AI Article Synopsis
- Pironetin is a strong inhibitor that prevents tubulin assembly and stops cells from progressing through the M phase of the cell cycle.
- It binds covalently to tubulin, with experiments showing that biotinylated pironetin effectively inhibits tubulin assembly both in controlled lab settings and within cells.
- The specific binding site for pironetin on tubulin was identified as Lys352 on the C-terminal of alpha-tubulin, which impacts the interaction between tubulin's alpha and beta subunits.
Article Abstract
Pironetin is a potent inhibitor of tubulin assembly and arrests cell cycle progression in M phase. Analyses of its structure-activity relationships suggested that pironetin covalently binds tubulin. To determine the binding site of pironetin, we synthesized biotinylated pironetin, which inhibited tubulin assembly both in vitro and in situ. The biotinylated pironetin selectively and covalently bound with tubulin. Partial digestion of biotinylated pironetin-treated tubulin by several proteases revealed that the binding site is the C-terminal portion of alpha-tubulin. By systematic alanine scanning, the pironetin binding site was determined to be Lys352 of alpha-tubulin. Lys352 is located at the entrance of a small pocket of alpha-tubulin, and this pocket faces the beta-tubulin of the next dimer. This is the first compound that covalently binds to the alpha subunit of tubulin and Lys352 of alpha-tubulin and inhibits the interaction of tubulin heterodimers.
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| http://dx.doi.org/10.1016/j.chembiol.2004.03.028 | DOI Listing |
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