The bioactive conformation of glucose-dependent insulinotropic polypeptide by NMR and CD spectroscopy

Inigo Alana, J Paul G Malthouse, Finbarr PM O'Harte, Chandralal M Hewage

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal incretin hormone, which modulates physiological insulin secretion. Because of its glucose-sensitive insulinotropic activity, there has been a considerable interest in utilizing the hormone as a potential treatment for type 2 diabetes. Structural parameters obtained from NMR spectroscopy combined with molecular modeling techniques play a vital role in the design of new therapeutic drugs. Therefore, to understand the structural requirements for the biological activity of GIP, the solution structure of GIP was investigated by circular dichroism (CD) followed by proton nuclear magnetic resonance (NMR) spectroscopy. CD studies showed an increase in the helical character of the peptide with increasing concentration of trifluoroethanol (TFE) up to 5%. Therefore, the solution structure of GIP in 50% TFE was determined. It was found that there was an a-helix between residues 6 and 29, which tends to extend further up to residue 36. The implications of the C-terminal extended helical segment in the inhibitory properties of GIP on gastric acid secretion are discussed. It is shown that the adoption by GIP of an a-helical secondary structure is a requirement for its biological activity. Knowledge of the solution structure of GIP will help in the understanding of how the peptide interacts with its receptor and aids in the design of new therapeutic agents useful for the treatment of diabetes.
LanguageEnglish
Pages92-99
JournalProteins
Volume68
Issue number1
DOIs
Publication statusPublished - Jul 2007

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Circular dichroism spectroscopy
Conformations
Nuclear magnetic resonance
Glucose
Peptides
Trifluoroethanol
Medical problems
Bioactivity
Nuclear magnetic resonance spectroscopy
Incretins
Molecular modeling
Hormones
Insulin

Cite this

Alana, Inigo ; Malthouse, J Paul G ; O'Harte, Finbarr PM ; Hewage, Chandralal M. / The bioactive conformation of glucose-dependent insulinotropic polypeptide by NMR and CD spectroscopy. In: Proteins. 2007 ; Vol. 68, No. 1. pp. 92-99.
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abstract = "Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal incretin hormone, which modulates physiological insulin secretion. Because of its glucose-sensitive insulinotropic activity, there has been a considerable interest in utilizing the hormone as a potential treatment for type 2 diabetes. Structural parameters obtained from NMR spectroscopy combined with molecular modeling techniques play a vital role in the design of new therapeutic drugs. Therefore, to understand the structural requirements for the biological activity of GIP, the solution structure of GIP was investigated by circular dichroism (CD) followed by proton nuclear magnetic resonance (NMR) spectroscopy. CD studies showed an increase in the helical character of the peptide with increasing concentration of trifluoroethanol (TFE) up to 5{\%}. Therefore, the solution structure of GIP in 50{\%} TFE was determined. It was found that there was an a-helix between residues 6 and 29, which tends to extend further up to residue 36. The implications of the C-terminal extended helical segment in the inhibitory properties of GIP on gastric acid secretion are discussed. It is shown that the adoption by GIP of an a-helical secondary structure is a requirement for its biological activity. Knowledge of the solution structure of GIP will help in the understanding of how the peptide interacts with its receptor and aids in the design of new therapeutic agents useful for the treatment of diabetes.",
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The bioactive conformation of glucose-dependent insulinotropic polypeptide by NMR and CD spectroscopy. / Alana, Inigo; Malthouse, J Paul G; O'Harte, Finbarr PM; Hewage, Chandralal M.

In: Proteins, Vol. 68, No. 1, 07.2007, p. 92-99.

Research output: Contribution to journalArticle

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AB - Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal incretin hormone, which modulates physiological insulin secretion. Because of its glucose-sensitive insulinotropic activity, there has been a considerable interest in utilizing the hormone as a potential treatment for type 2 diabetes. Structural parameters obtained from NMR spectroscopy combined with molecular modeling techniques play a vital role in the design of new therapeutic drugs. Therefore, to understand the structural requirements for the biological activity of GIP, the solution structure of GIP was investigated by circular dichroism (CD) followed by proton nuclear magnetic resonance (NMR) spectroscopy. CD studies showed an increase in the helical character of the peptide with increasing concentration of trifluoroethanol (TFE) up to 5%. Therefore, the solution structure of GIP in 50% TFE was determined. It was found that there was an a-helix between residues 6 and 29, which tends to extend further up to residue 36. The implications of the C-terminal extended helical segment in the inhibitory properties of GIP on gastric acid secretion are discussed. It is shown that the adoption by GIP of an a-helical secondary structure is a requirement for its biological activity. Knowledge of the solution structure of GIP will help in the understanding of how the peptide interacts with its receptor and aids in the design of new therapeutic agents useful for the treatment of diabetes.

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