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2g54

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[[Image:2g54.jpg|left|200px]]<br /><applet load="2g54" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2g54, resolution 2.25&Aring;" />
 
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'''Crystal structure of Zn-bound human insulin-degrading enzyme in complex with insulin B chain'''<br />
 
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==Overview==
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==Crystal structure of Zn-bound human insulin-degrading enzyme in complex with insulin B chain==
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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.
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<StructureSection load='2g54' size='340' side='right'caption='[[2g54]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2g54]] 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=2G54 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2G54 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.25&#8491;</td></tr>
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<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>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2g54 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2g54 OCA], [https://pdbe.org/2g54 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2g54 RCSB], [https://www.ebi.ac.uk/pdbsum/2g54 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2g54 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g5/2g54_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2g54 ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]], Hyperproinsulinemia, familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]], MODY, one form OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]]
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*[[Insulin 3D Structures|Insulin 3D Structures]]
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*[[Insulin-Degrading Enzyme|Insulin-Degrading Enzyme]]
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==About this Structure==
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*[[Insulin-degrading enzyme 3D structures|Insulin-degrading enzyme 3D structures]]
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2G54 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=DIO:'>DIO</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G54 OCA].
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== References ==
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<references/>
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==Reference==
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__TOC__
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=17051221 17051221]
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Insulysin]]
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[[Category: Large Structures]]
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[[Category: Protein complex]]
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[[Category: Shen Y]]
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[[Category: Shen, Y.]]
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[[Category: Tang W-J]]
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[[Category: Tang, W J.]]
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[[Category: DIO]]
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[[Category: ZN]]
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[[Category: protein-peptide complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:28:17 2008''
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Current revision

Crystal structure of Zn-bound human insulin-degrading enzyme in complex with insulin B chain

PDB ID 2g54

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