Interaction of the antitumor compound cryptophycin-52 with tubulin

Panda, Dulal ; Ananthnarayan, Vidya ; Larson, Gary ; Shih, Chuan ; Jordan, Mary Ann ; Wilson, Leslie (2000) Interaction of the antitumor compound cryptophycin-52 with tubulin Biochemistry, 39 (46). pp. 14121-14127. ISSN 0006-2960

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Official URL: http://pubs.acs.org/doi/abs/10.1021/bi0010827

Related URL: http://dx.doi.org/10.1021/bi0010827

Abstract

Cryptophycin-52 (LY355703) is currently undergoing clinical evaluation for cancer chemotherapy. It is a potent suppresser of microtubule dynamics in vitro, and low picomolar concentrations appear to inhibit cancer cell proliferation at mitosis by stabilizing spindle microtubules. In the present study, using [3H]cryptophycin-52, we found that the compound bound to tubulin at a single high-affinity site [apparent Ka(3.6±1)×106 L/mol, 34°C]. The binding of cryptophycin-52 to tubulin was rapid, not appreciably temperature-dependent, and very poorly reversible. However, we could remove [3H]cryptophycin-52 from [3H]cryptophycin-52-tubulin complex by denaturing the complex with either urea treatment or boiling. These data suggest that the binding of cryptophycin-52 to tubulin is not covalent. A van't Hoff plot of the binding data indicated that the binding of cryptophycin-52 to tubulin is primarily entropy-driven with a minimum enthalpy contribution. In addition, cryptophycin-52 perturbed the far-ultraviolet circular dichroic spectrum of tubulin and it inhibited the colchicine-induced guanosine triphosphatase activity of tubulin, indicating that its binding to tubulin induces a conformational change in the tubulin. Competition experiments with vinblastine suggest that the binding site for crytophycin-52 may overlap with the vinblastine binding site.

Item Type:Article
Source:Copyright of this article belongs to American Chemical Society.
ID Code:34908
Deposited On:14 Apr 2011 13:43
Last Modified:14 Apr 2011 13:43

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