期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 523, 期 2, 页码 336-341出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2019.12.054
关键词
Galectin-3; Heparin derivatives; Differential scanning fluorimetry; Isothermal titration calorimetry
资金
- Medical Research Council Industry Case Studentship [MR/L014327/1]
- BBSRC [BB/D020794/1] Funding Source: UKRI
- MRC [MR/M009114/1, G1000772] Funding Source: UKRI
The beta-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 K-D 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. (C) 2019 Elsevier Inc. All rights reserved.
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