2021 Fiscal Year Final Research Report
Atomic-scale dynamic structural analysis of Ras by SACLA, which provide promising information on designing cancer therapeutic agents
| Project/Area Number |
19K06525
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 43020:Structural biochemistry-related
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| Research Institution | Kobe University |
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Principal Investigator |
Shima Fumi 神戸大学, 科学技術イノベーション研究科, 教授 (60335445)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 分子動画 / がん遺伝子産物 / Ｘ線自由電子レーザー / Ｘ線結晶構造解析 / 核磁気共鳴法 / シグナル伝達 |
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| Outline of Final Research Achievements |
Small GTPase Ras functions as a molecular switch by cycling between GTP-bound active and GDP-bound inactive forms in cell signaling pathways. Despite its importance as a cancer driver gene product, dedicated efforts to directly target Ras for decades still have not yielded therapeutic efficacy, due to limited structural information on natural GTP-bound Ras and its ‘undruggable’ nature of drug-binding site, i.e., structural dynamics hampering stable drug-binding, that is intriguingly linked to its GTP hydrolysis activity. Here to elucidate structural dynamics of natural GTP-bound Ras, we performed time-dependent structural analysis of photo-controllable caged-GTP-bound Ras on GTP hydrolysis process by SACLA, SPring-8 and NMR. Photo-irradiation to caged-GTP-bound Ras yielded natural GTP-bound Ras, leading to GTP hydrolysis for production of Ras-GDP. These results provide new insight into the structural dynamics of Ras, realizing novel strategies for development of Ras inhibitors.
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| Free Research Field |
分子生物学
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| Academic Significance and Societal Importance of the Research Achievements |
Rasの機能攻略の難易度の高さの一要因として、他の抗がん剤の標的の薬剤結合ポケットにはない大きな揺らぎ＝開閉運動の存在があげられる。ここでは、申請者が同定したリード化合物（特許取得済）の効率的な構造最適化を可能にするために、最新鋭のX線自由電子レーザー施設SACLAとPring-8をフル利用し、従来技術では解析困難だったRasの活性制御に直結した薬剤結合ポケットの開閉運動の構造ダイナミクスを原子スケールで解明する。Rasの構造・活性変化の世界初の原子レベルでのコマ撮り動画が作成できれば学術的インパクトは大きく、Ras阻害剤の構造デザインに活用できれば、健康社会への貢献も極めて大である。
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