3c6p: Difference between revisions
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==Small molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling== | |||
<StructureSection load='3c6p' size='340' side='right'caption='[[3c6p]], [[Resolution|resolution]] 2.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3c6p]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Arabidopsis_thaliana Arabidopsis thaliana]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3C6P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3C6P FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2S3:(2S)-2-(1H-INDOL-3-YL)PENTANOIC+ACID'>2S3</scene>, <scene name='pdbligand=IHP:INOSITOL+HEXAKISPHOSPHATE'>IHP</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3c6p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3c6p OCA], [https://pdbe.org/3c6p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3c6p RCSB], [https://www.ebi.ac.uk/pdbsum/3c6p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3c6p ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/SKP1A_ARATH SKP1A_ARATH] Involved in ubiquitination and subsequent proteasomal degradation of target proteins. Together with CUL1, RBX1 and a F-box protein, it forms a SCF E3 ubiquitin ligase complex. The functional specificity of this complex depends of the type of F-box protein. In the SCF complex, it serves as an adapter that links the F-box protein to CUL1. SCF(UFO) is required for vegetative and floral organ development as well as for male gametogenesis. SCF(TIR1) is involved in auxin signaling pathway. SCF(COI1) regulates responses to jasmonates. SCF(EID1) and SCF(AFR) are implicated in phytochrome A light signaling. SCF(ADO1), SCF(ADO2), SCF(ADO3) are related to the circadian clock. SCF(ORE9) seems to be involved in senescence. SCF(EBF1/EBF2) may regulate ethylene signaling. Plays a role during embryogenesis and early postembryonic development, especially during cell elongation and division. Contributes to the correct chromosome segregation during tetrad formation.<ref>PMID:10528262</ref> <ref>PMID:10398681</ref> <ref>PMID:10500191</ref> <ref>PMID:11526079</ref> <ref>PMID:12970487</ref> <ref>PMID:14688296</ref> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c6/3c6p_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3c6p ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
Small-molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling.,Hayashi K, Tan X, Zheng N, Hatate T, Kimura Y, Kepinski S, Nozaki H Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5632-7. Epub 2008 Apr 7. PMID:18391211<ref>PMID:18391211</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3c6p" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Transport inhibitor response 1|Transport inhibitor response 1]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Arabidopsis thaliana]] | [[Category: Arabidopsis thaliana]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Tan | [[Category: Tan X]] | ||
Latest revision as of 15:23, 30 August 2023
Small molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signalingSmall molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling
Structural highlights
FunctionSKP1A_ARATH Involved in ubiquitination and subsequent proteasomal degradation of target proteins. Together with CUL1, RBX1 and a F-box protein, it forms a SCF E3 ubiquitin ligase complex. The functional specificity of this complex depends of the type of F-box protein. In the SCF complex, it serves as an adapter that links the F-box protein to CUL1. SCF(UFO) is required for vegetative and floral organ development as well as for male gametogenesis. SCF(TIR1) is involved in auxin signaling pathway. SCF(COI1) regulates responses to jasmonates. SCF(EID1) and SCF(AFR) are implicated in phytochrome A light signaling. SCF(ADO1), SCF(ADO2), SCF(ADO3) are related to the circadian clock. SCF(ORE9) seems to be involved in senescence. SCF(EBF1/EBF2) may regulate ethylene signaling. Plays a role during embryogenesis and early postembryonic development, especially during cell elongation and division. Contributes to the correct chromosome segregation during tetrad formation.[1] [2] [3] [4] [5] [6] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe 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. Small-molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling.,Hayashi K, Tan X, Zheng N, Hatate T, Kimura Y, Kepinski S, Nozaki H Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5632-7. Epub 2008 Apr 7. PMID:18391211[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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