Structural Basis for Nuclear Receptor Dimer Activation Based on Multi-Molecular Interaction Analysis
| Project/Area Number |
17K08236
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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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| Research Field |
Physical pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 核内受容体 / PPAR / RXR / NMR / 転写共役因子 / PPARγ / RXRα |
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| Outline of Final Research Achievements |
In transcriptional regulation by nuclear receptors, transcriptional cofactors bind to the receptor in a ligand-dependent manner. In this study, we analyzed the effect of agonists on the selection of transcriptional cofactor-derived peptides by a heterodimer consisting of the nuclear receptor PPARγ/RXRα, which is important for metabolic regulation. We found the existence of a dynamic equilibrium in solution among multiple states where each receptor has a different binding peptide. Ligand binding to one of the receptors regulates cofactor binding to the other receptor, indicating a dynamic allosteric communication between receptors.
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| Academic Significance and Societal Importance of the Research Achievements |
核内レセプターは生活習慣病やがんの薬剤標的として重要であり、これまで多くの構造的な知見が集積されてきた。しかし核内レセプターによる転写制御は多数の分子が関わる非常に複雑な過程であり、作動薬を合理的に分子設計することは、未だ困難である。本研究で明らかとした、核内レセプターによる転写共役因子選択の新たな機構は、望ましい応答を惹起できる適切な作動薬の設計や評価に役立つと期待される。
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Report
(4 results)
Research Products
(3 results)
