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8bzb
From Proteopedia
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<table><tr><td colspan='2'>[[8bzb]] 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=8BZB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BZB FirstGlance]. <br> | <table><tr><td colspan='2'>[[8bzb]] 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=8BZB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BZB 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]] 1.7Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GEH:2-(4-chloranylphenoxy)-2-methyl-~{N}-(2-sulfanylethyl)propanamide'>GEH</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand= | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GEH:2-(4-chloranylphenoxy)-2-methyl-~{N}-(2-sulfanylethyl)propanamide'>GEH</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SDM:4-ethoxy-1-benzothiophene-2-carboximidamide'>SDM</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=8bzb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bzb OCA], [https://pdbe.org/8bzb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bzb RCSB], [https://www.ebi.ac.uk/pdbsum/8bzb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bzb ProSAT]</span></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=8bzb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bzb OCA], [https://pdbe.org/8bzb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bzb RCSB], [https://www.ebi.ac.uk/pdbsum/8bzb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bzb ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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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. | 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 | + | 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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
co-soak stabilizers for ERa - 14-3-3 interaction (884_AZ275)
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