3C6N

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

Summary for 3C6N

• Entry DOI: 10.2210/pdb3c6n/pdb
• Related: 3C6O 3C6P
• Descriptor: SKP1-like protein 1A, TRANSPORT INHIBITOR RESPONSE 1, INOSITOL HEXAKISPHOSPHATE, ... (5 entities in total)
• Functional Keywords: auxin, ubiquitin ligase, small molecules, plant physiology, chemical biology, auxin signaling pathway, chromosome partition, cytoplasm, cytoskeleton, developmental protein, ethylene signaling pathway, nucleus, ubl conjugation pathway, cell cycle, leucine-rich repeat, plant defense, signaling protein
• Biological source: Arabidopsis thaliana (thale cress); More
• Total number of polymer chains: 2
• Total formula weight: 85785.99

Authors

Tan, X.,Zheng, N.,Hayashi, K. (deposition date: 2008-02-04, release date: 2008-04-22, Last modification date: 2023-08-30)

Primary citation

Hayashi, K.,Tan, X.,Zheng, N.,Hatate, T.,Kimura, Y.,Kepinski, S.,Nozaki, H.
Small-molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling.
Proc.Natl.Acad.Sci.Usa, 105:5632-5637, 2008

PubMed 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.

PubMed: 18391211
DOI: 10.1073/pnas.0711146105

Experimental method

X-RAY DIFFRACTION (2.6 Å)