Structure-function analysis of a series of novel GIP analogues containing different helical length linkers.
Biochemistry
; 42(10): 3081-8, 2003 Mar 18.
Article
em En
| MEDLINE
| ID: mdl-12627975
ABSTRACT
Glucose-dependent insulinotropic polypeptide (GIP1-42) is a potent glucose-lowering intestinal peptide hormone. The equipotent GIP1-30NH2 was structurally modified by linking N- and C-terminal fragments with several different linkers. Substitution of the middle region of GIP by a flexible aminohexanoic linker resulted in greatly reduced binding affinity and reduction or complete loss of bioactivity. Connection of the bioactive domains GIP1-14 and GIP19-30NH2 by EKEK or AAAA linkers resulted in peptide agonists with approximately 3-4-fold increased bioactivity as compared to GIP1-30NH2. Conformational analysis by CD spectroscopy of GIP fragments and analogues suggests a helical region in the C-terminal (19-30) portion of GIP. It was demonstrated that stabilization of this C-terminal helical region by the introduction of helical linkers favored binding and activation of the GIP receptor. Our results suggest an important contribution of a direct interaction of the first 14 amino acids with the GIP receptor, an appropriate relative orientation of N- and C-terminal parts of GIP, and the presence of helical linkers to be essential for bioactivity.
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Base de dados:
MEDLINE
Assunto principal:
Polipeptídeo Inibidor Gástrico
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Biochemistry
Ano de publicação:
2003
Tipo de documento:
Article
País de afiliação:
Alemanha