Small-molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling

被引:166
作者
Hayashi, Ken-ichiro [1 ]
Tan, Xu [3 ]
Zheng, Ning [3 ]
Hatate, Tatsuya [1 ]
Kimura, Yoshio [1 ]
Kepinski, Stefan [2 ]
Nozaki, Hiroshi [1 ]
机构
[1] Okayama Univ Sci, Dept Biochem, Okayama 7000005, Japan
[2] Univ Leeds, Fac Biol Sci, Ctr Plant Sci, Leeds LS2 9JT, W Yorkshire, England
[3] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA
基金
英国生物技术与生命科学研究理事会;
关键词
chemical biology; TIR1; ubiquitin ligase; SCF; plant hormones;
D O I
10.1073/pnas.0711146105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:5632 / 5637
页数:6
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