Structural and Pharmacological Characterization of Novel Potent and Selective Monoclonal Antibody Antagonists of Glucose-dependent Insulinotropic Polypeptide Receptor
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Le résumé fourni par la source
Glucose-dependent insulinotropic polypeptide (GIP) is an endogenous hormonal factor (incretin) that, upon binding to its receptor (GIPr; a class B G-protein-coupled receptor), stimulates insulin secretion by beta cells in the pancreas. There has been a lack of potent inhibitors of the GIPr with prolonged in vivo exposure to support studies on GIP biology. Here we describe the generation of an antagonizing antibody to the GIPr, using phage and ribosome display libraries. Gipg013 is a specific competitive antagonist with equally high potencies to mouse, rat, dog, and human GIP receptors with a K i of 7 nm for the human GIPr. Gipg013 antagonizes the GIP receptor and inhibits GIP-induced insulin secretion in vitro and in vivo . A crystal structure of Gipg013 Fab in complex with the human GIPr extracellular domain (ECD) shows that the antibody binds through a series of hydrogen bonds from the complementarity-determining regions of Gipg013 Fab to the N-terminal α-helix of GIPr ECD as well as to residues around its highly conserved glucagon receptor subfamily recognition fold. The antibody epitope overlaps with the GIP binding site on the GIPr ECD, ensuring competitive antagonism of the receptor. This well characterized antagonizing antibody to the GIPr will be useful as a tool to further understand the biological roles of GIP. Background: GIPr mediates insulin secretion upon GIP stimulation. Results: Gipg013 is a highly specific and potent antagonist of GIPr with a fully characterized mode of action. Conclusion: Gipg013 antagonizes GIPr in vivo , as exemplified by inhibition of GIP-induced insulin secretion. Significance: This antagonizing antibody to the GIPr will be useful as a tool to further understand the biological roles of GIP.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Structural and Pharmacological Characterization of Novel Potent and Selective Monoclonal Antibody Antagonists of Glucose-dependent Insulinotropic Polypeptide Receptor
- Date Crossref
- 01/07/2013
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Recombinant Antibody Technology (United Kingdom) pays non établi dans la noticeEntreprise
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University of Zurich the Department of Biochemistry pays non établi dans la noticeUniversité ou école supérieure
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AstraZeneca (United Kingdom) pays non établi dans la noticeEntreprise
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AstraZeneca (Sweden) pays non établi dans la noticeEntreprise
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Department of Antibody Discovery and Protein Engineering pays non établi dans la noticeInstitution
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Discovery Science pays non établi dans la noticeInstitution
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Bioscience pays non établi dans la noticeInstitution
Recombinant Antibody Technology (United Kingdom), the Department of Biochemistry — University of Zurich et AstraZeneca (United Kingdom), avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.