View source for 8arq


==Small molecular stabilizer for ERalpha and 14-3-3 (1080266)==
<StructureSection load='8arq' size='340' side='right'caption='[[8arq]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8arq]] 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=8ARQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ARQ 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]] 1.4&#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=NKL:2-chloranyl-1-[2-[4-[(4-chlorophenyl)amino]oxan-4-yl]carbonyl-2,7-diazaspiro[3.5]nonan-7-yl]ethanone'>NKL</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=8arq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8arq OCA], [https://pdbe.org/8arq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8arq RCSB], [https://www.ebi.ac.uk/pdbsum/8arq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8arq ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The stabilization of protein-protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. The identification of suitable starting points for stabilizing native PPIs and their subsequent elaboration into selective and potent molecular glues lacks structure-guided optimization strategies. We have previously identified a disulfide fragment that stabilized the hub protein 14-3-3sigma bound to several of its clients, including ERalpha and C-RAF. Here, we show the structure-based optimization of the nonselective fragment toward selective and highly potent small-molecule stabilizers of the 14-3-3sigma/ERalpha complex. The more elaborated molecular glues, for example, show no stabilization of 14-3-3sigma/C-RAF up to 150 muM compound. Orthogonal biophysical assays, including mass spectrometry and fluorescence anisotropy, were used to establish structure-activity relationships. The binding modes of 37 compounds were elucidated with X-ray crystallography, which further assisted the concomitant structure-guided optimization. By targeting specific amino acids in the 14-3-3sigma/ERalpha interface and locking the conformation with a spirocycle, the optimized covalent stabilizer 181 achieved potency, cooperativity, and selectivity similar to the natural product Fusicoccin-A. This case study showcases the value of addressing the structure, kinetics, and cooperativity for molecular glue development.

Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3sigma/ERalpha Protein-Protein Interaction from Nonselective Fragments.,Konstantinidou M, Visser EJ, Vandenboorn E, Chen S, Jaishankar P, Overmans M, Dutta S, Neitz RJ, Renslo AR, Ottmann C, Brunsveld L, Arkin MR J Am Chem Soc. 2023 Sep 20;145(37):20328-20343. doi: 10.1021/jacs.3c05161. Epub , 2023 Sep 7. PMID:37676236<ref>PMID:37676236</ref>

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