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Chem Biol. 2012 Jun 22;19(6):686-98. doi: 10.1016/j.chembiol.2012.05.008.

Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules.

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1
School of Biological Sciences, Victoria University of Wellington, Wellington 6012, New Zealand.

Abstract

Zampanolide and its less active analog dactylolide compete with paclitaxel for binding to microtubules and represent a new class of microtubule-stabilizing agent (MSA). Mass spectrometry demonstrated that the mechanism of action of both compounds involved covalent binding to β-tubulin at residues N228 and H229 in the taxane site of the microtubule. Alkylation of N228 and H229 was also detected in α,β-tubulin dimers. However, unlike cyclostreptin, the other known MSA that alkylates β-tubulin, zampanolide was a strong MSA. Modeling the structure of the adducts, using the NMR-derived dactylolide conformation, indicated that the stabilizing activity of zampanolide is likely due to interactions with the M-loop. Our results strongly support the existence of the luminal taxane site of microtubules in tubulin dimers and suggest that microtubule nucleation induction by MSAs may proceed through an allosteric mechanism.

PMID:
22726683
PMCID:
PMC3383615
DOI:
10.1016/j.chembiol.2012.05.008
[Indexed for MEDLINE]
Free PMC Article

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