Computational protocol: The UPR inducer DPP23 inhibits the metastatic potential of MDA-MB-231 human breast cancer cells by targeting the Akt–IKK–NF-κB–MMP-9 axis

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Protocol publication

[…] The phosphatidylinositol 3-kinase (PI3K)-Akt signalling pathway can activate NF-κB by phosphorylating IKK. Three Akt isoforms (Akt1, Akt2, and Akt3) are expressed in MDA-MB-231 cells. As Akt2 is the predominant form amplified in breast cancer cells and is involved in the invasion and metastasis of breast cancer cells, it is tempting to speculate that DPP23 inhibits NFκB by targeting Akt2. To test this possibility, we determined whether DPP23 could bind to Akt2 using in silico molecular docking simulations. A pan-Akt inhibitor, GSK690693, was used as a reference ligand. The LigPlot analysis showed that twenty-two residues of Akt2 (Leu158, Gly159, Lys160, Phe163, Val166, Ala179, Lys181, Glu200, Leu204, Phe227, Met229, Glu230, Tyr231, Ala232, Glu236, Glu279, Met282, Thr292, Asp293, Phe294, Phe439, and Phe443) were involved in GSK690693 binding; four residues (Lys160, Glu230, Ala232, and Asp293) formed five hydrogen bonds (H-bonds), and eighteen residues formed hydrophobic interactions (, left panel). Similarly, ten residues (Lys160, Phe163, Val166, Lys181, Thr213, Met229, Glu279, Met282, Thr292, and Asp293) were located in close proximity to the DPP23 binding site (, right panel). All of these residues except Thr213 were observed in both complexes, two residues (Lys181 and Asp293) formed two H-bonds, and ten residues formed hydrophobic interactions. PyMOL showed that five H-bonds were formed between Akt2 and GSK690693 (, left panel), while two H-bonds were formed in the Akt2 and DPP23 complex (, right panel). Based on these data, we suggest that DPP23 may bind to the catalytic domain of Akt2. […]

Pipeline specifications

Software tools LigPlot+, PyMOL
Application Protein interaction analysis
Organisms Homo sapiens, Mus musculus