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6eds

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'''Unreleased structure'''
 
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The entry 6eds is ON HOLD
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==Structure of Cysteine-free Human Insulin-Degrading Enzyme in complex with Glucagon and Substrate-selective Macrocyclic Inhibitor 63==
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<StructureSection load='6eds' size='340' side='right'caption='[[6eds]], [[Resolution|resolution]] 3.18&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6eds]] 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=6EDS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EDS FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.1807172&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DIO:1,4-DIETHYLENE+DIOXIDE'>DIO</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=J22:{(8R,9S,10S)-9-(2,3-dimethyl[1,1-biphenyl]-4-yl)-6-[(1-methyl-1H-imidazol-2-yl)sulfonyl]-1,6-diazabicyclo[6.2.0]decan-10-yl}methanol'>J22</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6eds FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eds OCA], [https://pdbe.org/6eds PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6eds RCSB], [https://www.ebi.ac.uk/pdbsum/6eds PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6eds ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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Authors:
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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<ref>PMID:31086331</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 6eds" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Glucagon|Glucagon]]
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*[[Insulin-degrading enzyme 3D structures|Insulin-degrading enzyme 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Liu DR]]
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[[Category: Maianti JP]]
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[[Category: Seeliger MA]]
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[[Category: Tan GA]]
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[[Category: Welsh AJ]]

Current revision

Structure of Cysteine-free Human Insulin-Degrading Enzyme in complex with Glucagon and Substrate-selective Macrocyclic Inhibitor 63

PDB ID 6eds

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