The antiangiogenic and antitumor activities of the N-terminal fragment of endostatin augmented by Ile/Arg substitution: The overall structure implicated the biological activity.
Biochim Biophys Acta
; 1864(12): 1765-1774, 2016 12.
Article
em En
| MEDLINE
| ID: mdl-27693049
ABSTRACT
The antiangiogenic and antitumor activities of the 27-amino acid fragment corresponding to the N-terminal domain of endostatin were shown to be dependent on a Zn-binding loop in the N-terminus. To investigate whether the regions outside of the N-terminal loop play a role in the peptide function, the structure and function of a variant containing Ile26Arg mutation (ES-R) were compared with those of the native peptide (ES-Zn). Structural analysis using far-UV CD, intrinsic fluorescence and molecular dynamics simulation provided information regarding the overall changes upon the mutation. In addition, the docking simulations predicted a higher affinity of ES-R to integrins αvß3 and α5ß1 than ES-Zn and a profound reorganization of the binding residues throughout the sequence. In Human Umbilical Vein Endothelial Cells (HUVECs), ES-R inhibited the tube formation and activated caspase-3 more strongly than do ES-Zn. Based on in vivo studies, the growth of breast tumor and expression of CD31, Bcl-2 and nonfunctional p53 were inhibited more effectively by ES-R than by ES-Zn. We conclude that the C-terminal region is involved in the peptide function through some global structural effects.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores da Angiogênese
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Endostatinas
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Biochim Biophys Acta
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Irã