Having determined how paclitaxel fits into a cancer cell's reproductive machinery, the team is optimistic that simpler molecules can be designed as future medicines.
Kingston will present the research that brought the team to this point at the 227th Annual Meeting of the American Chemical Society, being held in Anaheim, Calif., March 28 through April 1, 2004.
Paclitaxel, a natural compound from yew trees, is a relatively scarce resource, but synthetic forms and analogs have, so far, been less effective. So scientists have continued to study how the paclitaxel molecule works in order to develop more effective products.
Kingston explains that paclitaxel binds to tubulin, a protein molecule that forms the backbone of microtubules. Microtubules are a cell component whose duties include allowing chromosomes to move into the correct position for the cell to divide into two daughter cells.
"When paclitaxel binds to tubulin, it stabilizes the microtubules and messes up the equilibrium between tubulin and microtubule," says Kingston. "A cell with stable microtubules proceeds to programmed cell death without dividing,"
How does paclitaxel bind to tubulin? There is a binding pocket in the protein into which part of the paclitaxel molecule fits. This binding pocket has been visualized by some elegant electron crystallography experiments carried out by scientists at the Lawrence Berkeley National Laboratory (Nogales et al., Cell, 1999, 96, 79). Paclitaxel consists of a rigid ring system attached to a flexible side chain, but the exact arrangement of the side chain in space is not known. Kingston explains, "The issue has been, what is the shape or orientation of the side chain when pa
Contact: Susan Trulove