| Project/Area Number |
17K15106
|
|---|
| Research Category |
Grant-in-Aid for Young Scientists (B)
|
| Allocation Type | Multi-year Fund |
|---|
| Research Field |
Biophysics
|
|---|
| Research Institution | Kyoto University (2021)
Institute of Physical and Chemical Research (2018-2020)
Kobe University (2017) |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2017-04-01 – 2022-03-31
|
| Project Status |
Completed (Fiscal Year 2021)
|
| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
|
|---|
| Keywords | Ras / がん変異体 / X線結晶構造解析 / 分子動力学計算 / 動的平衡 / state transition / 分子動力学シミュレーション / 立体構造 / State遷移 / ダイナミクス / NMR |
|---|
| Outline of Final Research Achievements |
GTP-bound forms of Ras proteins adopt two interconverting conformations, “inactive” state 1 and “active” state 2. The crystal structure of wild-type H-Ras in state 1 showed that Gln61, on which an oncogenic mutation frequently occurs, plays a central role in its conformational stabilization. Here, aiming at investigating the relationships between the representative mutations, Q61L and Q61H, and their activation mechanism, we determine their crystal structures in state 1, and carry out the molecular dynamics simulations to obtain the dynamics properties. The results show that these mutations induce rearrangements of the interaction manners in the neighboring regions, and further, Q61L mutation results in acquirement of “active” state 2-like structural features.
|
| Academic Significance and Societal Importance of the Research Achievements |
低分子量GTPaseであるがん遺伝子産物Rasは、ヒトのがん全体の20－30%において突然変異による恒常的活性化が見られることから、学術的側面のみならずがん治療薬開発の標的として社会的に重要な生体高分子である。これまで変異によるRasの恒常的活性化メカニズムはGTP加水分解活性の低下の側面から主に議論されてきた。本研究の成果はがん変異により引き起こされる構造的特徴の変調を介した別の活性化メカニズムの存在を示唆しており、新たな作用機序を持つ分子標的薬開発のための手掛かりを与えるかもしれない。
|
