6tlg | pdb_00006tlg
Ligand-free state of human 14-3-3 sigma isoform
Structural highlights
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 PubMedThe 14-3-3/c-Abl protein-protein interaction (PPI) is related to carcinogenesis and in particular to pathogenesis of chronic myeloid leukaemia (CML). Previous studies have demonstrated that molecules able to disrupt this interaction improve the nuclear translocation of c-Abl, inducing apoptosis in leukaemia cells. Through an X-ray crystallography screening program, we have identified two phosphate-containing compounds, inosine monophosphate (IMP) and pyridoxal phosphate (PLP), as binders of human 14-3-3sigma, by targeting the protein amphipathic groove. Interestingly, they also act as weak inhibitors of the 14-3-3/c-Abl PPI, demonstrated by NMR, SPR and FP data. A 37-compound library of PLP and IMP analogues was investigated using a FP assay, leading to the identification of three further molecules acting as weak inhibitors of the 14-3-3/c-Abl complex formation. The antiproliferative activity of IMP, PLP and the three derivatives was tested against K-562 cells, showing that the parent compounds had the most pronounced effect on tumour cells. PLP and IMP were also effective in promoting the c-Abl nuclear translocation in c-Abl overexpressing cells. Further, these compounds demonstrated low cytotoxicity on human Hs27 fibroblasts. In conclusion, our data suggest that 14-3-3sigma targeting compounds represent promising hits for further development of drugs against c-Abl-dependent cancers. Identification of phosphate-containing compounds as new inhibitors of 14-3-3/c-Abl protein-protein interaction.,Iralde-Lorente L, Tassone G, Clementi L, Franci L, Munier CC, Cau Y, Mori M, Chiariello M, Angelucci A, Perry MWD, Pozzi C, Mangani S, Botta M ACS Chem Biol. 2020 Mar 6. doi: 10.1021/acschembio.0c00039. PMID:32142251[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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