Publication: Identification and Characterization of an Intermediate Taxol Binding Site Within Microtubule Nanopores and a Mechanism for Tubulin Isotype Binding Selectivity
All || By Area || By Year| Title | Identification and Characterization of an Intermediate Taxol Binding Site Within Microtubule Nanopores and a Mechanism for Tubulin Isotype Binding Selectivity | Authors/Editors* | H. Freedman, T. Huzil, T. Luchko, R. Luduena, J.A. Tuszynski, |
|---|---|
| Where published* | Journal of Chemical Informatics and Modeling |
| How published* | Journal |
| Year* | 2009 |
| Volume | 49 |
| Number | 2 |
| Pages | 424-436 |
| Publisher | |
| Keywords | |
| Link | |
| Abstract |
The tubulin molecule, the subunit of microtubules, is remarkable for the variety of small molecules to which it binds. Many of these molecules are very useful or promising agents in cancer chemotherapy. One of the most useful of these is paclitaxel. The tubulin molecule is itself an α/β heterodimer, both α and β existing as multiple isotypes. Despite the success of paclitaxel as an anti-cancer drug, resistance often occurs in cancer cells and has been associated with variations in tubulin isotype levels, most notably with increased βIII. Paclitaxel is thought to reach its binding site on tubulin by diffusion through nanopores in the microtubule wall. It has been suggested that a transitional step in this process may be the binding of paclitaxel to an intermediate site within a nanopore, from which it moves directly to its binding site in the microtubule interior. To test this hypothesis, we have computationally docked paclitaxel within a microtubule nanopore and simulated its passage to the luminal binding site. Targeted molecular dynamics was used to test the hypothesis that paclitaxel may use the H6/H7 loop as a hinge to move directly from the intermediate binding site to the luminal binding site. We observed that this motion is apparently stabilized by the formation of a hydrogen bond involving serine 275 in β tubulin isotypes I, IIa, IIb, IVa, IVb, V, VII, and VIII. Interestingly, this residue is replaced by alanine in the βIII isotype. This raises the possibility that the observed isotype difference in paclitaxel binding may be a kinetic effect arising from the isotype difference at this residue. Based on this observation, we are able to suggest derivatives of paclitaxel that may reverse the isotype-specificity, or lead to an alternate stabilizing hydrogen-bond interaction with tubulin, thus increasing the rate of passage to the luminal binding site. |
Back to page 39 of list