Structural analysis of in vivo protein-ligand interactions by 19F-NMR and PRE
Project/Area Number |
17K07298
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Structural biochemistry
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Research Institution | Tohoku University |
Principal Investigator |
Koshiba Seizo 東北大学, 未来型医療創成センター, 教授 (70332301)
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Project Period (FY) |
2017-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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)
|
Keywords | NMR / クライオ電子顕微鏡 / 動的構造 / Keap1 / PAH / In-Cell NMR / 19F-NMR / 酵素 |
Outline of Final Research Achievements |
For Keap1-Nrf2 system, we investigated the mechanism of Nrf2 activation by NMR and found that Nrf2 is dissociated from Keap1 by non-electrophilic inhibitors (Nrf2 inducers) or p62, but is not by electrophilic inhibitors, such as CDDO-Im. While there are two Keap1-binding sites (DLGex and ETGE motifs) in Nrf2, these non-electrophilic inhibitors preferentially inhibit the interaction of DLGex, resulting to the intermediate state in which only one binding site, ETGE motif, interacts with Keap1. These results indicate that there are several Nrf2-activation mechanisms and non-electrophilic inhibitors activate Nrf2 by using "Hinge-Latch mechanism". This study provides significant insights for the pharmacological development of new Nrf2 inducers.
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Academic Significance and Societal Importance of the Research Achievements |
本研究では、生体内におけるストレス応答システムKeap1-Nrf2経路を対象に、各種化合物によるNrf2の活性化のメカニズムの詳細を高次構造変化の視点から明らかにした。Keap1-Nrf2は生体内において様々な疾患に関わることが報告されており、創薬ターゲットとして世界中で研究開発が進められている。本研究成果は今後の創薬開発において重要な情報を提供するものである。
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Report
(7 results)
Research Products
(49 results)
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[Journal Article] Plasma metabolic disturbances during pregnancy and postpartum in women with depression2022
Author(s)
Z Yu, N Matsukawa, D Saigusa, I. N. Motoike, C Ono, Y Okamura, T Onuma, Y Takahashi, M Sakai, H Kudo, T Obara, K Murakami, M Shirota, S Kikuchi, N Kobayashi, Y Kikuchi, J Sugawara, N Minegishi, S Ogishima, K Kinoshita, M Yamamoto, N Yaegashi, S Kuriyama, S Koshiba, H Tomita
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Journal Title
iScience
Volume: 25(12)
Issue: 12
Pages: 105666-105666
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Study Profile of the Tohoku Medical Megabank Community-Based Cohort Study2021
Author(s)
Hozawa A, Tanno K, Nakaya N, Nakamura T, Tsuchiya N, Hirata T, Narita A, Kogure M, Nochioka K, Sasaki R, Takanashi N, Otsuka K, Sakata K, Kuriyama S, Kikuya M, 13名略, Kobayashi T, 53名略, Yamamoto M.
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Journal Title
Journal of Epidemiology
Volume: 31
Issue: 1
Pages: 65-76
DOI
NAID
ISSN
0917-5040, 1349-9092
Year and Date
2021-01-05
Related Report
Peer Reviewed / Open Access
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[Journal Article] Comparison of kit-based metabolomics with other methodologies in a large cohort, towards establishing reference values.2021
Author(s)
Saigusa D*, Hishinuma E, Matsukawa N, Takahashi M, Inoue J, Tadaka S, Motoike I N, Hozawa A, Izumi Y, Bamba T, Kinoshita K, Ekroos K, Koshiba S, Yamamoto M.
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Journal Title
Metabolites
Volume: 11(10)
Issue: 10
Pages: 652-652
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): rationale, progress and perspective.2020
Author(s)
Kuriyama S, Metoki H, Kikuya M, Obara T, Ishikuro M, Yamanaka C, Nagai M, Matsubara H, Kobayashi T, 57名略, Yamamoto M.
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Journal Title
Int J Epidemiol.
Volume: 49(1)
Issue: 1
Pages: 18-19
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Maternity Log study: a longitudinal lifelog monitoring and multiomics analysis for the early prediction of complicated pregnancy2019
Author(s)
Sugawara J, Ochi D, Yamashita R, Yamauchi T, Saigusa D, Wagata M, Obara T, Ishikuro M, Tsunemoto Y, 18名略, Hiyama S, Nagasaki M
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Journal Title
BMJ Open
Volume: 9(2)
Issue: 2
Pages: e025939-e025939
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Metabolomic changes in the mouse retina after optic nerve injury.2018
Author(s)
Sato K, Saigusa D, Saito R, Fujioka A, Nakagawa Y, Nishiguchi KM, Kokubun T, Motoike IN, Maruyama K, Omodaka K, Shiga Y, Uruno A, Koshiba S, Yamamoto M, Nakazawa T.
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Journal Title
Sci Rep
Volume: 8
Issue: 1
Pages: 11930-11930
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2,049 individuals2018
Author(s)
Y Yamaguchi-Kabata, J Yasuda, O Tanabe, Y Suzuki, H Kawame, N Fuse, M Nagasaki, Y Kawai, K Kojima, F Katsuoka, S Saito, I Danjoh, I Motoike, R Yamashita, S Koshiba, D Saigusa, G Tamiya, S Kure, N Yaegashi, Y Kawaguchi, F Nagami, S Kuriyama, J Sugawara, N Minegishi, A Hozawa, T Takai-Igarashi, K Kinoshita, M Yamamoto.
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Journal Title
Journal of Human Genetics.
Volume: 63
Issue: 2
Pages: 213-230
DOI
Related Report
Peer Reviewed / Open Access
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