Structural basis for the regulation of tubulin by vinblastine

Nature. 2005 May 26;435(7041):519-22. doi: 10.1038/nature03566.


Vinblastine is one of several tubulin-targeting Vinca alkaloids that have been responsible for many chemotherapeutic successes since their introduction in the clinic as antitumour drugs. In contrast with the two other classes of small tubulin-binding molecules (Taxol and colchicine), the binding site of vinblastine is largely unknown and the molecular mechanism of this drug has remained elusive. Here we report the X-ray structure of vinblastine bound to tubulin in a complex with the RB3 protein stathmin-like domain (RB3-SLD). Vinblastine introduces a wedge at the interface of two tubulin molecules and thus interferes with tubulin assembly. Together with electron microscopical and biochemical data, the structure explains vinblastine-induced tubulin self-association into spiral aggregates at the expense of microtubule growth. It also shows that vinblastine and the amino-terminal part of RB3-SLD binding sites share a hydrophobic groove on the alpha-tubulin surface that is located at an intermolecular contact in microtubules. This is an attractive target for drugs designed to perturb microtubule dynamics by interfacial interference, for which tubulin seems ideally suited because of its propensity to self-associate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Dimerization
  • Hydrophobic and Hydrophilic Interactions
  • Kinetics
  • Microtubule Proteins / chemistry
  • Models, Molecular
  • Phosphoproteins / chemistry
  • Protein Structure, Tertiary
  • Stathmin
  • Structure-Activity Relationship
  • Tubulin / chemistry*
  • Tubulin / metabolism*
  • Vinblastine / chemistry*
  • Vinblastine / metabolism
  • Vinblastine / pharmacology*


  • Microtubule Proteins
  • Phosphoproteins
  • Stathmin
  • Tubulin
  • Vinblastine