6mq3: Difference between revisions
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==Structure of Cysteine-free Human Insulin-Degrading Enzyme in complex with Substrate-selective Macrocycle Inhibitor 63== | |||
<StructureSection load='6mq3' size='340' side='right'caption='[[6mq3]], [[Resolution|resolution]] 3.57Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6mq3]] is a 2 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=6MQ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MQ3 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.569147Å</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=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></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=6mq3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mq3 OCA], [https://pdbe.org/6mq3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mq3 RCSB], [https://www.ebi.ac.uk/pdbsum/6mq3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mq3 ProSAT]</span></td></tr> | |||
</table> | |||
== 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> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:31086331</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6mq3" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Insulin-degrading enzyme 3D structures|Insulin-degrading enzyme 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Liu DR]] | |||
[[Category: Maianti JP]] | |||
[[Category: Seeliger MA]] | |||
[[Category: Tan GA]] | |||
[[Category: Welsh AJ]] | |||
Latest revision as of 09:36, 11 October 2023
Structure of Cysteine-free Human Insulin-Degrading Enzyme in complex with Substrate-selective Macrocycle Inhibitor 63Structure of Cysteine-free Human Insulin-Degrading Enzyme in complex with Substrate-selective Macrocycle Inhibitor 63
Structural highlights
FunctionIDE_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 PubMedEnzymes 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 AlsoReferences
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