Research on the molecular basis of conformational dynamics of oncogene product Ras for application to the development of its specific inhibitors
| Project/Area Number |
26293026
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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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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| Co-Investigator(Kenkyū-buntansha) |
田中 成典 神戸大学, その他の研究科, 教授 (10379480)
熊坂 崇 公益財団法人高輝度光科学研究センター, その他部局等, 研究員 (30291066)
片岡 徹 神戸大学, 医学(系)研究科(研究院), 教授 (40144472)
松本 篤幸 神戸大学, 医学(系)研究科(研究院), 助教 (00753906)
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| Co-Investigator(Renkei-kenkyūsha) |
KITAHARA Ryou 立命館大学, 薬学部, 教授 (70512284)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
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| Keywords | 医薬分子設計 / 分子標的薬 / がん / シグナル伝達 / がん遺伝子 / 癌 |
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| Outline of Final Research Achievements |
ras proto-oncogene products Ras, is a member of small GTPases, which is frequently activated in a wide variety of human cancers, making them promising anti-cancer drug targets. In the present study, we determined the novel druggable pocket structure of Ras by Synchrotron X-ray crystallography utilizing Humid Air and Glue-coating (HAG) mounting method, which unveiled the molecular basis of conformational transition between the open and closed pocket structures. Molecular Dynamics simulation of the solved structures lead us to a reasonable agreement with experimental observations and the consequent scenarios on the transition. Further, crystal structure analysis of Ras/fragment-compound complex by cross-linking method gave us useful information on the structure-based design of Ras inhibitors.
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Report
(4 results)
Research Products
(4 results)
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[Journal Article] Integrin-α10 dependency identifies RAC and RICTOR as therapeutic targets in high-grade myxofibrosarcoma.2016
Author(s)
Okada T, Lee AY, Qin LX, Agaram N, Mimae T, Shen Y, O'Connor R, López-Lago MA, Craig A, Miller ML, Agius P, Molinelli E, Socci ND, Crago AM, Shima F, Sander C, Singer S.
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Journal Title
Cancer Discov.
Volume: 6
Issue: 10
Pages: 1148-1165
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Molecular Mechanism for Conformational Dynamics of Ras·GTP Elucidated from In-Situ Structural Transition in Crystal.2016
Author(s)
Matsumoto S, Miyano N, Baba S, Liao J, Kawamura T, Tsuda C, Takeda A, Yamamoto M, Kumasaka T, Kataoka T, Shima F.
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Journal Title
Sci Rep.
Volume: -
Issue: 1
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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