Small-molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling
Small-molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling
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DOI：
10.1073/pnas.0711146105
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发表时间：
2008-04-08
影响因子：
11.1
通讯作者：
Nozaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Hayashi, Ken-ichiro;Tan, Xu;Nozaki, Hiroshi
生长素对基因表达的调控是植物发育的重要机制。我们已经证明拟南芥F-box蛋白TIR1是生长素的受体，我们最近的结构研究揭示了生长素感知的分子机制。TIR1是泛素连接酶复合物SCIF TIR1的底物受体。生长素结合增强了TIR1与其底物Aux/IAA抑制因子之间的相互作用，从而促进了Aux/IAA的泛素化和降解，改变了数百个基因的表达。TIR1是一类新的激素受体的原型，也是第一个由小分子调节的SCF泛素连接酶的例子。在这里，我们描述了一系列生长素激动剂和拮抗剂的设计、合成和表征。我们发现这些分子对拟南芥中TIR1介导的事件具有特异性，并且它们与TIR1结合的作用模式通过x射线晶体学分析得到了证实。此外，我们证明了这些探针在苔藓小立藓tir1介导的生长素信号分析中的实用性。我们的工作不仅为植物化学生物学提供了一个有用的工具，而且还展示了一个特定的小分子F-box蛋白底物募集抑制剂的例子。scf型泛素连接酶对底物的识别和随后的泛素化对真核生物的许多细胞过程至关重要，泛素连接酶的功能在几种人类疾病中受到影响。但这项工作支持了一种观点，即设计小分子药物来治疗性地调节泛素连接酶的功能是可能的。
The regulation of gene expression by the hormone auxin is a crucial mechanism in plant development. We have shown that the Arabidopsis F-box protein TIR1 is a receptor for auxin, and our recent structural work has revealed the molecular mechanism of auxin perception. TIR1 is the substrate receptor of the ubiquitin-ligase complex SCIF TIR1. Auxin binding enhances the interaction between TIR1 and its substrates, the Aux/IAA repressors, thereby promoting the ubiquitination and degradation of Aux/IAAs, altering the expression of hundreds of genes. TIR1 is the prototype of a new class of hormone receptor and the first example of an SCF ubiquitin-ligase modulated by a small molecule. Here, we describe the design, synthesis, and characterization of a series of auxin agonists and antagonists. We show these molecules are specific to TIR1-mediated events in Arabidopsis, and their mode of action in binding to TIR1 is confirmed by x-ray crystallographic analysis. Further, we demonstrate the utility of these probes for the analysis of TIR1-mediated auxin signaling in the moss Physcomitrella patens. Our work not only provides a useful tool for plant chemical biology but also demonstrates an example of a specific small-molecule inhibitor of F-box protein-substrate recruitment. Substrate recognition and subsequent ubiquitination by SCF-type ubiquitin ligases are central to many cellular processes in eukaryotes, and ubiquitin-ligase function is affected in several human diseases. bur work supports the idea that it may be possible to design small-molecule agents to modulate ubiquitin-ligase function therapeutically.