title: The tubulin binding mode of microtubule stabilizing agents studied by electron crystallography.
abstract: Since tubulin was discovered in 1967, drug probes have been used to manipulate mechanisms of microtubule polymerization and disassembly. In parallel, advances in optical imagery, electron microscopy, along with both electron and X-ray diffraction have provided ability to "see" the molecular underpinning of these machines. Nanoscale mapping of different tubulin polymers formed in the presence of different drugs and cofactors provide a context for examining the dynamic features relevant to their biological activity. Models built from EM maps have been used to understand the binding of stabilizing drugs such as taxanes and epothilones, to predict more effective molecules, and to explain mutation based resistance. Here, we discuss drug binding in the context of different polymeric forms and propose a trigger mechanism associated with microtubules' dynamic instability.
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Laboratory of Biochemical Pharmacology (LOBP) VA Medical Center - Medical Research, 151H/5A-146 1670 Clairmont Road, Decatur, GA 30033, USA, jnettle@emory.edu.
authors.forename: James H
authors.initials: JH
authors.lastname: Nettles
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Downing