6y1d

Binary complex of 14-3-3 sigma (C38N) with the Estrogen Related Receptor gamma (DBD) phosphopeptide

spinqualitylabelsall models 6y1d, resolution 1.38Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6y1d is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.38Å Ligands: CL, MG, NH2, 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 Protein-protein interaction (PPI) networks are fundamental for cellular processes. Small-molecule PPI enhancers have been shown to be powerful tools to fundamentally study PPIs and as starting points for potential new therapeutics. Yet, systematic approaches for their discovery are not widely available, and the design prerequisites of "molecular glues" are poorly understood. Covalent fragment-based screening can identify chemical starting points for these enhancers at specific sites in PPI interfaces. We recently reported a mass spectrometry-based disulfide-trapping (tethering) approach for a cysteine residue in the hub protein 14-3-3, an important regulator of phosphorylated client proteins. Here, we invert the strategy and report the development of a functional read-out for systematic identification of PPI enhancers based on fluorescence anisotropy (FA-tethering) with the reactive handle now on a client-derived peptide. Using the DNA-binding domain of the nuclear receptor Estrogen Related Receptor gamma (ERRgamma), we target a native cysteine positioned at the 14-3-3 PPI interface and identify several fragments that form a disulfide bond to ERRgamma and stabilize the complex up to 5-fold. Crystallography indicates that fragments bind in a pocket comprised of 14-3-3 and the ERRgamma phosphopeptide. FA-tethering presents a streamlined methodology to discover molecular glues for protein complexes. Fluorescence Anisotropy-Based Tethering for Discovery of Protein-Protein Interaction Stabilizers.,Sijbesma E, Somsen BA, Miley GP, Leijten-van de Gevel IA, Brunsveld L, Arkin MR, Ottmann C ACS Chem Biol. 2020 Nov 16. doi: 10.1021/acschembio.0c00646. PMID:33196173 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also 14-3-3 protein 3D structures

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