Thermodynamics of calmodulin and tubulin binding to the vinca-alkaloid vinorelbine

• Published in: Molecular biology (New York) 2011-08, Vol.45 (4), p.641-646
• Main Authors: Tsvetkov, P. O., Kulikova, A. A., Devred, F., Zernii, E. Yu, Lafitte, D., Makarov, A. A.
• Format: Article
• Language: eng ; rus
• Subjects: Binding sites; Biochemistry; Biomedical and Life Sciences; Calcium-binding protein; Calmodulin; Cell cycle; Human Genetics; Leukemia; Life Sciences; Mitosis; Molecular biology; Neuroprotection; Phytochemicals; Proteins; Reaction mechanisms; Spindles; Structural and Functional Analysis of Biopolymers and Their Complexes; Thermodynamics; Tubulin; Tumors; Vinblastine; vinorelbine
• ISSN: 0026-8933; 1608-3245
• DOI: 10.1134/S0026893311040108

Vinca-alkaloids, such as vinblastine, and some of their derivatives, for example vinorelbine, are widely used in clinical therapy of leukemia and several types of tumors. Their effects are associated with the disfunctioning of the mitotic spindle, which leads to mitosis blockage and a shutting down of the cell cycle. Their primary target is tubulin; however, recent research has shown that some of the vinca-alkaloids inhibit calmodulin binding to its targets. Vinca-alkaloids binding with other proteins could be responsible for their efficiency and neuroprotection. Here, we investigated the thermodynamics of vinorelbine interactions with calmodulin and tubulin. It was determined that, unlike the other vinca-alkaloids, both vinorelbine binding sites are located in the C -domain of calmodulin and they are characterized by association constants of 4.0 × 10 5 and 5.4 × 10 4 M −1 . At the same time, the thermodynamics of vinorelbine binding to tubulin are not much different from that of other vinca-alkaloids. These results will allow us to get a better insight on the reaction mechanisms of vinca-alkaloids on a secondary protein target.