4hj0: Difference between revisions
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==Crystal structure of the human GIPr ECD in complex with Gipg013 Fab at 3-A resolution== | |||
<StructureSection load='4hj0' size='340' side='right' caption='[[4hj0]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4hj0]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HJ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HJ0 FirstGlance]. <br> | |||
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GIPR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4hj0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hj0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hj0 RCSB], [http://www.ebi.ac.uk/pdbsum/4hj0 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Glucose-dependent insulinotropic polypeptide (GIP) is an endogenous hormonal factor (incretin) that upon binding to its receptor (GIPr; a class B GPCR), 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 investigate GIP biology. Here we describe here 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 antagonises the GIP receptor and inhibits GIP induced insulin secretion in vivo. A crystal structure of Gipg013 Fab in complex with the human GIPr ECD indicates that the antibody binds through a series of hydrogen bonds from the CDRs of Gipg013 Fab to the N-terminal alpha-helix of GIPr extracellular domain (ECD) as well as to residues around its highly conserved glucagon receptor sub-family recognition fold. The antibody epitope overlaps with the GIP binding site on 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. | |||
Structural and Pharmacological Characterisation of Novel Potent and Selective Monoclonal Antibody Antagonists of Glucose-Dependent Insulinotropic Polypeptide Receptor.,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 RH J Biol Chem. 2013 May 20. PMID:23689510<ref>PMID:23689510</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Monoclonal Antibody|Monoclonal Antibody]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Gruetter, M G | [[Category: Gruetter, M G]] | ||
[[Category: Jackson, R H | [[Category: Jackson, R H]] | ||
[[Category: Madhurantakam, C | [[Category: Madhurantakam, C]] | ||
[[Category: Ravn, P | [[Category: Ravn, P]] | ||
[[Category: Glucagon receptor sub-family recognition fold]] | [[Category: Glucagon receptor sub-family recognition fold]] | ||
[[Category: Immune system]] | [[Category: Immune system]] | ||
Revision as of 15:22, 21 December 2014
Crystal structure of the human GIPr ECD in complex with Gipg013 Fab at 3-A resolutionCrystal structure of the human GIPr ECD in complex with Gipg013 Fab at 3-A resolution
Structural highlights
Publication Abstract from PubMedGlucose-dependent insulinotropic polypeptide (GIP) is an endogenous hormonal factor (incretin) that upon binding to its receptor (GIPr; a class B GPCR), 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 investigate GIP biology. Here we describe here 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 antagonises the GIP receptor and inhibits GIP induced insulin secretion in vivo. A crystal structure of Gipg013 Fab in complex with the human GIPr ECD indicates that the antibody binds through a series of hydrogen bonds from the CDRs of Gipg013 Fab to the N-terminal alpha-helix of GIPr extracellular domain (ECD) as well as to residues around its highly conserved glucagon receptor sub-family recognition fold. The antibody epitope overlaps with the GIP binding site on 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. Structural and Pharmacological Characterisation of Novel Potent and Selective Monoclonal Antibody Antagonists of Glucose-Dependent Insulinotropic Polypeptide Receptor.,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 RH J Biol Chem. 2013 May 20. PMID:23689510[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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