Elucidation of cytoprotective mechanisms by structural analysis of stress sensor Keap1

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K19417
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Tohoku University
• Principal Investigator: Yamamoto Masayuki 東北大学, 医学系研究科, 教授 (50166823)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Keywords: ストレス応答

Outline of Final Research Achievements

Stress sensor Keap1 is a key factor that controls ubiquitination reaction of transcription factor Nrf2 and plays a central role in the stress defense mechanism. Keap1 regulates Nrf2 ubiquitination in response to various stress stimuli. Regarding the molecular basis of the stress response, it has been suggested that the structural change of the Keap1 protein is the key, but the details are unknown. In this study, we aimed to clarify how the activity of the ubiquitin ligase complex containing Keap1 is inactivated by stress stimulation, and challenged to elucidate the molecular mechanism of Nrf2 activation in our body.

Free Research Field

医化学

Academic Significance and Societal Importance of the Research Achievements

Keap1のストレス感知機構を構造生物学的に理解することは、現在大きく展開中のNrf2誘導剤の創薬開発に有益な情報を提供する。Nrf2誘導剤はストレス防御・疾患予防などへの応用が期待されているが、これまで開発されてきたNrf2誘導剤には特異性の問題点が指摘されている。Keap1に特異的に反応しNrf2を活性化できる化合物を開発することができれば、より副作用の少ない安全なNrf2誘導剤の開発につながるものと期待される。この点で、本研究の成果は有益な創薬ツールを提供する。