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[[Image:2g56.jpg|left|200px]]
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{{STRUCTURE_2g56|  PDB=2g56  |  SCENE=  }}
'''crystal structure of human insulin-degrading enzyme in complex with insulin B chain'''


==crystal structure of human insulin-degrading enzyme in complex with insulin B chain==
<StructureSection load='2g56' size='340' side='right'caption='[[2g56]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2g56]] 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=2G56 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2G56 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]] 2.2&#8491;</td></tr>
<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></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=2g56 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2g56 OCA], [https://pdbe.org/2g56 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2g56 RCSB], [https://www.ebi.ac.uk/pdbsum/2g56 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2g56 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>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g5/2g56_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2g56 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Insulin-degrading enzyme (IDE), a Zn2+-metalloprotease, is involved in the clearance of insulin and amyloid-beta (refs 1-3). Loss-of-function mutations of IDE in rodents cause glucose intolerance and cerebral accumulation of amyloid-beta, whereas enhanced IDE activity effectively reduces brain amyloid-beta (refs 4-7). Here we report structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon). The amino- and carboxy-terminal domains of IDE (IDE-N and IDE-C, respectively) form an enclosed cage just large enough to encapsulate insulin. Extensive contacts between IDE-N and IDE-C keep the degradation chamber of IDE inaccessible to substrates. Repositioning of the IDE domains enables substrate access to the catalytic cavity. IDE uses size and charge distribution of the substrate-binding cavity selectively to entrap structurally diverse polypeptides. The enclosed substrate undergoes conformational changes to form beta-sheets with two discrete regions of IDE for its degradation. Consistent with this model, mutations disrupting the contacts between IDE-N and IDE-C increase IDE catalytic activity 40-fold. The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-beta and blood sugar concentrations.


==Overview==
Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.,Shen Y, Joachimiak A, Rosner MR, Tang WJ Nature. 2006 Oct 19;443(7113):870-4. Epub 2006 Oct 11. PMID:17051221<ref>PMID:17051221</ref>
Insulin-degrading enzyme (IDE), a Zn2+-metalloprotease, is involved in the clearance of insulin and amyloid-beta (refs 1-3). Loss-of-function mutations of IDE in rodents cause glucose intolerance and cerebral accumulation of amyloid-beta, whereas enhanced IDE activity effectively reduces brain amyloid-beta (refs 4-7). Here we report structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon). The amino- and carboxy-terminal domains of IDE (IDE-N and IDE-C, respectively) form an enclosed cage just large enough to encapsulate insulin. Extensive contacts between IDE-N and IDE-C keep the degradation chamber of IDE inaccessible to substrates. Repositioning of the IDE domains enables substrate access to the catalytic cavity. IDE uses size and charge distribution of the substrate-binding cavity selectively to entrap structurally diverse polypeptides. The enclosed substrate undergoes conformational changes to form beta-sheets with two discrete regions of IDE for its degradation. Consistent with this model, mutations disrupting the contacts between IDE-N and IDE-C increase IDE catalytic activity 40-fold. The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-beta and blood sugar concentrations.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2G56 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G56 OCA].
</div>
<div class="pdbe-citations 2g56" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism., Shen Y, Joachimiak A, Rosner MR, Tang WJ, Nature. 2006 Oct 19;443(7113):870-4. Epub 2006 Oct 11. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17051221 17051221]
*[[Insulin 3D Structures|Insulin 3D Structures]]
*[[Insulin-degrading enzyme 3D structures|Insulin-degrading enzyme 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Insulysin]]
[[Category: Large Structures]]
[[Category: Protein complex]]
[[Category: Shen Y]]
[[Category: Shen, Y.]]
[[Category: Tang W-J]]
[[Category: Tang, W J.]]
[[Category: Protein-peptide complex]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 04:41:59 2008''

Latest revision as of 09:35, 30 August 2023

crystal structure of human insulin-degrading enzyme in complex with insulin B chain

2g56, resolution 2.20Å

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