The anticancer natural product pironetin selectively targets Lys352 of alpha-tubulin.
Chem Biol
; 11(6): 799-806, 2004 Jun.
Article
em En
| MEDLINE
| ID: mdl-15217613
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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pironas
/
Moduladores de Tubulina
/
Lisina
/
Antineoplásicos
Limite:
Animals
Idioma:
En
Revista:
Chem Biol
Assunto da revista:
BIOLOGIA
/
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Japão