Allosteric modulators that recognize the transition-states of receptor channels
| Project/Area Number |
18K06945
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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 48040:Medical biochemistry-related
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| Research Institution | The University of Tokyo (2020-2021)
National Institute of Advanced Industrial Science and Technology (2018-2019) |
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Principal Investigator |
Kubo Tai 東京大学, 大学院新領域創成科学研究科, 特任研究員 (10178030)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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)
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| Keywords | アロステリック / アセチルコリン受容体 / 進化工学 / 分子動態 / 遷移状態 |
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| Outline of Final Research Achievements |
To establish the new drug development platform for the allosteric modulators, in vitro evolution (IVE) technology and a single molecular dynamic study were applied to the neuronal nicotinic acetylcholine receptor (nAChR) alpha 7. The nAChR alpha 7 molecules undergo molecular dynamic motions with/without ligands. In our previous study, both the agonistic and antagonistic receptor ligands were successfully identified by IVE technology from the three-finger (3-F) scaffold-based library. Thus, the alpha 7 binder peptides that recognize the various dynamic states were screened from the library. The candidate peptides were under investigation to characterize the positive/negative allostericity of the nAChR alpha 7. Diffracted X-ray Tracking method was applied to study the transition states of alpha 7 receptor, and ivermectine, one of the Positive Allosteric Modulators (PAMs), showed to induce molecular motions to the receptor distinct from the ligand acetylcholine.
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| Academic Significance and Societal Importance of the Research Achievements |
現在進められている創薬研究の多くは、標的となるタンパク質の活性中心やリガンドポケットを狙う、所謂「オルソステリック創薬」が中心となっている。一方この方法では、リガンド結合領域を含む機能領域の配列や構造が類似するファミリータンパク質において広く作用することが多く、これに起因する副作用問題が重大な課題となっている。本研究では、タンパク質が生体機能を発揮する過程で分子がダイナミックに分子内運動をすることに着目し、その遷移状態を特異的に認識するペプチドを創製することにより、従来の問題を回避する新たな創薬「アロステリック創薬」のプラットフォームを確立するための基盤となる。
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Report
(5 results)
Research Products
(15 results)
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[Journal Article] Diffracted X-ray blinking tracks single protein motions2018
Author(s)
Sekiguchi, H., Kuramochi, M., Ikesaki, K., Okamura, Y., Yoshimura, K., Matsubara, K., Chang, J. W., Ohta, N., Kubo, T., Mio, K., Suzuki, Y., Chavas, L. M., & Sasaki, Y.
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Journal Title
Scientific Reports
Volume: 8
Issue: 1
Pages: 1709-1709
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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