SPATIAL DISTRIBUTION OF TUBULIN MUTATIONS CONFERRING RESISTANCE TO ANTIMICROTUBULAR COMPOUNDS

摘要

Resistance to antimicrotubular drugs results from single amino acid replacements in α- and β-tubulin subunits. Two possible mechanisms of action of these replacements are proposed based on analyses of their spatial distribution in the three-dimensional protein model. The main mechanism of action is typical for mutations that are localized in the immediate proximity of binding sites for antimicrotubular drugs. In this case, amino acid replacements can directly influence binding site spatial structure, and result in decreased protein affinity causing resistance only to compounds binding at this site. Mutations that cause multidrug resistance can have an alternative mechanism of action. Spatial distribution of these mutations does not correlate with the ligands' binding sites. One may assume that they effect global changes in the tubulin molecule (e.g., increasing or decreasing the general level of molecular oscillations). Therefore, theses mutations can determine either nonspecific resistance to a number of different microtubule depolymerising agents and, simultaneously, hypersen-sitivity to microtubule stabilizing compounds, or vice versa.