AI Article Synopsis
- Microtubules, essential components of the cytoskeleton, are potential targets for cancer treatments, and microtubule-stabilizing agents (MSAs) help prevent their breakdown by promoting tubulin polymerization.
- A crystal structure of tubulin bound to the MSA taccalonolide AJ reveals that it covalently attaches to β-tubulin and induces a conformational change that aids in polymerization.
- The binding of AJ also prevents the hydrolysis of GTP at the E-site of tubulin, suggesting a mechanism for its stabilizing effect and informing future designs of MSAs to counteract drug resistance in cancer therapies.
Article Abstract
As a major component of the cytoskeleton, microtubules consist of αβ-tubulin heterodimers and have been recognized as attractive targets for cancer chemotherapy. Microtubule-stabilizing agents (MSAs) promote polymerization of tubulin and stabilize the polymer, preventing depolymerization. The molecular mechanisms by which MSAs stabilize microtubules remain elusive. Here we report a 2.05 Å crystal structure of tubulin complexed with taccalonolide AJ, a newly identified taxane-site MSA. Taccalonolide AJ covalently binds to β-tubulin D226. On AJ binding, the M-loop undergoes a conformational shift to facilitate tubulin polymerization. In this tubulin-AJ complex, the E-site of tubulin is occupied by GTP rather than GDP. Biochemical analyses confirm that AJ inhibits the hydrolysis of the E-site GTP. Thus, we propose that the β-tubulin E-site is locked into a GTP-preferred status by AJ binding. Our results provide experimental evidence for the connection between MSA binding and tubulin nucleotide state, and will help design new MSAs to overcome taxane resistance.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467209 | PMC |
| http://dx.doi.org/10.1038/ncomms15787 | DOI Listing |
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