View source for 8bxi


==fragment-linked stabilizer for ERa - 14-3-3 interaction (1074361)==
<StructureSection load='8bxi' size='340' side='right'caption='[[8bxi]], [[Resolution|resolution]] 1.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8bxi]] 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=8BXI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BXI 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]] 1.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=S0O:~{N}-[3-(5-carbamimidoylthiophen-3-yl)phenyl]-2-methyl-2-phenoxy-propanamide'>S0O</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=8bxi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bxi OCA], [https://pdbe.org/8bxi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bxi RCSB], [https://www.ebi.ac.uk/pdbsum/8bxi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bxi ProSAT]</span></td></tr>
</table>
== Function ==
[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.
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== Publication Abstract from PubMed ==
Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERalpha) protein. Two classes of fragments-a covalent and a noncovalent fragment-were co-crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25-fold stabilization of the 14-3-3/ERalpha interaction. The high-resolution structures of both the single fragments, their co-crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment.

From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions through Fragment Linking.,Visser EJ, Jaishankar P, Sijbesma E, Pennings MAM, Vandenboorn EMF, Guillory X, Neitz RJ, Morrow J, Dutta S, Renslo AR, Brunsveld L, Arkin MR, Ottmann C Angew Chem Int Ed Engl. 2023 Sep 11;62(37):e202308004. doi: , 10.1002/anie.202308004. Epub 2023 Aug 1. PMID:37455289<ref>PMID:37455289</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8bxi" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ottmann C]]
[[Category: Vandenboorn EMF]]
[[Category: Visser EJ]]