6TLG

Ligand-free state of human 14-3-3 sigma isoform

6TLG の概要

• エントリーDOI: 10.2210/pdb6tlg/pdb
• 関連するPDBエントリー: 6TLF
• 分子名称: 14-3-3 protein sigma, DI(HYDROXYETHYL)ETHER, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: human protein, 14-3-3, sigma isoform, h14-3-3sigma, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31867.19

構造登録者

Tassone, G.,Pozzi, C.,Mangani, S. (登録日: 2019-12-02, 公開日: 2020-03-18, 最終更新日: 2024-01-24)

主引用文献

Iralde-Lorente, L.,Tassone, G.,Clementi, L.,Franci, L.,Munier, C.C.,Cau, Y.,Mori, M.,Chiariello, M.,Angelucci, A.,Perry, M.W.D.,Pozzi, C.,Mangani, S.,Botta, M.
Identification of Phosphate-Containing Compounds as New Inhibitors of 14-3-3/c-Abl Protein-Protein Interaction.
Acs Chem.Biol., 15:1026-1035, 2020

PubMed Abstract: The 14-3-3/c-Abl protein-protein interaction (PPI) is related to carcinogenesis and in particular to pathogenesis of chronic myeloid leukemia (CML). Previous studies have demonstrated that molecules able to disrupt this interaction improve the nuclear translocation of c-Abl, inducing apoptosis in leukemia 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 14-3-3σ, 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 tumor 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 14-3-3σ targeting compounds represent promising hits for further development of drugs against c-Abl-dependent cancers.

PubMed: 32142251
DOI: 10.1021/acschembio.0c00039

実験手法

X-RAY DIFFRACTION (2.4 Å)