6ygj

small-molecule stabilizer of 14-3-3 and the Carbohydrate Response Element Binding Protein (ChREBP) protein-protein interaction

spinqualitylabelsall models 6ygj, resolution 2.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ygj is a 4 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 2.07Å Ligands: OQE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 1433B_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. Negative regulator of osteogenesis. Blocks the nuclear translocation of the phosphorylated form (by AKT1) of SRPK2 and antagonizes its stimulatory effect on cyclin D1 expression resulting in blockage of neuronal apoptosis elicited by SRPK2. Publication Abstract from PubMed The systematic stabilization of protein-protein interactions (PPI) has great potential as innovative drug discovery strategy to target novel and hard-to-drug protein classes. The current lack of chemical starting points and focused screening opportunities limits the identification of small molecule stabilizers that engage two proteins simultaneously. Starting from our previously described virtual screening strategy to identify inhibitors of 14-3-3 proteins, we report a conceptual molecular docking approach providing concrete entries for discovery and rational optimization of stabilizers for the interaction of 14-3-3 with the carbohydrate-response element-binding protein (ChREBP). X-ray crystallography reveals a distinct difference in the binding modes between weak and general inhibitors of 14-3-3 complexes and a specific, potent stabilizer of the 14-3-3/ChREBP complex. Structure-guided stabilizer optimization results in selective, up to 26-fold enhancement of the 14-3-3/ChREBP interaction. This study demonstrates the potential of rational design approaches for the development of selective PPI stabilizers starting from weak, promiscuous PPI inhibitors. Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein-protein interactions.,Sijbesma E, Visser E, Plitzko K, Thiel P, Milroy LG, Kaiser M, Brunsveld L, Ottmann C Nat Commun. 2020 Aug 7;11(1):3954. doi: 10.1038/s41467-020-17741-0. PMID:32770072 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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