title: Centrin: another target of monastrol, an inhibitor of mitotic spindle.
abstract: 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 Lu(3+)-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.
authors.affiliation: School of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Duan
authors.affiliation: School of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China.
authors.forename: Tong-Qing
authors.initials: TQ
authors.lastname: Wang
authors.affiliation: School of Preclinical Medicine, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Bian
authors.affiliation: School of Preclinical Medicine, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: School of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China. Electronic address: sunyue@tyut.edu.cn.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Molecular Science, Shanxi University, Taiyuan 030006, China. Electronic address: yangbs@sxu.edu.cn.
authors.forename: Bin-Sheng
authors.initials: BS
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D004926:Escherichia coli / Q000254:growth & development; D006801:Humans; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D008941:Spindle Apparatus; D013871:Thiones / Q000737:chemistry*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D011994:Recombinant Proteins; D013871:Thiones; C400223:monastrol; D015662:Trimethoprim, Sulfamethoxazole Drug Combination
keywords: Centrin; Hydrophobic force; Monastrol; Self-assembly inhibition