Cyclostreptin binds covalently to microtubule pores and lumenal taxoid binding sites

Rubén M. Buey, Enrique Calvo, Isabel Barasoain, Oriol Pineda, Michael C. Edler, Ruth Matesanz, Gemma Cerezo, Christopher D. Vanderwal, Billy W. Day, Erik J. Sorensen, Juan Antonio López, José Manuel Andreu, Ernest Hamel, J. Fernando Díaz

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126 Scopus citations


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 β-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 β-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.

Original languageEnglish (US)
Pages (from-to)117-125
Number of pages9
JournalNature Chemical Biology
Issue number2
StatePublished - Feb 2007

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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