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| | <StructureSection load='3hgz' size='340' side='right'caption='[[3hgz]], [[Resolution|resolution]] 2.91Å' scene=''> | | <StructureSection load='3hgz' size='340' side='right'caption='[[3hgz]], [[Resolution|resolution]] 2.91Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3hgz]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HGZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HGZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3hgz]] is a 4 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=3HGZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HGZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.91Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IDE ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Insulysin Insulysin], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.56 3.4.24.56] </span></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=3hgz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hgz OCA], [https://pdbe.org/3hgz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hgz RCSB], [https://www.ebi.ac.uk/pdbsum/3hgz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hgz ProSAT]</span></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=3hgz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hgz OCA], [https://pdbe.org/3hgz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hgz RCSB], [https://www.ebi.ac.uk/pdbsum/3hgz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hgz ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/IDE_HUMAN IDE_HUMAN]] Plays a role in the cellular breakdown of insulin, IAPP, glucagon, bradykinin, kallidin and other peptides, and thereby plays a role in intercellular peptide signaling. Degrades amyloid formed by APP and IAPP. May play a role in the degradation and clearance of naturally secreted amyloid beta-protein by neurons and microglia.<ref>PMID:10684867</ref> <ref>PMID:17613531</ref> <ref>PMID:18986166</ref> [[https://www.uniprot.org/uniprot/IAPP_HUMAN IAPP_HUMAN]] Selectively inhibits insulin-stimulated glucose utilization and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism.
| + | [https://www.uniprot.org/uniprot/IAPP_HUMAN IAPP_HUMAN] Selectively inhibits insulin-stimulated glucose utilization and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | <jmolCheckbox> | | <jmolCheckbox> |
| | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hg/3hgz_consurf.spt"</scriptWhenChecked> | | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hg/3hgz_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Insulysin]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bian, Y]] | + | [[Category: Bian Y]] |
| - | [[Category: Guo, Q]] | + | [[Category: Guo Q]] |
| - | [[Category: Tang, W J]] | + | [[Category: Tang WJ]] |
| - | [[Category: Amidation]]
| + | |
| - | [[Category: Amylin]]
| + | |
| - | [[Category: Amyloid]]
| + | |
| - | [[Category: Cleavage on pair of basic residue]]
| + | |
| - | [[Category: Cystein free]]
| + | |
| - | [[Category: Cytoplasm]]
| + | |
| - | [[Category: Disulfide bond]]
| + | |
| - | [[Category: Hormone]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Ide]]
| + | |
| - | [[Category: Insulin degrading enzyme]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Metalloprotease]]
| + | |
| - | [[Category: Polymorphism]]
| + | |
| - | [[Category: Protease]]
| + | |
| - | [[Category: Secreted]]
| + | |
| - | [[Category: Zinc]]
| + | |
| Structural highlights
Function
IAPP_HUMAN Selectively inhibits insulin-stimulated glucose utilization and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Insulin-degrading enzyme (IDE) is involved in the clearance of many bioactive peptide substrates, including insulin and amyloid-beta, peptides vital to the development of diabetes and Alzheimer's disease, respectively. IDE can also rapidly degrade hormones that are held together by intramolecular disulfide bond(s) without their reduction. Furthermore, IDE exhibits a remarkable ability to preferentially degrade structurally similar peptides such as the selective degradation of insulin-like growth factor (IGF)-II and transforming growth factor-alpha (TGF-alpha) over IGF-I and epidermal growth factor, respectively. Here, we used high-accuracy mass spectrometry to identify the cleavage sites of human IGF-II, TGF-alpha, amylin, reduced amylin, and amyloid-beta by human IDE. We also determined the structures of human IDE-IGF-II and IDE-TGF-alpha at 2.3 A and IDE-amylin at 2.9 A. We found that IDE cleaves its substrates at multiple sites in a biased stochastic manner. Furthermore, the presence of a disulfide bond in amylin allows IDE to cut at an additional site in the middle of the peptide (amino acids 18-19). Our amylin-bound IDE structure offers insight into how the structural constraint from a disulfide bond in amylin can alter IDE cleavage sites. Together with NMR structures of amylin and the IGF and epidermal growth factor families, our work also reveals the structural basis of how the high dipole moment of substrates complements the charge distribution of the IDE catalytic chamber for the substrate selectivity. In addition, we show how the ability of substrates to properly anchor their N-terminus to the exosite of IDE and undergo a conformational switch upon binding to the catalytic chamber of IDE can also contribute to the selective degradation of structurally related growth factors.
Molecular basis for the recognition and cleavages of IGF-II, TGF-alpha, and amylin by human insulin-degrading enzyme.,Guo Q, Manolopoulou M, Bian Y, Schilling AB, Tang WJ J Mol Biol. 2010 Jan 15;395(2):430-43. Epub 2009 Nov 5. PMID:19896952[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Guo Q, Manolopoulou M, Bian Y, Schilling AB, Tang WJ. Molecular basis for the recognition and cleavages of IGF-II, TGF-alpha, and amylin by human insulin-degrading enzyme. J Mol Biol. 2010 Jan 15;395(2):430-43. Epub 2009 Nov 5. PMID:19896952 doi:10.1016/j.jmb.2009.10.072
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