Structural and Functional Analysis of the Natural JNK1 Inhibitor Quercetagetin

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• 作者：Sohee Baek¹ ; ² ; ³ ; ^&dagger ; ; Nam Joo Kang⁴ ; ⁵ ; ^&dagger ; ; Grzegorz M. Popowicz¹ ; Marcelino Arciniega¹ ; ² ; Sung Keun Jung⁵ ; Sanguine Byun⁵ ; ⁶ ; Nu Ry Song⁵ ; ⁶ ; Yong-Seok Heo⁷ ; Bo Yeon Kim⁸ ; Hyong Joo Lee⁶ ; Tad A. Holak¹ ; ⁹ ; Martin Augustin¹⁰ ; Ann M. Bode⁵ ; Robert Huber¹ ; ² ; ¹¹ ; ¹² ; Zigang Dong⁵ ; ^{zgdong@hi.umn.edu} ; Ki Won Lee³ ; ⁶ ; ^{kiwon@snu.ac.kr}
• 关键词：JNK ; c-Jun NH2-terminal kinase ; PI3-K ; phosphatidylinositol 3-kinase ; IMAP ; immobilized metal ion affinity-based fluorescence polarization ; ERK ; extracellular signal-regulated kinase ; AP-1 ; activator protein-1 ; PDB ; Protein Data Bank
• 刊名：Journal of Molecular Biology
• 出版年：2013
• 出版时间：23 January, 2013
• 年：2013
• 卷：425
• 期：2
• 页码：411-423
• 全文大小：1362 K

文摘

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¡ä,4¡ä,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-¦ÊB 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 p110¦Ã 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.