Chemical regulation of intrinsically disordered proteins in animal and plant cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02077
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: Shinshu University
• Principal Investigator: Ohkanda Junko 信州大学, 学術研究院農学系, 教授 (50233052)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 天然変性蛋白質 / 蛋白質間相互作用 / リン酸化翻訳後修飾 / 概日時計転写因子 / フシコクシン / 不可逆的阻害剤 / 植物成長促進剤

Outline of Final Research Achievements

Naturally denatured proteins (IDPs), which do not have a fixed structure under physiological conditions, are extremely important players in biological reactions and have attracted attention as new drug targets because of their involvement in various diseases. However, there is no rational IDP drug discovery strategy due to experimental difficulties. In this study, we prepared a library of electrophilic small molecules and identified compounds that significantly inhibit the interaction between the circadian clock transcription factor BMAL1 and CLOCK. We also focused on 14-3-3, a regulatory protein of phosphorylated IDPs, and succeeded in creating 14-3-3 sigma-selective fluorescent labeling agents that react with specific cysteine residues. We also succeeded in promoting plant growth with a compound that stabilizes the 14-3-3/IDP interaction in plant guard cells.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

天然変性蛋白質(IDP)についてはその生物学的役割の重要性と多様な疾患との関りが明らかにされつつある一方で、構造情報が欠けまた実験的な扱いが難しいことから従来の創薬技術が適用できない創薬困難な標的として知られる。本研究の成果は、IDPの制御においては共有結合反応性の不可逆的阻害剤の有効性を示した点、IDPの制御因子側に着目した化学戦略によりIDP選択的な化学制御の可能性を示唆した点、さらに植物体内のIDP相互作用の安定化により個体成長を促進可能であることを証明した点において、創薬及び農学の見地から学術的意義および社会的意義があると考えられる。