Journal
ACS CHEMICAL BIOLOGY
Volume 6, Issue 8, Pages 789-799Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb200099u
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Funding
- MICINN [BIO2010-16351, BQU2009-08536]
- Comunidad de Madrid
- EPSRC
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The binding interactions of two antitumor agents that target the paclitaxel site, docetaxel and discodermolide, to unassembled alpha/beta-tubulin heterodimers and microtubules have been studied using biochemical and NMR techniques. The use of discodermolide as a water-soluble paclitaxel biomimetic and extensive NMR experiments allowed the detection of binding of microtubule-stabilizing agents to unassembled tubulin alpha/beta-heterodimers. The bioactive 3D structures of docetaxel and discodermolide bound to alpha/beta-heterodimers were elucidated and compared to those bound to microtubules, where subtle changes in the conformations, of docetaxel in its different bound states were evident Moreover, the combination of experimental TR-NOE and STD NMR data with CORCEMA-ST calculations indicate that docetaxel and discodermolide target an additional binding site at the pore of the microtubules, which is different from the internal binding site at the lumen previously, determined by electron crystallography. Binding to this pore site can then be considered as the first ligand-protein recognition event that takes place in advance of the drug internalization process and interaction with the lumen of the micro tubules.
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