Conformational, receptor interaction and alanine scan studies of glucose-dependent insulinotropic polypeptide.

KC Venneti, JP Malthouse, Finbarr O'Harte, CM Hewage

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) is an insulinotropic incretin hormone that stimulates insulin secretion during a meal. GIP has glucose lowering abilities and hence is considered as a potential target molecule for type 2 diabetes therapy. In this article, we present the solution structure of GIP in membrane-mimicking environments by proton NMR spectroscopy and molecular modelling. GIP adopts an α-helical conformation between residues Phe(6)-Gly(31) and Ala(13)-Gln(29) for micellar and bicellar media, respectively. Previously we examined the effect of N-terminal Ala substitution in GIP, but here eight GIP analogues were synthesised by replacing individual residues within the central 8-18 region with alanine. These studies showed relatively minor changes in biological activity as assessed by insulin releasing potency. However, at higher concentration, GIP(Ala(16)), and GIP(Ala(18)) showed insulin secreting activity higher than the native GIP (P
LanguageEnglish
Pages882-888
JournalBiochim Biophys Acta.
Volume1814
Issue number7
Publication statusPublished - 1 Jul 2011

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Glucose
Peptides
Insulin
alanine receptor
Incretins
Alanine
Type 2 Diabetes Mellitus
Meals
Protons
Magnetic Resonance Spectroscopy
Hormones
Membranes

Cite this

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Conformational, receptor interaction and alanine scan studies of glucose-dependent insulinotropic polypeptide. / Venneti, KC; Malthouse, JP; O'Harte, Finbarr; Hewage, CM.

Vol. 1814, No. 7, 01.07.2011, p. 882-888.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Venneti, KC

AU - Malthouse, JP

AU - O'Harte, Finbarr

AU - Hewage, CM

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AB - Glucose-dependent insulinotropic polypeptide (GIP) is an insulinotropic incretin hormone that stimulates insulin secretion during a meal. GIP has glucose lowering abilities and hence is considered as a potential target molecule for type 2 diabetes therapy. In this article, we present the solution structure of GIP in membrane-mimicking environments by proton NMR spectroscopy and molecular modelling. GIP adopts an α-helical conformation between residues Phe(6)-Gly(31) and Ala(13)-Gln(29) for micellar and bicellar media, respectively. Previously we examined the effect of N-terminal Ala substitution in GIP, but here eight GIP analogues were synthesised by replacing individual residues within the central 8-18 region with alanine. These studies showed relatively minor changes in biological activity as assessed by insulin releasing potency. However, at higher concentration, GIP(Ala(16)), and GIP(Ala(18)) showed insulin secreting activity higher than the native GIP (P

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