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| | <StructureSection load='6byz' size='340' side='right'caption='[[6byz]], [[Resolution|resolution]] 2.96Å' scene=''> | | <StructureSection load='6byz' size='340' side='right'caption='[[6byz]], [[Resolution|resolution]] 2.96Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6byz]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Escherichia_coli_bl21(de3) Escherichia coli bl21(de3)] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BYZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BYZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6byz]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_BL21(DE3) Escherichia coli BL21(DE3)] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BYZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BYZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=J18:[(8R,9S,10S)-9-(2,3-dimethyl[1,1-biphenyl]-4-yl)-6-{[2-(trifluoromethyl)phenyl]sulfonyl}-1,6-diazabicyclo[6.2.0]decan-10-yl]methanol'>J18</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]] 2.9562485Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IDE ([http://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=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=J18:[(8R,9S,10S)-9-(2,3-dimethyl[1,1-biphenyl]-4-yl)-6-{[2-(trifluoromethyl)phenyl]sulfonyl}-1,6-diazabicyclo[6.2.0]decan-10-yl]methanol'>J18</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Insulysin Insulysin], with EC number [http://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=6byz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6byz OCA], [https://pdbe.org/6byz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6byz RCSB], [https://www.ebi.ac.uk/pdbsum/6byz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6byz 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=6byz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6byz OCA], [http://pdbe.org/6byz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6byz RCSB], [http://www.ebi.ac.uk/pdbsum/6byz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6byz ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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/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> |
| | <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 6byz" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6byz" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Insulin-degrading enzyme 3D structures|Insulin-degrading enzyme 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Insulysin]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Liu, D R]] | + | [[Category: Liu DR]] |
| - | [[Category: Maianti, J P]] | + | [[Category: Maianti JP]] |
| - | [[Category: Seeliger, M A]] | + | [[Category: Seeliger MA]] |
| - | [[Category: Tan, G A]] | + | [[Category: Tan GA]] |
| - | [[Category: Diabetes]]
| + | |
| - | [[Category: Exo-site]]
| + | |
| - | [[Category: Glucagon]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-inhibitor complex]]
| + | |
| - | [[Category: Insulin]]
| + | |
| Structural highlights
Function
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.[1] [2] [3]
Publication Abstract from PubMed
Enzymes that act on multiple substrates are common in biology but pose unique challenges as therapeutic targets. The metalloprotease insulin-degrading enzyme (IDE) modulates blood glucose levels by cleaving insulin, a hormone that promotes glucose clearance. However, IDE also degrades glucagon, a hormone that elevates glucose levels and opposes the effect of insulin. IDE inhibitors to treat diabetes, therefore, should prevent IDE-mediated insulin degradation, but not glucagon degradation, in contrast with traditional modes of enzyme inhibition. Using a high-throughput screen for non-active-site ligands, we discovered potent and highly specific small-molecule inhibitors that alter IDE's substrate selectivity. X-ray co-crystal structures, including an IDE-ligand-glucagon ternary complex, revealed substrate-dependent interactions that enable these inhibitors to potently block insulin binding while allowing glucagon cleavage, even at saturating inhibitor concentrations. These findings suggest a path for developing IDE-targeting therapeutics, and offer a blueprint for modulating other enzymes in a substrate-selective manner to unlock their therapeutic potential.
Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme.,Maianti JP, Tan GA, Vetere A, Welsh AJ, Wagner BK, Seeliger MA, Liu DR Nat Chem Biol. 2019 Jun;15(6):565-574. doi: 10.1038/s41589-019-0271-0. Epub 2019 , May 13. PMID:31086331[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ. Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci. 2000 Mar 1;20(5):1657-65. PMID:10684867
- ↑ Im H, Manolopoulou M, Malito E, Shen Y, Zhao J, Neant-Fery M, Sun CY, Meredith SC, Sisodia SS, Leissring MA, Tang WJ. Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. J Biol Chem. 2007 Aug 31;282(35):25453-63. Epub 2007 Jul 5. PMID:17613531 doi:10.1074/jbc.M701590200
- ↑ Malito E, Ralat LA, Manolopoulou M, Tsay JL, Wadlington NL, Tang WJ. Molecular Bases for the Recognition of Short Peptide Substrates and Cysteine-Directed Modifications of Human Insulin-Degrading Enzyme. Biochemistry. 2008 Nov 6. PMID:18986166 doi:10.1021/bi801192h
- ↑ Maianti JP, Tan GA, Vetere A, Welsh AJ, Wagner BK, Seeliger MA, Liu DR. Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme. Nat Chem Biol. 2019 Jun;15(6):565-574. doi: 10.1038/s41589-019-0271-0. Epub 2019 , May 13. PMID:31086331 doi:http://dx.doi.org/10.1038/s41589-019-0271-0
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