Structural and Functional Analysis of the Natural JNK1 Inhibitor Quercetagetin

被引：46

作者：

Baek, Sohee ^{[1
,2
,3
]}

Kang, Nam Joo ^{[4
,5
]}

Popowicz, Grzegorz M. ^{[1
]}

Arciniega, Marcelino ^{[1
,2
]}

Jung, Sung Keun ^{[5
]}

Byun, Sanguine ^{[5
,6
]}

Song, Nu Ry ^{[5
,6
]}

Heo, Yong-Seok ^{[7
]}

Kim, Bo Yeon ^{[8
]}

Lee, Hyong Joo ^{[6
]}

Holak, Tad A. ^{[1
,9
]}

Augustin, Martin ^{[10
]}

Bode, Ann M. ^{[5
]}

Huber, Robert ^{[1
,2
,11
,12
]}

Dong, Zigang ^{[5
]}

Lee, Ki Won ^{[3
,6
]}

机构：

[1] Max Planck Inst Biochem, D-82152 Martinsried, Germany

[2] Tech Univ Munich, Dept Chem, D-85748 Garching, Germany

[3] Seoul Natl Univ, Adv Inst Convergence Technol, Suwon 443270, South Korea

[4] Kyungpook Natl Univ, Sch Appl Biosci, Taegu 702701, South Korea

[5] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA

[6] Seoul Natl Univ, Dept Agr Biotechnol, WCU Biomodulat Major, Seoul 151921, South Korea

[7] Konkuk Univ, Dept Chem, Seoul 143701, South Korea

[8] Korea Res Inst Biosci & Biotechnol, Chem Biol Res Ctr, Cheongwongun 363883, South Korea

[9] Jagiellonian Univ, Dept Chem, PL-30060 Krakow, Poland

[10] Proteros Biostruct GmbH, D-82152 Martinsried, Germany

[11] Cardiff Univ, Sch Biosci, Cardiff CF10 3US, S Glam, Wales

[12] Univ Duisburg Essen, Ctr Med Biotechnol, D-45117 Essen, Germany

来源：

JOURNAL OF MOLECULAR BIOLOGY | 2013年 / 425卷 / 02期

基金：

美国国家卫生研究院;

关键词：

INDUCED TRANSFORMATION; AP-1; ACTIVITY; KINASE; CANCER; REFINEMENT; ACTIVATION; DOCKING; PATHWAY; GLIDE; CELLS;

D O I：

10.1016/j.jmb.2012.10.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：411 / 423

页数：13

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