Centrin: Another target of monastrol, an inhibitor of mitotic spindle

• Published in: Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy Molecular and biomolecular spectroscopy, 2015-02, Vol.137, p.1086-1091
• Main Authors: Duan, Lian, Wang, Tong-Qing, Bian, Wei, Liu, Wen, Sun, Yue, Yang, Bin-Sheng
• Format: Article
• Language: English
• Subjects: Centrin; Hydrophobic force; Monastrol; Self-assembly inhibition
• ISSN: 1386-1425
• DOI: 10.1016/j.saa.2014.08.050

[Display omitted] •The inhibition of monastrol on the self-assembly of EoCen were investigated by the UV–vis and fluorescent spectra.•The binding pattern and the binding constants of monastrol and EoCen were obtained.•The main acting force between EoCen and monastrol were investigated by the detailed thermodynamic analysis. Monastrol, a cell-permeable inhibitor, considered to specifically inhibit kinesin Eg5, can cause mitotic arrest and monopolar spindle formation, thus exhibiting antitumor properties. Centrin, a ubiquitous protein associated with centrosome, plays a critical role in centrosome duplication. Moreover, a correlation between centrosome amplification and cancer has been reported. In this study, it is proposed for the first time that centrin may be another target of the anticancer drug monastrol since monastrol can effectively inhibit not only the growth of the transformed Escherichia coli cells in vivo, but also the Lu3+-dependent self-assembly of EoCen in vitro. The two closely related compounds (Compounds 1 and 2) could not take the same effect. Fluorescence titration experiments suggest that four monastrols per protein is the optimum binding pattern, and the binding constants at different temperatures were obtained. Detailed thermodynamic analysis indicates that hydrophobic force is the main acting force between monastrol and centrin, and the extent of monastrol inhibition of centrin self-assembly is highly dependent upon the hydrophobic region of the protein, which is largely exposed by the binding of metal ions.