9sa9

14-3-3sigma protein binding to macrocycle 2

spinqualitylabelsall models 9sa9, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9sa9 is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: A1JNX, B3S, BAL, CA, CL, NH2, PPN, SEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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