Antascomicin B stabilizes FKBP51-Akt1 complexes as a molecular glue.
Bioorg Med Chem Lett
; 104: 129728, 2024 May 15.
Article
em En
| MEDLINE
| ID: mdl-38582133
ABSTRACT
Antascomicin B is a natural product that similarly to the macrolides FK506 and Rapamycin binds to the FK506-binding protein 12 (FKBP12). FK506 and Rapamycin act as molecular glues by inducing ternary complexes between FKBPs and additional target proteins. Whether Antascomicin B can induce ternary complexes is unknown. Here we show that Antascomicin B binds tightly to larger human FKBP homologs. The cocrystal structure of FKBP51 in complex with Antascomicin B revealed that large parts of Antascomicin B are solvent-exposed and available to engage additional proteins. Cellular studies demonstrated that Antascomicin B enhances the interaction between human FKBP51 and human Akt. Our studies show that molecules with molecular glue-like properties are more prominent in nature than previously thought. We predict the existence of additional 'orphan' molecular glues that evolved to induce ternary protein complexes but where the relevant ternary complex partners are unknown.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tacrolimo
/
Proteínas de Ligação a Tacrolimo
/
Proteínas Proto-Oncogênicas c-akt
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Alemanha