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14-3-3 sigma with RelA/p65 binding site pS45 and covalently bound TCF521
Structural highlights
Function1433S_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 PubMedSmall-molecule stabilization of protein-protein interactions (PPI) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a 'bottom-up' approach is largely unanswered. Here we report a novel concept for identifying initial chemical matter for PPI stabilization based on covalent imine forming fragments. The imine bond offers a covalent anchor for site-directed fragment targeting, whereas its transient nature allows an efficient structure activity relationship analysis. This bond enables fragment identification and optimisation using protein crystallography. We report novel fragments which bind specifically to a lysine at the PPI interface of the p65 subunit-derived peptide of NF-kappaB with the adapter protein 14-3-3. Those fragments that subsequently establish contacts with the p65-derived peptide, rather than with 14-3-3, efficiently stabilize the 14-3-3/p65 complex and offer novel starting points for molecular glues. Fragment Based Protein-Protein Interaction Stabilizers via Imine-Based Tethering.,Ottmann C, Wolter M, Valenti D, Cossar PJ, Levy LM, Hristeva S, Genski T, Hoffmann T, Brunsveld L, Tzalis D Angew Chem Int Ed Engl. 2020 Aug 20. doi: 10.1002/anie.202008585. PMID:32816380[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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