The structure of an MDM2-Nutlin-3a complex solved by the use of a validated MDM2 surface-entropy reduction mutant.
Acta Crystallogr D Biol Crystallogr
; 69(Pt 8): 1358-66, 2013 Aug.
Article
em En
| MEDLINE
| ID: mdl-23897459
ABSTRACT
The p53-binding site of MDM2 holds great promise as a target for therapeutic intervention in MDM2-amplified p53 wild-type forms of cancer. Despite the extensive validation of this strategy, there are relatively few crystallographically determined co-complex structures for small-molecular inhibitors of the MDM2-p53 interaction available in the PDB. Here, a surface-entropy reduction mutant of the N-terminal domain of MDM2 that has been designed to enhance crystallogenesis is presented. This mutant has been validated by comparative ligand-binding studies using differential scanning fluorimetry and fluorescence polarization anisotropy and by cocrystallization with a peptide derived from p53. Using this mutant, the cocrystal structure of MDM2 with the benchmark inhibitor Nutlin-3a has been determined, revealing subtle differences from the previously described co-complex of MDM2 with Nutlin-2.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Proteínas Proto-Oncogênicas c-mdm2
/
Imidazóis
Limite:
Humans
Idioma:
En
Revista:
Acta Crystallogr D Biol Crystallogr
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Reino Unido