Inhibition of transcription factor NF-κB by sesquiterpene lactones:: a proposed molecular mechanism of action
Inhibition of transcription factor NF-κB by sesquiterpene lactones:: a proposed molecular mechanism of action
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DOI：
10.1016/s0968-0896(99)00195-9
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发表时间：
1999-11-01
影响因子：
3.5
通讯作者：
Schmidt, TJ
中科院分区：
文献类型：
--
作者：
Rüngeler, P;Castro, V;Schmidt, TJ
许多倍半萜内酯（SL）具有相当大的抗炎活性。它们可能通过与半胱氨酸残基反应选择性烷基化其p65亚基来抑制转录因子NF-κ B。在这里，我们测定了28种倍半萜内酯抑制NF-κ B的能力。大多数有效的NF-κ B抑制剂具有亚甲基-γ-内酯基团和α，β-或α，β，γ，δ-不饱和羰基基团形式的两个反应中心。基于计算机分子模拟，我们提出了一个分子的作用机制，这是能够解释的SL的p65的选择性和所观察到的相关性的高活性与烷化剂的双功能性。单个双功能SL分子可以烷基化DNA结合环1（L1）中的半胱氨酸残基（Cys 38）和附近E'区中的另一个半胱氨酸（Cys 120）。这种交联改变了酪氨酸36和其他氨基酸的位置，使得它们与DNA的特异性相互作用变得不可能。我们还创建了一个单功能SL的模型。(C)1999爱思唯尔科技有限公司。保留所有权利。
Many sesquiterpene lactones (SLs) possess considerable anti-inflammatory activity. They inhibit the transcription factor NF-kappa B by selectively alkylating its p65 subunit probably by reacting with cysteine residues. Here we assayed 28 sesquiterpene lactones for their ability to inhibit NF-kappa B. The majority of the potent NF-kappa B inhibitors possess two reactive centers in form of an amethylene-gamma-lactone group and an alpha,beta- or alpha,beta,gamma,delta-unsaturated carbonyl group. Based on computer molecular modelling we propose a molecular mechanism of action, which is able to explain the p65 selectivity of the SLs and the observed correlation of high activity with alkylant bifunctionality. A single bifunctional SL molecule can alkylate the cysteine residue (Cys 38) in the DNA binding loop 1 (L1) and a further cysteine (Cys 120) in the nearby E' region. This cross link alters the position of tyrosine 36 and additional amino acids in such a way that their specific interactions with the DNA become impossible. We also created a model for monofunctional SLs. (C) 1999 Elsevier Science Ltd. All rights reserved.