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 Band Horwitz, José FernandoDíaz, Michel O. Steinmetz

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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 epothiloneA, but distinct from paclitaxel. Together, our data reveal differential binding mechanisms of DDM and KS-1-199-32 on tubulin.

Original languageEnglish (US)
JournalChemBioChem
DOIs
StateAccepted/In press - 2017

Fingerprint

Tubulin
Microtubules
Excipients
Stabilization
Paclitaxel
Conformations
S 10
Chemotherapy
X ray crystallography
X Ray Crystallography
Drug Therapy
discodermolide

Keywords

  • Drug design
  • Microtubules
  • Molecular mechanism of action
  • Structure elucidation
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Cite this

Prota, A. E., Bargsten, K., Redondo-Horcajo, M., Smith, A. B., Yang, C-P. H., McDaid, H. M., ... Steinmetz, M. O. (Accepted/In press). Structural Basis of Microtubule Stabilization by Discodermolide. ChemBioChem. https://doi.org/10.1002/cbic.201600696

Structural Basis of Microtubule Stabilization by Discodermolide. / Prota, Andrea E.; Bargsten, Katja; Redondo-Horcajo, Mariano; Smith, Amos B.; Yang, Chia-Ping H.; McDaid, Hayley M.; Paterson, Ian; Band Horwitz, Susan; FernandoDíaz, José; Steinmetz, Michel O.

In: ChemBioChem, 2017.

Research output: Contribution to journalArticle

Prota, AE, Bargsten, K, Redondo-Horcajo, M, Smith, AB, Yang, C-PH, McDaid, HM, Paterson, I, Band Horwitz, S, FernandoDíaz, J & Steinmetz, MO 2017, 'Structural Basis of Microtubule Stabilization by Discodermolide', ChemBioChem. https://doi.org/10.1002/cbic.201600696
Prota, Andrea E. ; Bargsten, Katja ; Redondo-Horcajo, Mariano ; Smith, Amos B. ; Yang, Chia-Ping H. ; McDaid, Hayley M. ; Paterson, Ian ; Band Horwitz, Susan ; FernandoDíaz, José ; Steinmetz, Michel O. / Structural Basis of Microtubule Stabilization by Discodermolide. In: ChemBioChem. 2017.
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