Rotational-echo double-resonance NMR distance measurements for the tubulin-bound Paclitaxel conformation

J Am Chem Soc. 2007 Jan 17;129(2):361-70. doi: 10.1021/ja0656604.

Abstract

The important anticancer drug Taxol (paclitaxel, PTX) owes its unique activity to its ability to bind to tubulin in a stoichiometric ratio and promote its assembly into microtubules. The conformation of the microtubule-bound drug has been the focus of numerous research efforts, since the inability of polymerized tubulin to form crystals precludes structure proof by X-ray crystallography. Likewise, although the alpha,beta-tubulin dimer structure has been solved by electron crystallography, the 3.7 A resolution is too low to permit direct determination of either ligand conformation or binding pose. In this article, we present experimental results from 2H{19F} REDOR NMR that provide direct confirmation that paclitaxel adopts a T-shaped conformation when it is bound to tubulin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Binding Sites
  • Cattle
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy / methods*
  • Models, Molecular
  • Molecular Conformation
  • Paclitaxel / chemical synthesis
  • Paclitaxel / chemistry*
  • Paclitaxel / pharmacology
  • Protein Conformation
  • Rotation
  • Sensitivity and Specificity
  • Stereoisomerism
  • Structure-Activity Relationship
  • Time Factors
  • Tubulin / chemistry*

Substances

  • Ligands
  • Tubulin
  • Paclitaxel