Duan Lian, Wang Tong-Qing, Bian Wei, Liu Wen, Sun Yue, Yang Bin-Sheng
School of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China.
School of Preclinical Medicine, Shanxi Medical University, Taiyuan 030001, China.
Spectrochim Acta A Mol Biomol Spectrosc. 2015 Feb 25;137:1086-91. doi: 10.1016/j.saa.2014.08.050. Epub 2014 Sep 3.
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.
莫那可林，一种可穿透细胞的抑制剂，被认为能特异性抑制驱动蛋白Eg5，可导致有丝分裂停滞和单极纺锤体形成，从而展现出抗肿瘤特性。中心蛋白，一种与中心体相关的普遍存在的蛋白质，在中心体复制中起关键作用。此外，已有报道称中心体扩增与癌症之间存在关联。在本研究中，首次提出中心蛋白可能是抗癌药物莫那可林的另一个靶点，因为莫那可林不仅能有效抑制体内转化大肠杆菌细胞的生长，还能在体外抑制依赖镥离子的中心蛋白自组装。两种密切相关的化合物（化合物1和化合物2）无法产生相同的效果。荧光滴定实验表明，每个蛋白质结合四个莫那可林是最佳结合模式，并获得了不同温度下的结合常数。详细的热力学分析表明，疏水作用力是莫那可林与中心蛋白之间的主要作用力，莫那可林对中心蛋白自组装的抑制程度高度依赖于蛋白质的疏水区域，该区域在金属离子结合时大量暴露。
