Cyclostreptin binds covalently to microtubule pores and lumenal taxoid binding sites

Cyclostreptin (1), a natural product from Streptomyces sp. 9885, irreversibly stabilizes cellular microtubules, causes cell cycle arrest, evades drug resistance mediated by P-glycoprotein in a tumor cell line and potently inhibits paclitaxel binding to microtubules, yet it only weakly induces tubuli...

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Published in:	Nature chemical biology Vol. 3; no. 2; pp. 117 - 125
Main Authors:	Díaz, J Fernando, Buey, Rubén M, Calvo, Enrique, Barasoain, Isabel, Pineda, Oriol, Edler, Michael C, Matesanz, Ruth, Cerezo, Gemma, Vanderwal, Christopher D, Day, Billy W, Sorensen, Erik J, López, Juan Antonio, Andreu, José Manuel, Hamel, Ernest
Format:	Journal Article
Language:	English
Published:	United States Nature Publishing Group 01-02-2007
Subjects:	Alkanes - metabolism Amino Acid Sequence Asparagine - metabolism Binding Sites Binding, Competitive Biology Carbamates - metabolism Cell cycle Cell Cycle - drug effects Cell Line, Tumor Cell Proliferation - drug effects Chemistry Drug resistance Epothilones - metabolism Humans Inhibitory Concentration 50 Lactones - metabolism Mass Spectrometry Microtubules - chemistry Microtubules - drug effects Microtubules - metabolism Models, Chemical Models, Molecular Molecular Sequence Data Paclitaxel - metabolism Paclitaxel - pharmacology Polycyclic Compounds - chemistry Polycyclic Compounds - metabolism Polycyclic Compounds - pharmacology Protein Binding Pyrones - metabolism Streptomyces Taxoids - metabolism Taxoids - pharmacology Threonine - metabolism Tubulin - chemistry Tubulin - metabolism Tubulin Modulators - chemistry Tubulin Modulators - metabolism Tubulin Modulators - pharmacology
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Summary:	Cyclostreptin (1), a natural product from Streptomyces sp. 9885, irreversibly stabilizes cellular microtubules, causes cell cycle arrest, evades drug resistance mediated by P-glycoprotein in a tumor cell line and potently inhibits paclitaxel binding to microtubules, yet it only weakly induces tubulin assembly. In trying to understand this paradox, we observed irreversible binding of synthetic cyclostreptin to tubulin. This results from formation of covalent crosslinks to beta-tubulin in cellular microtubules and microtubules formed from purified tubulin in a 1:1 total stoichiometry distributed between Thr220 (at the outer surface of a pore in the microtubule wall) and Asn228 (at the lumenal paclitaxel site). Unpolymerized tubulin was only labeled at Thr220. Thus, the pore region of beta-tubulin is an undescribed binding site that (i) elucidates the mechanism by which taxoid-site compounds reach the kinetically unfavorable lumenal site and (ii) explains how taxoid-site drugs induce microtubule formation from dimeric and oligomeric tubulin.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1552-4450 1552-4469
DOI:	10.1038/nchembio853