Taccalonolide binding to tubulin imparts microtubule stability and potent in vivo activity.

@article{Risinger2013TaccalonolideBT,
  title={Taccalonolide binding to tubulin imparts microtubule stability and potent in vivo activity.},
  author={A. L. Risinger and J. Li and M. Bennett and C. Rohena and J. Peng and D. Schriemer and S. Mooberry},
  journal={Cancer research},
  year={2013},
  volume={73 22},
  pages={
          6780-92
        }
}
The taccalonolides are highly acetylated steroids that stabilize cellular microtubules and overcome multiple mechanisms of taxane resistance. Recently, two potent taccalonolides, AF and AJ, were identified that bind to tubulin directly and enhance microtubule polymerization. Extensive studies were conducted to characterize these new taccalonolides. AF and AJ caused aberrant mitotic spindles and bundling of interphase microtubules that differed from the effects of either paclitaxel or… Expand
Mechanism of microtubule stabilization by taccalonolide AJ
TLDR
This work proposes that the β-tubulin E-site is locked into a GTP-preferred status by AJ binding, and provides experimental evidence for the connection between MSA binding and tubulin nucleotide state, and will help design new MSAs to overcome taxane resistance. Expand
Taccalonolide Microtubule Stabilizers.
TLDR
The recent identification of a site on the taccalonolide scaffold that is amenable to modification has provided evidence of the specificity of the tcolynolide-tubulin interaction, which affords an opportunity to further optimize the targeted delivery of the Tacca class of microtubule stabilizers to further improve their anticancer efficacy and potential for clinical development. Expand
The taccalonolides and paclitaxel cause distinct effects on microtubule dynamics and aster formation
TLDR
It is concluded that the increased resistance of microtubule plus ends to catastrophe may play a role in the observed inability of taccalonolide-induced asters to coalesce during mitosis, giving rise to the distinct morphologies observed after exposure to these agents. Expand
Elucidating target specificity of the taccalonolide covalent microtubule stabilizers employing a combinatorial chemical approach
TLDR
These carefully optimized, cell-permeable probes outperform commercial taxane-based probes and enable direct visualization of taccalonolides in both live and fixed cells with dramatic microtubule colocalization. Expand
Zampanolide Binding to Tubulin Indicates Cross-Talk of Taxane Site with Colchicine and Nucleotide Sites.
TLDR
The covalent binding of zampanolide to β-tubulin affects both the colchicine site, causing a change of the quantum yield of the bound ligand, and the exchangeable nucleotide binding site, reducing the affinity for the nucleotide. Expand
Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands
TLDR
The findings suggest a relationship between a diminished interaction of taxane-site ligands with βIII-tubulin and βIII tubulin-mediated drug resistance, which supports the idea that overexpression of βIII increases microtubule dynamicity by counteracting the enhanced micro Tubulin stability promoted by covalent taxanes-site binding ligands. Expand
Zampanolide, a Microtubule-Stabilizing Agent, Is Active in Resistant Cancer Cells and Inhibits Cell Migration
TLDR
Zampanolide was an effective inhibitor of migration of human umbilical vein endothelial cells (HUVEC) and fibroblast cells (D551) and was not susceptible to single amino acid mutations at the taxoid site of β-tubulin in human ovarian cancer 1A9 cells. Expand
Unravelling the covalent binding of zampanolide and taccalonolide AJ to a minimalist representation of a human microtubule
TLDR
Evidence supporting the existence of a commonly neglected intramolecular disulfide bond between Cys241 and Cys356 in β-tubulin that contributes to protein compactness and is absent in the βIII isotype associated with resistance to taxanes and other drugs is obtained. Expand
Pharmacokinetic Analysis and in Vivo Antitumor Efficacy of Taccalonolides AF and AJ.
TLDR
Why some, but not all, taccalonolides inhibit the growth of tumors at systemically tolerable doses is defined and prompt studies to further improve their pharmacokinetic profile and antitumor efficacy are prompt. Expand
An overview of tubulin modulators deposited in protein data bank
Microtubules are cytoskeletal polymers of tubulin and composed of α- and β-tubulin heterodimers, which are regarded as one of the most important, promising and successful targets for chemotherapeuticExpand
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