The anticancer natural product pironetin selectively targets Lys352 of α-tubulin

Takeo Usui, Hiroyuki Watanabe, Hiroshi Nakayama, Yukio Tada, Naoki Kanoh, Masuo Kondoh, Tetsuji Asao, Koji Takio, Hidenori Watanabe, Kiyohiro Nishikawa, Takeshi Kitahara, Hiroyuki Osada

Research output: Contribution to journalArticlepeer-review

85 Citations (Scopus)


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 α-tubulin. By systematic alanine scanning, the pironetin binding site was determined to be Lys352 of α-tubulin. Lys352 is located at the entrance of a small pocket of α-tubulin, and this pocket faces the β-tubulin of the next dimer. This is the first compound that covalently binds to the α subunit of tubulin and Lys352 of α-tubulin and inhibits the interaction of tubulin heterodimers.

Original languageEnglish
Pages (from-to)799-806
Number of pages8
JournalChemistry and Biology
Issue number6
Publication statusPublished - 2004 Jun
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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