ArticleInternational journal of molecular sciences2019
Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands.
Article in International journal of molecular sciences, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 28 citations in OpenAlex.
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- Molecular Evolution of Tubulins in Diatoms.International journal of molecular sciences · 2022Article
- Taccalonolides: Structure, semi-synthesis, and biological activity.Frontiers in pharmacology · 2022Review
- CLIP-170S is a microtubule +TIP variant that confers resistance to taxanes by impairing drug-target engagement.Developmental cell · 2021Article
- Efficacy of a Covalent Microtubule Stabilizer in Taxane-Resistant Ovarian Cancer Models.Molecules (Basel, Switzerland) · 2021Article
- Taccalonolide C-6 Analogues, Including Paclitaxel Hybrids, Demonstrate Improved Microtubule Polymerizing Activities.Journal of natural products · 2021Article
- Multicomponent reaction-derived covalent inhibitor space.Science advances · 2021Article
- Synthesis and Biological Evaluations of Electrophilic Steroids Inspired by the Taccalonolides.ACS medicinal chemistry letters · 2020Article
- Targeting and extending the eukaryotic druggable genome with natural products: cytoskeletal targets of natural products.Natural product reports · 2020Review
- Elucidating target specificity of the taccalonolide covalent microtubule stabilizers employing a combinatorial chemical approach.Nature communications · 2020Article
- Taccalonolide Microtubule Stabilizers.Progress in the chemistry of organic natural products · 2020Review
- Revisiting microtubule targeting agents: α-Tubulin and the pironetin binding site as unexplored targets for cancer therapeutics.Bioorganic & medicinal chemistry letters · 2019Review
- Unravelling the covalent binding of zampanolide and taccalonolide AJ to a minimalist representation of a human microtubule.Journal of computer-aided molecular design · 2019Article
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Authors and funding
14 authors at 8 institutions in 3 countries.
Funding
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.
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