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PDBsum entry 3c6o
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Signaling protein
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PDB id
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3c6o
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References listed in PDB file
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Key reference
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Title
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Small-Molecule agonists and antagonists of f-Box protein-Substrate interactions in auxin perception and signaling.
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Authors
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K.Hayashi,
X.Tan,
N.Zheng,
T.Hatate,
Y.Kimura,
S.Kepinski,
H.Nozaki.
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Ref.
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Proc Natl Acad Sci U S A, 2008,
105,
5632-5637.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 5.
Crystal structure and molecular docking analysis of
TIR1–probe complexes. (A and B) Crystal structure of
TIR1–probe complexes. TIR1 is shown as silver ribbon. Probes
3, 4, and 8 are shown as blue, yellow, and green, respectively.
IAA7 degron peptide (pink, surface-filled model) and IAA (red)
were superimposed on the coordinates in the crystal structure of
the TIR1-IAA-IAA7 complex. (C) Molecular docking of TIR1 probe.
Predicted binding conformers of 3 (blue) and 4 (yellow) to TIR1
auxin-binding site. Fifty possible binding conformers were
predicted by the program AutoDock. Ten representative conformers
were shown based on rmsd values to the coordinates of IAA moiety
in 3 and 4 in crystal structure.
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Figure 6.
The TIR1/AFB specific probe 8 blocks auxin responses of moss
P. patens. (A) Effects of 8 on NAA-induced elongation of P.
patens gametophores. The juvenile gametophore was incubated for
60 h with chemicals (2 μM NAA and/or 20 μM 8). Arrows indicate
the elongation zone in response to NAA. (Scale bar, 10 mm.) (B)
Effects of 8 and NAA on the development of chloronemata.
Chloronema cells were cultured on a BCDATG medium for 10 days in
the presence of 0.5 μM NAA and/or 10 μM 8. Arrows indicate
caulonemata.
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