

For Keap1-Nrf2 system, we investigated the mechanism of Nrf2 activation by NMR and found that Nrf2 is dissociated from Keap1 by non-electrophilic inhibitors (Nrf2 inducers) or p62, but is not by electrophilic inhibitors, such as CDDO-Im. While there are two Keap1-binding sites (DLGex and ETGE motifs) in Nrf2, these non-electrophilic inhibitors preferentially inhibit the interaction of DLGex, resulting to the intermediate state in which only one binding site, ETGE motif, interacts with Keap1. These results indicate that there are several Nrf2-activation mechanisms and non-electrophilic inhibitors activate Nrf2 by using "Hinge-Latch mechanism". This study provides significant insights for the pharmacological development of new Nrf2 inducers.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、生体内におけるストレス応答システムKeap1-Nrf2経路を対象に、各種化合物によるNrf2の活性化のメカニズムの詳細を高次構造変化の視点から明らかにした。Keap1-Nrf2は生体内において様々な疾患に関わることが報告されており、創薬ターゲットとして世界中で研究開発が進められている。本研究成果は今後の創薬開発において重要な情報を提供するものである。