Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases.
J Am Chem Soc
; 133(32): 12474-7, 2011 Aug 17.
Article
em En
| MEDLINE
| ID: mdl-21790156
ABSTRACT
Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 Å-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
/
Tiazóis
/
Depsipeptídeos
/
Inibidores de Histona Desacetilases
/
Histona Desacetilases
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2011
Tipo de documento:
Article