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| | ==Ternary complex of Estrogen Receptor alpha peptide and 14-3-3 sigma C42 mutant bound to disulfide fragment PPI stabilizer 5== | | ==Ternary complex of Estrogen Receptor alpha peptide and 14-3-3 sigma C42 mutant bound to disulfide fragment PPI stabilizer 5== |
| - | <StructureSection load='6hn2' size='340' side='right' caption='[[6hn2]], [[Resolution|resolution]] 1.70Å' scene=''> | + | <StructureSection load='6hn2' size='340' side='right'caption='[[6hn2]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6hn2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HN2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HN2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6hn2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HN2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HN2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GF8:2-(3,4-dichlorophenyl)-~{N}-(2-sulfanylethyl)ethanamide'>GF8</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GF8:2-(3,4-dichlorophenyl)-~{N}-(2-sulfanylethyl)ethanamide'>GF8</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SFN, HME1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6hn2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hn2 OCA], [https://pdbe.org/6hn2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6hn2 RCSB], [https://www.ebi.ac.uk/pdbsum/6hn2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6hn2 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6hn2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hn2 OCA], [http://pdbe.org/6hn2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hn2 RCSB], [http://www.ebi.ac.uk/pdbsum/6hn2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hn2 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/1433S_HUMAN 1433S_HUMAN]] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression. | + | [https://www.uniprot.org/uniprot/1433S_HUMAN 1433S_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6hn2" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6hn2" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[14-3-3 protein 3D structures|14-3-3 protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Arkin, M R]] | + | [[Category: Large Structures]] |
| - | [[Category: Hallenbeck, K K]] | + | [[Category: Arkin MR]] |
| - | [[Category: Leysen, S]] | + | [[Category: Hallenbeck KK]] |
| - | [[Category: Ottmann, C]] | + | [[Category: Leysen S]] |
| - | [[Category: Sijbesma, E]] | + | [[Category: Ottmann C]] |
| - | [[Category: Fragment]]
| + | [[Category: Sijbesma E]] |
| - | [[Category: Protein binding]]
| + | |
| - | [[Category: Protein-protein interaction]]
| + | |
| - | [[Category: Stabilizer]]
| + | |
| - | [[Category: Tethering]]
| + | |
| Structural highlights
Function
1433S_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression.
Publication Abstract from PubMed
Modulation of protein-protein interactions (PPIs) by small molecules has emerged as a valuable approach in drug discovery. Compared to direct inhibition, PPI stabilization is vastly underexplored but has strong advantages, including the ability to gain selectivity by targeting an interface formed only upon association of proteins. Here, we present the application of a site-directed screening technique based on disulfide trapping (tethering) to select for fragments that enhance the affinity between protein partners. We target the phosphorylation-dependent interaction between the hub protein 14-3-3sigma and a peptide derived from Estrogen Receptor alpha (ERalpha), an important breast cancer target that is negatively regulated by 14-3-3sigma. We identify orthosteric stabilizers that increase 14-3-3/ERalpha affinity up to 40-fold and propose the mechanism of stabilization based on X-ray crystal structures. These fragments already display partial selectivity toward ERalpha-like motifs over other representative 14-3-3 clients. This first of its kind study illustrates the potential of the tethering approach to overcome the hurdles in systematic PPI stabilizer discovery.
Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction Stabilizers.,Sijbesma E, Hallenbeck KK, Leysen S, de Vink PJ, Skora L, Jahnke W, Brunsveld L, Arkin MR, Ottmann C J Am Chem Soc. 2019 Feb 19. doi: 10.1021/jacs.8b11658. PMID:30707565[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sijbesma E, Hallenbeck KK, Leysen S, de Vink PJ, Skora L, Jahnke W, Brunsveld L, Arkin MR, Ottmann C. Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction Stabilizers. J Am Chem Soc. 2019 Feb 19. doi: 10.1021/jacs.8b11658. PMID:30707565 doi:http://dx.doi.org/10.1021/jacs.8b11658
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