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  Structural and Functional Analysis of the Natural JNK1 Inhibitor Quercetagetin

Baek, S., Kang, N. J., Popowicz, G. M., Arciniega Castro, M., Jung, S. K., Byun, S., et al. (2013). Structural and Functional Analysis of the Natural JNK1 Inhibitor Quercetagetin. JOURNAL OF MOLECULAR BIOLOGY, 425(2), 411-423. doi:10.1016/j.jmb.2012.10.019.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-ED5C-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-ED5D-7
Genre: Journal Article

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 Creators:
Baek, Sohee1, Author              
Kang, Nam Joo2, Author
Popowicz, Gregorz Maria1, Author              
Arciniega Castro, Marcelino3, Author              
Jung, Sung Keun2, Author
Byun, Sanguine2, Author
Song, Nu Ry2, Author
Heo, Yong-Seok2, Author
Kim, Bo Yeon2, Author
Lee, Hyong Joo2, Author
Holak, Tad A.1, Author              
Augustin, Martin2, Author              
Bode, Ann M.2, Author
Huber, Robert3, Author              
Dong, Zigang2, Author
Lee, Ki Won2, Author
Affiliations:
1Holak, Tad / NMR Spectroscopy, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565154              
2external, ou_persistent22              
3Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              

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Free keywords: INDUCED TRANSFORMATION; AP-1 ACTIVITY; KINASE; CANCER; REFINEMENT; ACTIVATION; DOCKING; PATHWAY; GLIDE; CELLS
 Abstract: c-Jun NH2-terminal kinases (JNKs) and phosphatidylinositol 3-kinase (PI3-K) play critical roles in chronic diseases such as cancer, type II diabetes, and obesity. We describe here the binding of quercetagetin (3,3',4',5,6,7-hydroxyflavone), related flavonoids, and SP600125 to JNK1 and PI3-K by ATP-competitive and immobilized metal ion affinity-based fluorescence polarization assays and measure the effect of quercetagetin on JNK1 and PI3-K activities. Quercetagetin attenuated the phosphorylation of c-Jun and AKT, suppressed AP-1 and NF-kappa B promoter activities, and also reduced cell transformation. It attenuated tumor incidence and reduced tumor volumes in a two-stage skin carcinogenesis mouse model. Our crystallographic structure determination data show that quercetagetin binds to the ATP-binding site of JNK1. Notably, the interaction between Lys55, Asp169, and Glu73 of JNK1 and the catechol moiety of quercetagetin reorients the N-terminal lobe of JNK1, thereby improving compatibility of the ligand with its binding site. The results of a theoretical docking study suggest a binding mode of PI3-K with the hydroxyl groups of the catechol moiety forming hydrogen bonds with the side chains of Asp964 and Asp841 in the p110y catalytic subunit. These interactions could contribute to the high inhibitory activity of quercetagetin against PI3-K. Our study suggests the potential use of quercetagetin in the prevention or therapy of cancer and other chronic diseases. (C) 2012 Elsevier Ltd. All rights reserved.

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Language(s): eng - English
 Dates: 2013-01-23
 Publication Status: Published in print
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000315305700015
DOI: 10.1016/j.jmb.2012.10.019
 Degree: -

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Title: JOURNAL OF MOLECULAR BIOLOGY
Source Genre: Journal
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Publ. Info: 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND : ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Pages: - Volume / Issue: 425 (2) Sequence Number: - Start / End Page: 411 - 423 Identifier: ISSN: 0022-2836