The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
Cyclostreptin binds covalently to microtubule pores and lumenal taxoid binding sites
Abstract
Cyclostreptin (1), a natural product from Streptomyces sp. 9885, irreversibly stabilizes cellular microtubules, causes cell cycle arrest, evades drug resistance mediated by P-glycoprotein in a tumor cell line and potently inhibits paclitaxel binding to microtubules, yet it only weakly induces tubulin assembly. In trying to understand this paradox, we observed irreversible binding of synthetic cyclostreptin to tubulin. This results from formation of covalent crosslinks to beta-tubulin in cellular microtubules and microtubules formed from purified tubulin in a 1:1 total stoichiometry distributed between Thr220 (at the outer surface of a pore in the microtubule wall) and Asn228 (at the lumenal paclitaxel site). Unpolymerized tubulin was only labeled at Thr220. Thus, the pore region of beta-tubulin is an undescribed binding site that (i) elucidates the mechanism by which taxoid-site compounds reach the kinetically unfavorable lumenal site and (ii) explains how taxoid-site drugs induce microtubule formation from dimeric and oligomeric tubulin.
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“These nucleophilic centers are also present in DNA and other biologically relevant compounds, such as glutathione.116–121”
From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [119]
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Metadata
- Authors
- Buey, R. M., Calvo, E., Barasoain, I., Pineda, O., Edler, M. C., Matesanz, R., Cerezo, G., Vanderwal, C. D., Day, B. W., Sorensen, E. J., López, J. A., Andreu, J. M., Hamel, E., & Díaz, J. F.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Spanish National Centre for Cardiovascular Research (ES)
- Universitat de Barcelona (ES)
- National Institutes of Health (US)
- PharmaMar (Spain) (ES)
- University of California, Irvine (US)
- University of Pittsburgh (US)
- Princeton University (US)
- Corresponding author
- Díaz, J Fernando
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2007-01-07
- Volume
- 3
- Issue
- 2
- Pages
- 117-125
- ISSN
- 1552-4450 (ISSN-L)
- OpenAlex
- W1968782838
- Cited by
- 156
- References
- 31
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 7 · 2021: 3 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 14 · 2016: 5 · 2015: 9 · 2014: 12 · 2013: 11 · 2012: 10
- FWCI
- 5.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
- Keywords
- microtubule stabilization, beta-tubulin, covalent binding, cell cycle arrest, tubulin assembly
- MeSH terms
- Docetaxel, Alkanes, Amino Acid Sequence, Asparagine, Binding Sites, Binding, Competitive, Carbamates, Cell Cycle, Humans, Lactones, Microtubules, Models, Chemical, Models, Molecular, Molecular Sequence Data, Polycyclic Compounds, Protein Binding, Pyrones, Mass Spectrometry, Threonine, Tubulin, Paclitaxel, Inhibitory Concentration 50, Epothilones, Taxoids, Cell Line, Tumor, Cell Proliferation, Tubulin Modulators
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