Structural basis for the action of drugs that affect microtubule dynamics

Abstract

The microtubule cytoskeleton is a highly regulated system. Depending on the time in the cell cycle and position within the organism, microtubules can be very stable or highly dynamic. Both stability and dynamics are regulated by interaction with a large number of proteins that themselves may change at specific points in the cell cycle. Other ligands can disrupt the normal processes by either increasing or decreasing microtubule stability, thereby inhibiting the dynamic behaviour. Because altering the natural dynamics can easily lead to inhibition of cell proliferation, tubulin, the main component of microtubules, has been a successful target in cancer therapy and in treatment of a number of other diseases. The recent determination of the structure of tubulin makes it now possible to begin to understand the details of these interactions. We review here the structure of the tubulin dimer as it relates both to the protein-protein interactions involved in microtubule dynamics and to how drugs may bind and modulate these dynamics. Understanding the drug-protein interaction may lead to faster development of drugs that may be better targeted to tubulin isotypes common in tumours or to specific infectious organisms.

• antimitotic drugs
• benzimidazoles
• colchicine
• dinitroanilines
• dynamic instability
• microtubules
• Taxol (paclitaxel)
• tubulin
• vinblastine