6mq3: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==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. 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='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> | |||
</table> | |||
== 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> | |||
<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. | |||
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> | |||
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> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Insulysin]] | |||
[[Category: Large Structures]] | |||
[[Category: Liu, D R]] | |||
[[Category: Maianti, J P]] | |||
[[Category: Seeliger, M A]] | |||
[[Category: Tan, G A]] | |||
[[Category: Welsh, A J]] | |||
[[Category: Diabetes]] | |||
[[Category: Exo-site]] | |||
[[Category: Glucagon]] | |||
[[Category: Hydrolase]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
[[Category: Insulin]] | |||