Reaction mechanism and inhibitor development of a histone demethylase

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K21626
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Chemical biology; Molecular biology
• Research Institution: Yokohama City University (2018); Institute of Physical and Chemical Research (2015-2017)
• Principal Investigator: Sengoku Toru 横浜市立大学, 医学部, 講師 (60576312)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: エピジェネティクス / 酵素 / 阻害剤開発

Outline of Final Research Achievements

Small molecules that control post-translational modification of proteins are useful as biological research tools and have rich potential as lead compounds for drug discovery. In this study, for the following two types of enzymes involved in modification of basic residues, we aimed at understanding the reaction mechanism of the enzymes and developing inhibitors of following two modification enzymes. We performed structural analysis and inhibitor development of histone H3K27 demethylase KDM6A and found that one of the compounds obtained by in silico screening inhibited the proliferation of glioma cells with abnormal H3K27 methylation. We also determined the structure of the arginine rhamnosyltransferase EarP in complex with its target protein, translation factor EF-P, and elucidated the structural basis of its reaction mechanism.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では予備的ながら細胞実験でグリオーマ細胞の増殖を抑制する活性を持ったKDM6阻害剤候補化合物を見出すことができた。本化合物の化学構造を最適化することにより、実験ツールや薬剤候補化合物として有用な分子の創出につながると期待される。また、本研究で解明されたラムノース転移酵素の新規反応機構は、様々な種類の糖転移酵素に幅広く共有される基本的な機構であると考えられると同時に、その新規阻害剤のデザインに有用な情報を提供する。