4re9: Difference between revisions
New page: '''Unreleased structure''' The entry 4re9 is ON HOLD until Paper Publication Authors: Liang, W.G., Deprez, R., Deprez, B., Tang, W.J. Description: Crystal structure of human insulin de... |
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==Crystal structure of human insulin degrading enzyme (IDE) in complex with compound 71290== | |||
<StructureSection load='4re9' size='340' side='right'caption='[[4re9]], [[Resolution|resolution]] 2.91Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4re9]] 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=4RE9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RE9 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]] 2.908Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=3M9:4-FLUORO-N-({1-[(2R)-4-(HYDROXYAMINO)-1-(NAPHTHALEN-2-YL)-4-OXOBUTAN-2-YL]-1H-1,2,3-TRIAZOL-5-YL}METHYL)BENZAMIDE'>3M9</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4re9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4re9 OCA], [https://pdbe.org/4re9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4re9 RCSB], [https://www.ebi.ac.uk/pdbsum/4re9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4re9 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 == | |||
Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-beta. Knockout and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray scattering analyses show that it locks IDE in a closed conformation. Among a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases insulin signalling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes. | |||
Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.,Deprez-Poulain R, Hennuyer N, Bosc D, Liang WG, Enee E, Marechal X, Charton J, Totobenazara J, Berte G, Jahklal J, Verdelet T, Dumont J, Dassonneville S, Woitrain E, Gauriot M, Paquet C, Duplan I, Hermant P, Cantrelle FX, Sevin E, Culot M, Landry V, Herledan A, Piveteau C, Lippens G, Leroux F, Tang WJ, van Endert P, Staels B, Deprez B Nat Commun. 2015 Sep 23;6:8250. doi: 10.1038/ncomms9250. PMID:26394692<ref>PMID:26394692</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4re9" 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: Deprez B]] | |||
[[Category: Deprez R]] | |||
[[Category: Liang WG]] | |||
[[Category: Tang WJ]] | |||