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Biochemistry. 1995 May 30;34(21):7010-9.

Vinca site agents induce structural changes in tubulin different from and antagonistic to changes induced by colchicine site agents.

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Laboratory of Biochemical Pharmacology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.


Vinca site agents are antimicrotubule compounds that bind to the same site on tubulin as do the vinca alkaloids. These include agents that induce the formation of nonmicrotubule oligomers of tubulin (vinblastine and vincristine) and agents that do not (maytansine and rhizoxin). All of these quench the fluorescence of tubulin upon binding. Quenching preferentially affects the red side of tubulin emission, likely affecting more than one solvent-exposed tryptophan. Similar quenching is observed upon binding to either tubulin or tubulin-colchicine. None of these agents induces the local unfolding of the amphipathic helix in the carboxyl terminal region of beta-tubulin that colchicine and other colchicine site ligands do. All four vinca site agents inhibit this unfolding in tubulin-colchicine complexes without displacing colchicine. Both groups of vinca site agents enhance the chymotryptic cleavage of beta-tubulin after Tyr-281. Both groups of vinca site agents increase the beta-tubulin specificity of photolabeling with colchicine, and both groups inhibit colchicine-stimulated GTP hydrolysis. All of these effects common to both groups of vinca site agents are interpreted as due to vinca site occupancy alone. The vinca alkaloids differ from maytansine and rhizoxin by causing a large enhancement of chymotryptic cleavage of beta and a large inhibition of typtic cleavage of alpha, after Arg-339. These effects are interpreted as due to vinca induced oligomerization of tubulin. It is argued that the common binding site for the vinca site agents is located on beta-tubulin, close to the helix that is disrupted by colchicine.

[Indexed for MEDLINE]

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