Download MendeleyCrystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands.
Balaguer, F.A., Muhlethaler, T., Estevez-Gallego, J., Calvo, E., Gimenez-Abian, J.F., Risinger, A.L., Sorensen, E.J., Vanderwal, C.D., Altmann, K.H., Mooberry, S.L., Steinmetz, M.O., Oliva, M.A., Prota, A.E., Diaz, J.F.(2019) Int J Mol Sci 20
- PubMed: 30897704
- DOI: https://doi.org/10.3390/ijms20061392
- Primary Citation of Related Structures:
6QTN - PubMed 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.
Organizational Affiliation:
Structural and Chemical Biology Department. Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain. [email protected].
