Physiochemical aspects of tubulin-interacting antimitotic drugs.
A diverse group of natural biological compounds bind to microtubules and suppress microtubule dynamics. Here we review the mechanism of microtubule assembly and dynamics as well as structural features that are important for nucleotide binding, GTP hydrolysis and stabilization of longitudinal and lateral protofilament contacts. Specific emphasis is placed upon the polar structure of the microtubule, the exposure of the nucleotide hydrolysis site at the + end and the conformational and configurational plasticity of the microtubule lattice. These features have important implications for the mechanism of dynamic instability and the disruptive action of antimitotic drugs. We then discuss the various classes of tubulin binding drugs emphasizing their site and mode of binding as well as the structural and energetic basis for their effects on microtubule assembly and dynamics. A common feature of tubulin-interacting compounds is a linkage to assembly, either the stabilization of a microtubule lattice by compounds like taxol or epothilone A, or the preferential formation of alternate lattice contacts and polymers at microtubule ends by compounds like colchicine, vinca alkaloids and cryptophycin-52. Finally, we explore the likely possibility that these drugs also disrupt the regulation of microtubule dynamics. Future generations of these compounds may be selectively developed to directly target the proteins that regulate mitotic spindle dynamics.
Correia
J J
JJ
Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS 39216, USA. correia@biochem.umsmed.edu
Lobert
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D003078:Colchicine / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects; D017239:Paclitaxel / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D014748:Vinca Alkaloids / Q000378:metabolism
D000970:Antineoplastic Agents; D014404:Tubulin; D014748:Vinca Alkaloids; D017239:Paclitaxel; D003078:Colchicine