Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands

Open access
Date
2019-03-02Type
- Journal Article
Citations
Cited 16 times in
Web of Science
Cited 15 times in
Scopus
ETH Bibliography
yes
Altmetrics
Abstract
It has been proposed that one of the mechanisms of taxane-site ligand-mediated tubulin activation is modulation of the structure of a switch element (the M-loop) from a disordered form in dimeric tubulin to a folded helical structure in microtubules. Here, we used covalent taxane-site ligands, including cyclostreptin, to gain further insight into this mechanism. The crystal structure of cyclostreptin-bound tubulin reveals covalent binding to βHis229, but no stabilization of the M-loop. The capacity of cyclostreptin to induce microtubule assembly compared to other covalent taxane-site agents demonstrates that the induction of tubulin assembly is not strictly dependent on M-loop stabilization. We further demonstrate that most covalent taxane-site ligands are able to partially overcome drug resistance mediated by βIII-tubulin (βIII) overexpression in HeLa cells, and compare their activities to pironetin, an interfacial covalent inhibitor of tubulin assembly that displays invariant growth inhibition in these cells. Our findings suggest a relationship between a diminished interaction of taxane-site ligands with βIII-tubulin and βIII tubulin-mediated drug resistance. This supports the idea that overexpression of βIII increases microtubule dynamicity by counteracting the enhanced microtubule stability promoted by covalent taxane-site binding ligands. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000336644Publication status
publishedExternal links
Journal / series
International Journal of Molecular SciencesVolume
Pages / Article No.
Publisher
MDPISubject
cyclostreptin; tubulin; microtubules; multidrug resistance; taxanesOrganisational unit
03647 - Altmann, Karl-Heinz / Altmann, Karl-Heinz
More
Show all metadata
Citations
Cited 16 times in
Web of Science
Cited 15 times in
Scopus
ETH Bibliography
yes
Altmetrics