6mq3: Difference between revisions

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 <StructureSection load='6mq3' size='340' side='right'caption='[[6mq3]], [[Resolution|resolution]] 3.57&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6mq3]] is a 2 chain structure. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MQ3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6mq3]] is a 2 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=6MQ3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MQ3 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=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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lte|4lte]], [[6byz|6byz]], [[6eds|6eds]], [[2g49|2g49]]</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='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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6mq3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mq3 OCA], [http://pdbe.org/6mq3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mq3 RCSB], [http://www.ebi.ac.uk/pdbsum/6mq3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mq3 ProSAT]</span></td></tr>
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 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide-/- mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE's physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.
+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.
-Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones.,Maianti JP, McFedries A, Foda ZH, Kleiner RE, Du XQ, Leissring MA, Tang WJ, Charron MJ, Seeliger MA, Saghatelian A, Liu DR Nature. 2014 May 21. doi: 10.1038/nature13297. PMID:24847884<ref>PMID:24847884</ref>
+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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Insulysin]]
 [[Category: Large Structures]]