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Publication Abstract from PubMed

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 betaHis229, 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 betaIII-tubulin (betaIII) 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 betaIII-tubulin and betaIII tubulin-mediated drug resistance. This supports the idea that overexpression of betaIII increases microtubule dynamicity by counteracting the enhanced microtubule stability promoted by covalent taxane-site binding ligands.

Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands.,Balaguer FA, Muhlethaler T, Estevez-Gallego J, Calvo E, Gimenez-Abian JF, Risinger AL, Sorensen EJ, Vanderwal CD, Altmann KH, Mooberry SL, Steinmetz MO, Oliva MA, Prota AE, Diaz JF Int J Mol Sci. 2019 Mar 20;20(6). pii: ijms20061392. doi: 10.3390/ijms20061392. PMID:30897704^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.