A pathway to the design of even more effective versions of the powerful anti-cancer drug Taxol has been opened with the most detailed look ever at the assembly and disassembly of microtubules, tiny fibers of tubulin protein that form the cytoskeletons of living cells and play a crucial role in mitosis. Through a combination of high-resolution cryo-electron microscopy (cryo-EM) and new methodology for image analysis and structure interpretation, researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) Berkeley have produced images of microtubule assembly and disassembly at the unprecedented resolution of 5 angstroms (). Among other insights, these observations provide the first explanation of Taxol's success as a cancer chemotherapy agent.
"This is the first experimental demonstration of the link between nucleotide state and tubulin conformation within the microtubules and, by extension, the relationship between tubulin conformation and the transition from assembled to disassembled microtubule structure," says Eva Nogales, a biophysicist with Berkeley Lab's Life Sciences Division who led this research. "We now have a clear understanding of how hydrolysis of guanosine triphosphate (GTP) leads to microtubule destabilization and how Taxol works to inhibit this activity."
Nogales, who is also a professor of biophysics and structural biology at UC Berkeley, as well as an investigator with the Howard Hughes Medical Institute, is the corresponding author of a paper describing this research in the journal Cell. The paper is entitled "High resolution αβ microtubule structures reveal the structural transitions in tubulin upon GTP hydrolysis." Co-authors are Gregory Alushin, Gabriel Lander, Elizabeth Kellogg, Rui Zhang and David Baker.
During mitosis, the process by which a dividing cell duplicates its chromosomes and distributes them between two daughter cells, microtubules
|Contact: Lynn Yarris|
DOE/Lawrence Berkeley National Laboratory