Stapled Peptides with γ-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction.
Angew Chem Int Ed Engl
; 55(13): 4252-5, 2016 Mar 18.
Article
em En
| MEDLINE
| ID: mdl-26928945
ABSTRACT
"Stapled" peptides are typically designed to replace two non-interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl group in the γ-position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivatorâ
2, which interacts with estrogen receptorâ
α. The best peptide (IC50 =89â
nm) replaces isoleucineâ
689 with an S-γ-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760â
nm). Through X-ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S-γ-methyl peptide minimizes the syn-pentane interactions between the α- and γ-methyl groups.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Receptores de Estrogênio
/
Hidrocarbonetos
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos