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| | ==A Molecular Basis for Negative Regulation of the Glucagon Receptor== | | ==A Molecular Basis for Negative Regulation of the Glucagon Receptor== |
| - | <StructureSection load='4ers' size='340' side='right' caption='[[4ers]], [[Resolution|resolution]] 2.64Å' scene=''> | + | <StructureSection load='4ers' size='340' side='right'caption='[[4ers]], [[Resolution|resolution]] 2.64Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ers]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ERS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ERS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ers]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ERS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ERS FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GCGR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ers FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ers OCA], [https://pdbe.org/4ers PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ers RCSB], [https://www.ebi.ac.uk/pdbsum/4ers PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ers ProSAT]</span></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=4ers FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ers OCA], [http://pdbe.org/4ers PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ers RCSB], [http://www.ebi.ac.uk/pdbsum/4ers PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ers ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GLR_HUMAN GLR_HUMAN]] This is a receptor for glucagon which plays a central role in regulating the level of blood glucose by controlling the rate of hepatic glucose production and insulin secretion. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and also a phosphatidylinositol-calcium second messenger system. | + | [https://www.uniprot.org/uniprot/GLR_HUMAN GLR_HUMAN] This is a receptor for glucagon which plays a central role in regulating the level of blood glucose by controlling the rate of hepatic glucose production and insulin secretion. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and also a phosphatidylinositol-calcium second messenger system. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4ers" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4ers" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Glucagon receptor|Glucagon receptor]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Koth, C M]] | + | [[Category: Large Structures]] |
| - | [[Category: Mukund, S]] | + | [[Category: Koth CM]] |
| - | [[Category: Murray, J M]] | + | [[Category: Mukund S]] |
| - | [[Category: Class-b gpcr]] | + | [[Category: Murray JM]] |
| - | [[Category: Extra-cellular]]
| + | |
| - | [[Category: Fab]]
| + | |
| - | [[Category: Glucagon receptor]]
| + | |
| - | [[Category: Glycosylation]]
| + | |
| - | [[Category: Immune system]]
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| Structural highlights
Function
GLR_HUMAN This is a receptor for glucagon which plays a central role in regulating the level of blood glucose by controlling the rate of hepatic glucose production and insulin secretion. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and also a phosphatidylinositol-calcium second messenger system.
Publication Abstract from PubMed
Members of the class B family of G protein-coupled receptors (GPCRs) bind peptide hormones and have causal roles in many diseases, ranging from diabetes and osteoporosis to anxiety. Although peptide, small-molecule, and antibody inhibitors of these GPCRs have been identified, structure-based descriptions of receptor antagonism are scarce. Here we report the mechanisms of glucagon receptor inhibition by blocking antibodies targeting the receptor's extracellular domain (ECD). These studies uncovered a role for the ECD as an intrinsic negative regulator of receptor activity. The crystal structure of the ECD in complex with the Fab fragment of one antibody, mAb1, reveals that this antibody inhibits glucagon receptor by occluding a surface extending across the entire hormone-binding cleft. A second antibody, mAb23, blocks glucagon binding and inhibits basal receptor activity, indicating that it is an inverse agonist and that the ECD can negatively regulate receptor activity independent of ligand binding. Biochemical analyses of receptor mutants in the context of a high-resolution ECD structure show that this previously unrecognized inhibitory activity of the ECD involves an interaction with the third extracellular loop of the receptor and suggest that glucagon-mediated structural changes in the ECD accompany receptor activation. These studies have implications for the design of drugs to treat class B GPCR-related diseases, including the potential for developing novel allosteric regulators that target the ECDs of these receptors.
Molecular basis for negative regulation of the glucagon receptor.,Koth CM, Murray JM, Mukund S, Madjidi A, Minn A, Clarke HJ, Wong T, Chiang V, Luis E, Estevez A, Rondon J, Zhang Y, Hotzel I, Allan BB Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14393-8. Epub 2012 Aug 20. PMID:22908259[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Koth CM, Murray JM, Mukund S, Madjidi A, Minn A, Clarke HJ, Wong T, Chiang V, Luis E, Estevez A, Rondon J, Zhang Y, Hotzel I, Allan BB. Molecular basis for negative regulation of the glucagon receptor. Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14393-8. Epub 2012 Aug 20. PMID:22908259 doi:http://dx.doi.org/10.1073/pnas.1206734109
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