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Mechanism of microtubule stabilization by taccalonolide AJ.

<div class='caption-title'>Effect of AJ on tubulin oligomerization.</div>
<div class='caption-title'>AJ covalent binding to β-tubulin.</div>
<div class='caption-title'>Possible reaction mechanisms of the ester bond between taccalonolide AJ and β-tubulin D226.</div>
Wang Y, Yu Y, Li GB, Li SA, Wu C, Gigant B, Qin W, Chen H, Wu Y, Chen Q, Yang J
OpenAccess logo Nat Commun 8 15787 (2017)
Cited: 32 times
EuropePMC logo PMID: 28585532

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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