Conformational dynamics of Ras using by SACLA and NMR for the development of anti-cancer drugs

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16055
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: Kobe University
• Principal Investigator: Makino Yoshiteru 神戸大学, 医学研究科, 特命助教 (80822337)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: NMR / Ras蛋白質 / SACLA/SPring-8 / 創薬科学 / 構造生命科学 / 構造生物学

Outline of Final Research Achievements

Small GTPases Ras function as a molecular switch which regulates intracellular signal transduction, including cell proliferation, differentiation, and apoptosis, through the GTP hydrolysis process. In this study, in order to obtain basic knowledge for the development of novel anti-cancer drugs targeting Ras, we performed structural dynamics analysis of Ras in the GTP hydrolysis process by SACLA, SPring-8 and nuclear magnetic resonance (NMR) spectroscopy using photo-controllable caged-GTP. As a result, we found that the unique structural dynamics of Ras may be controlling the GTP hydrolysis mechanism.

Free Research Field

構造生命科学

Academic Significance and Societal Importance of the Research Achievements

Rasはがん全体の約30%で常時活性化しており、がん治療薬の標的分子である。そのため、本研究で得られた機能―構造相関の結果は新たな創薬基盤情報となり得る。さらに、RasのGTP加水分解反応は酵素触媒反応のひとつであり、その作用メカニズムを結晶構造解析のみならず溶液、固体NMRを融合して解明した試みは、他の低分子量G蛋白質等の作用メカニズムの解明へと波及することが期待される。