Structural and functional analysis of the natural JNK1 inhibitor quercetagetin.
Structural and functional analysis of the natural JNK1 inhibitor quercetagetin.
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DOI：
10.1016/j.jmb.2012.10.019
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发表时间：
2013-01-23
影响因子：
5.6
通讯作者：
Lee, Ki Won
中科院分区：
文献类型：
--
作者：
Baek, Sohee;Kang, Nam Joo;Popowicz, Grzegorz M.;Arciniega, Marcelino;Jung, Sung Keun;Byun, Sanguine;Song, Nu Ry;Heo, Yong-Seok;Kim, Bo Yeon;Lee, Hyong Joo;Holak, Tad A.;Augustin, Martin;Bode, Ann M.;Huber, Robert;Dong, Zigang;Lee, Ki Won
c-Jun NH 2-末端激酶（JNK）和磷脂酰肌醇3-激酶（PI 3-K）在慢性疾病如癌症、II型糖尿病和肥胖症中起关键作用。本文通过ATP竞争性和基于IMAP的FP测定法，研究了槲皮素（3，3 ′，4 ′，5，6，7-羟基黄酮）、相关黄酮和SP 600125与JNK 1和PI 3-K的结合，并测定了槲皮素对JNK 1和PI 3-K活性的影响。槲皮素减弱了c-Jun和AKT的磷酸化，抑制了AP-1和NF-κB启动子活性，也减少了细胞转化。在两阶段皮肤癌发生小鼠模型中，它减弱了肿瘤发生率并减少了肿瘤体积。我们的晶体结构测定数据表明，槲皮苷结合到JNK 1的ATP结合位点。值得注意的是，JNK 1的Lys 55、Asp 169和Glu 73与槲皮素的儿茶酚部分之间的相互作用使JNK 1的N-末端叶重新取向，从而改善配体与其结合位点的相容性。理论对接研究的结果表明，PI 3-K与邻苯二酚部分的羟基形成氢键与p110γ催化亚基中Asp 964和Asp 841的侧链的结合模式。这些相互作用可能有助于槲皮素对PI 3-K的高抑制活性。我们的研究表明，槲皮素在预防或治疗癌症和其他慢性疾病方面具有潜在的用途。
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 IMAP-based FP 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-κB 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-Kwith the hydroxyl groups of the catechol moiety forming hydrogen bonds with the side chains of Asp964 and Asp841 in the p110γ 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.
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影响因子：
5.7
作者：
Holder, Sheldon;Zemskova, Marina;Lilly, Michael B.
通讯作者：
Lilly, Michael B.
影响因子：
16
作者：
Walker, EH;Pacold, ME;Williams, RL
通讯作者：
Williams, RL
DOI：
10.1073/pnas.91.2.609
发表时间：
1994-01-18
影响因子：
11.1
作者：
DONG, ZG;BIRRER, MJ;COLBURN, NH
通讯作者：
COLBURN, NH
影响因子：
1.8
作者：
Sportsman, JR;Gaudet, EA;Boge, A
通讯作者：
Boge, A
DOI：
10.1073/pnas.96.17.9827
发表时间：
1999-08-17
影响因子：
11.1
作者：
Young, MR;Li, JJ;Colburn, N
通讯作者：
Colburn, N