2L70

NMR solution structure of GIP in micellular media

Summary for 2L70

• Entry DOI: 10.2210/pdb2l70/pdb
• Related: 1T5Q 2B4N 2L71 2OBU
• NMR Information: BMRB: 17330
• Descriptor: Gastric inhibitory polypeptide (1 entity in total)
• Functional Keywords: gip, docking, ala-scan, type 2 diabetes, hormone
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 4990.59

Authors

Venneti, K.C.,Alana, I.,O'Harte, F.P.M.,Malthouse, P.J.G.,Hewage, C.M. (deposition date: 2010-12-01, release date: 2011-10-19, Last modification date: 2024-05-15)

Primary citation

Venneti, K.C.,Malthouse, J.P.G.,O'Harte, F.P.M.,Hewage, C.M.
Conformational, receptor interaction and alanine scan studies of glucose-dependent insulinotropic polypeptide
Biochim.Biophys.Acta, 1814:882-888, 2011

PubMed 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<0.01 to P<0.001) in cultured pancreatic BRIN-BD11 cells. Receptor interaction studies of the native GIP with the extracellular domain of its receptor were performed by using two different docking algorithms. At the optimised docking conformation, the complex was stabilised by the presence of hydrophobic interactions and intermolecular hydrogen bonding. Further, we have identified some potentially important additional C-terminal interactions of GIP with its N-terminal extracellular receptor domain.

PubMed: 21539943
DOI: 10.1016/j.bbapap.2011.04.002

Experimental method

SOLUTION NMR