View source for 9sae


==14-3-3sigma protein binding to ChREBP peptide and macrocycle 4==
<StructureSection load='9sae' size='340' side='right'caption='[[9sae]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9sae]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9SAE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9SAE 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]] 2.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JND:2-[4-(1~{H}-1,2,3-triazol-4-yl)butylamino]ethanoic+acid'>A1JND</scene>, <scene name='pdbligand=B3S:(3R)-3-AMINO-4-HYDROXYBUTANOIC+ACID'>B3S</scene>, <scene name='pdbligand=BAL:BETA-ALANINE'>BAL</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=PPN:PARA-NITROPHENYLALANINE'>PPN</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=9sae FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9sae OCA], [https://pdbe.org/9sae PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9sae RCSB], [https://www.ebi.ac.uk/pdbsum/9sae PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9sae 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 ==
Molecular glues (MGs) stabilize protein-protein interactions (PPIs) by simultaneously binding two or more proteins at their composite interface. Macrocycles present attractive properties as MGs, including large contact surfaces to address the often flat and undefined composite PPI interfaces, but their structure-based design has remained intangible. We have designed peptidomimetic macrocycles capable of enhancing the PPI between 14-3-3 and the carbohydrate response element binding protein (ChREBP), a regulatory transcription factor. Biophysical characterization of these MGs revealed the importance of optimized linker length, displaying a reduced entropic cost compared to the linear counterparts, while preserving key contacts with 14-3-3. Binding assays demonstrated that the macrocycles selectively and cooperatively stabilized the 14-3-3/ChREBP complex, with an intriguing inverse relationship between intrinsic binding affinity to 14-3-3 and cooperativity in PPI stabilization. Ternary co-crystal structures of the macrocycles binding at the composite 14-3-3/ChREBP interface provided a molecular rationale for the affinity and cooperativity differences. Overall, this study highlights structural, kinetic, and thermodynamic features that guide effective macrocyclic MG design and brings forward the crucial interplay of affinity and cooperativity in stabilizing PPIs.

Macrocyclic Molecular Glues for the 14-3-3/ChREBP Interaction: Affinity and Cooperativity in an Inverse Relationship.,Pennings MAM, van den Bosch MAW, Oberheide A, Verhoef CJA, Ottmann C, Markvoort AJ, Miley GP, Brunsveld L Angew Chem Int Ed Engl. 2025 Dec 18:e21678. doi: 10.1002/anie.202521678. PMID:41414041<ref>PMID:41414041</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 9sae" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Brunsveld L]]
[[Category: Pennings MAM]]
[[Category: Van den Bosch MAW]]