Interaction with the heparin-derived binding inhibitors destabilizes galectin-3 protein structure.
Biochem Biophys Res Commun
; 523(2): 336-341, 2020 03 05.
Article
em En
| MEDLINE
| ID: mdl-31866013
The ß-galactoside-binding protein, galectin-3, is extensively involved in cancer development, progression and metastasis through multiple mechanisms. Inhibition of the galectin-3-mediated actions is increasingly considered as a promising therapeutic approach for cancer treatment. Our early studies have identified several novel galectin-3 binding inhibitors from chemical modification of the anticoagulant drug heparin. These heparin-derived galectin-3 binding inhibitors, which show no anticoagulant activity and bind to the galectin-3 canonical carbohydrate-binding site, induce galectin-3 conformational changes and inhibit galectin-3-mediated cancer cell adhesion, invasion and angiogenesis in vitro and reduce metastasis in mice. In this study, we determined the binding affinities of these heparin-derived ligands to galectin-3 using an isothermal titration calorimetry (ITC) ligand displacement approach. Such ITC experiments showed that the 2-de-O-sulphated, N-acetylated (compound E) and 6-de-O-sulphated, N-acetylated (F) heparin-derived ligands and their ultra-low molecular weight sub-fractions (E3 and F3) bind to galectin-3 with KD ranging from 0.96 to 1.32 mM.Differential scanning fluorimetry analysis revealed that, in contrast to the disaccharide ligand, N-acetyl-lactosamine, which binds to the fully folded form of galectin-3 and promotes galectin-3 thermal stability, the heparin-derived ligands preferentially bind to the unfolded state of galectin-3 and cause destabilization of the galectin-3 protein structure. These results provide molecular insights into the interaction of galectin-3 with the heparin-derived ligands and explain the previously demonstrated in vitro and in vivo effects of these binding inhibitors on galectin-3-mediated cancer cell behaviours.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Heparina
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Galectina 3
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article