Crystal structure of the cyclostreptin-tubulin adduct: Implications for tubulin activation by taxane-site ligands

Francisco de Asís Balaguer, Tobias Mühlethaler, Juan Estévez-Gallego, Enrique Calvo, Juan Francisco Giménez-Abián, April L. Risinger, Erik J. Sorensen, Christopher D. Vanderwal, Karl Heinz Altmann, Susan L. Mooberry, Michel O. Steinmetz, María Ángela Oliva, Andrea E. Prota, J. Fernando Díaz

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21 Scopus citations


It has been proposed that one of the mechanisms of taxane-site ligand-mediated tubulin activation is modulation of the structure of a switch element (the M-loop) from a disordered form in dimeric tubulin to a folded helical structure in microtubules. Here, we used covalent taxane-site ligands, including cyclostreptin, to gain further insight into this mechanism. The crystal structure of cyclostreptin-bound tubulin reveals covalent binding to βHis229, but no stabilization of the M-loop. The capacity of cyclostreptin to induce microtubule assembly compared to other covalent taxane-site agents demonstrates that the induction of tubulin assembly is not strictly dependent on M-loop stabilization. We further demonstrate that most covalent taxane-site ligands are able to partially overcome drug resistance mediated by βIII-tubulin (βIII) overexpression in HeLa cells, and compare their activities to pironetin, an interfacial covalent inhibitor of tubulin assembly that displays invariant growth inhibition in these cells. Our findings suggest a relationship between a diminished interaction of taxane-site ligands with βIII-tubulin and βIII tubulin-mediated drug resistance. This supports the idea that overexpression of βIII increases microtubule dynamicity by counteracting the enhanced microtubule stability promoted by covalent taxane-site binding ligands.

Original languageEnglish (US)
Article number1392
JournalInternational journal of molecular sciences
Issue number6
StatePublished - Mar 2 2019

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry


  • Cyclostreptin
  • Microtubules
  • Multidrug resistance
  • Taxanes
  • Tubulin


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