4HJ0

Crystal structure of the human GIPr ECD in complex with Gipg013 Fab at 3-A resolution

Summary for 4HJ0

• Entry DOI: 10.2210/pdb4hj0/pdb
• Descriptor: Gastric inhibitory polypeptide receptor, Gipg013 Fab, Antagonizing antibody to the GIP Receptor, Heavy chain, Gipg013 Fab, Antagonizing antibody to the GIP Receptor, Light chain (3 entities in total)
• Functional Keywords: glucagon receptor sub-family recognition fold, immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P48546
• Total number of polymer chains: 6
• Total formula weight: 124429.64

Authors

Madhurantakam, C.,Ravn, P.,Gruetter, M.G.,Jackson, R.H. (deposition date: 2012-10-12, release date: 2013-05-29, Last modification date: 2024-11-20)

Primary citation

Ravn, P.,Madhurantakam, C.,Kunze, S.,Matthews, E.,Priest, C.,O'Brien, S.,Collinson, A.,Papworth, M.,Fritsch-Fredin, M.,Jermutus, L.,Benthem, L.,Gruetter, M.,Jackson, R.H.
Structural and Pharmacological Characterization of Novel Potent and Selective Monoclonal Antibody Antagonists of Glucose-dependent Insulinotropic Polypeptide Receptor.
J.Biol.Chem., 288:19760-19772, 2013

PubMed Abstract: 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 Ki 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.

PubMed: 23689510
DOI: 10.1074/jbc.M112.426288

Experimental method

X-RAY DIFFRACTION (3 Å)