| Project/Area Number |
19K23721
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0701:Biology at molecular to cellular levels, and related fields
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| Research Institution | Tokyo Institute of Technology |
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Principal Investigator |
TRAN PHUOC DUY 東京工業大学, 生命理工学院, 助教 (50848546)
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| Project Period (FY) |
2019-08-30 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | a/dPaCS-MD / p53 / IDP / docking / koff / p53 protein / A2a receptor / eePaCS-MD / PaCS-MD / kinetic rate calculation / association simulation / dissociation simulation / DNA scanning / MD simulation / Markov State Model |
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| Outline of Research at the Start |
The oligomerization of p53 with itself (homo-) and other proteins (hetero-) determines whether it trigger the biological process or not. Specifically, we focus on three questions related to the oligomerization of p53 whether the oligomerization taking place on DNA from p53 monomers or not; whether the hetero-oligomer of p53 can still scanning the DNA; and is the DNA scanning style of p53 “spider-walk-on-the-roop” or “sliding-on-the-track”?
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| Outline of Final Research Achievements |
We developed the method to investigate the association and dissociation pathway of intrinsically disordered region of protein (IDR) to the targeted protein, and apply this method to p53 target. We find the detailed atomic mechanism of association and dissociation pathway through multiple states in which the IDR first perform the conformational selection to find the correct binding pocket following by the induced fitting mechanism to enter the correct native bound conformation. In the final state, the dehydration of the binding interfaces and secondary structure formation greatly contribute to the formation of the native bound structure. In addition, our recently developed method has ability to estimate the residence time in agreement with experimental data.
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| Academic Significance and Societal Importance of the Research Achievements |
This research results provide detailed atomic structures of TAD-p53 bound to MDM2 which can potentially treat as drug target to help to prevent the p53 related diseases such as cancer and neurodegenerative diseases.
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