The binding mode of epothilone A on alpha,beta-tubulin by electron crystallography

Science. 2004 Aug 6;305(5685):866-9. doi: 10.1126/science.1099190.

Abstract

The structure of epothilone A, bound to alpha,beta-tubulin in zinc-stabilized sheets, was determined by a combination of electron crystallography at 2.89 angstrom resolution and nuclear magnetic resonance-based conformational analysis. The complex explains both the broad-based epothilone structure-activity relationship and the known mutational resistance profile. Comparison with Taxol shows that the longstanding expectation of a common pharmacophore is not met, because each ligand exploits the tubulin-binding pocket in a unique and independent manner.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Crystallography
  • Crystallography, X-Ray
  • Epothilones / chemistry
  • Epothilones / metabolism*
  • Epothilones / pharmacology
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Mutation
  • Nuclear Magnetic Resonance, Biomolecular
  • Paclitaxel / metabolism
  • Protein Conformation
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tubulin / chemistry
  • Tubulin / genetics
  • Tubulin / metabolism*

Substances

  • Epothilones
  • Ligands
  • Tubulin
  • epothilone A
  • Paclitaxel