Vinca domain

HTI-286 binds to the tubulin heterodimer and induces formation of 13-membered tubulin rings [138], Photoaffinity labeling with analogues of HTI-286 mapped to residues of a-tubulin close to the interdimer interface [139], Competitive binding assays with dolastatin-10, cryptophycin A, vinblastine, PTX and colchicines, indicate that the hemiasterlins bind in a subsite of the Vinca domain, which is located at the interdimer interface [28],... 

Keywords Cytoskeleton, Microtubule dynamics, Mitosis, Structure Vinca domain... 

Most MT-Destabilizing Agents Bind to the Colchicine Site or to the Vinca Domain of Tubulin... 

They can be classified in two main classes (poly)macrocyclic molecules (e.g. vinblastine) and (mostly linear) pseudopeptides (e.g. dolastatin 10). Some ligands (e.g. phomopsin) have characteristics of both classes (Fig. 5). Whether the tubulin binding sites of these widely diverse molecules overlap or not remains to be established. Whatever the case, taken together these sites define the tubulin vinca domain [43]. 

In addition to the inhibition of MT polymerization, more properties are shared by vinca domain compounds. As a hallmark, they inhibit the tubulin GTPase activity linked to MT assembly [42] as well as that induced by colchicine (see [33] and... 

Note added in proof The structure of tubulin in complex with two other vinca domain ligands, namely with soblidotin, a dolastatin 10 analog, and with phomopsin A, has now been determined. These new results show that the site of these molecules overlaps only in part with the one of vinblastine. They put a structural explanation for the different properties of these compounds (e.g. an higher efficiency to inhibit the nucleotide exchange on tubulin) as compared to vinblastine [72]. 

The number of molecular modeling studies on vinca domain inhibitors is extremely restricted, presumably due to the high structural complexity of such compounds. To the best of our knowledge, the only modeling studies reported in this field focused on the localization of the binding site of antimitotic peptides and depsipeptides targeting the peptide site of the vinca domain [47],... 

Fig. 5 Interaction of antimitotic peptides and depsipeptides with the vinca domain with respect to the vinblastine binding site (1Z2B structure). Residues supposed to interact with the peptides are represented as blue sticks, vinblastine is represented as green sticks. Tubulin ribbons are colored as in Fig. 4...

Bai, R. L., Pauli, K. D., Herald, C. L., Malspeis, L., Pettit, G. R., and Hamel, E. (1991). Hali-chondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. J. Biol. Chem. 266, 15,882-15,889. 

Cruz-Monserrate, Z., Mullaney, J.T., Harran, P.G., Pettit, G.R., and Hamel, E. (2003) Dolastatin 15 binds in the vinca domain of tubulin as demonstrated by Hummel-Dreyer chromatography. Eur. J. Biochem., 270, 3822-3828. 

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