title: Small-molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling.
abstract: 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 SCF(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. Our work supports the idea that it may be possible to design small-molecule agents to modulate ubiquitin-ligase function therapeutically.
authors.affiliation: Department of Biochemistry, Okayama University of Science, Okayama 700-0005, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Xu
authors.initials: X
authors.lastname: Tan
authors.forename: Ning
authors.initials: N
authors.lastname: Zheng
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hatate
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kimura
authors.forename: Stefan
authors.initials: S
authors.lastname: Kepinski
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nozaki
mesh_terms: D029681:Arabidopsis Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D019068:Bryopsida; D018360:Crystallography, X-Ray; D044783:F-Box Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007210:Indoleacetic Acids / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D054875:Ubiquitination
chemical_list: D029681:Arabidopsis Proteins; D044783:F-Box Proteins; D007210:Indoleacetic Acids; D011956:Receptors, Cell Surface; C501405:TIR1 protein, Arabidopsis