Structural Basis of Microtubule Stabilization by Discodermolide

Andrea E. Prota, Katja Bargsten, Mariano Redondo-Horcajo, Amos B. Smith, Chia Ping H. Yang, Hayley M. McDaid, Ian Paterson, Susan B. Horwitz, José Fernando Díaz, Michel O. Steinmetz

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Microtubule-stabilizing agents (MSAs) are widely used in chemotherapy. Using X-ray crystallography we elucidated the detailed binding modes of two potent MSAs, (+)-discodermolide (DDM) and the DDM–paclitaxel hybrid KS-1-199-32, in the taxane pocket of β-tubulin. The two compounds bind in a very similar hairpin conformation, as previously observed in solution. However, they stabilize the M-loop of β-tubulin differently: KS-1-199-32 induces an M-loop helical conformation that is not observed for DDM. In the context of the microtubule structure, both MSAs connect the β-tubulin helices H6 and H7 and loop S9–S10 with the M-loop. This is similar to the structural effects elicited by epothilone A, but distinct from paclitaxel. Together, our data reveal differential binding mechanisms of DDM and KS-1-199-32 on tubulin.

Original languageEnglish (US)
Pages (from-to)905-909
Number of pages5
Issue number10
StatePublished - May 18 2017


  • X-ray crystallography
  • drug design
  • microtubules
  • molecular mechanism of action
  • structure elucidation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry


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