8c2g
14-3-3 sigma with Pin1 binding site pS72 and covalently bound CV1040
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 PubMedMolecular glues are powerful tools for the control of protein-protein interactions. Yet, the mechanisms underlying multi-component protein complex formation remain poorly understood. Native mass spectrometry (MS) detects multiple protein species simultaneously, providing an entry to elucidate these mechanisms. Here, for the first time, covalent molecular glue stabilization was kinetically investigated by combining native MS with biophysical and structural techniques. This approach elucidated the stoichiometry of a multi-component protein-ligand complex, the assembly order, and the contributions of covalent versus non-covalent binding events that govern molecular glue activity. Aldehyde-based molecular glue activity is initially regulated by cooperative non-covalent binding, followed by slow covalent ligation, further enhancing stabilization. This study provides a framework to investigate the mechanisms of covalent small molecule ligation and informs (covalent) molecular glue development. Tracking the mechanism of covalent molecular glue stabilization using native mass spectrometry.,Verhoef CJA, Kay DF, van Dijck L, Doveston RG, Brunsveld L, Leney AC, Cossar PJ Chem Sci. 2023 May 31;14(24):6756-6762. doi: 10.1039/d3sc01732j. eCollection 2023 , Jun 21. PMID:37350830[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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