Insulin-Degrading Enzyme: Difference between revisions

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IDE could help creating IDE-based therapies to control cerebral Aβ and blood sugar concentrations thanks to the understanding of its molecular mechanisms.
IDE could help creating IDE-based therapies to control cerebral Aβ and blood sugar concentrations thanks to the understanding of its molecular mechanisms.
IDE is an unusual enzyme because of its high affinity for substrates that are widely diverse in sequence and structure. IDE prefers to degrade <6 kDa bioactive peptides such as insulin, Aβ, glucagon, atrial natriuretic peptides or transforming growth factor α. Paradoxally, even though IDE targets a broad range of substrates, it shows a remarkable capacity to selectively cleave some peptides without degrading related family members.
IDE is an unusual enzyme because of its high affinity for substrates that are widely diverse in sequence and structure. IDE prefers to degrade <6 kDa bioactive peptides such as insulin, Aβ, glucagon, atrial natriuretic peptides or transforming growth factor α. Paradoxally, even though IDE targets a broad range of substrates, it shows a remarkable capacity to selectively cleave some peptides without degrading related family members.
See [[Human Insulin Degrading Enzyme (Hebrew)]].


== How are the structure and the functions of IDE related? ==
== How are the structure and the functions of IDE related? ==
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Virtual screening of the IDE protein (PDB ID: [[2jg4]]) was conducted using the binding site defined by the catalytic site of IDE protein. In silico results indicate that traditional Chinese medicine compounds <scene name='Journal:JBSD:29/Cv/5'>dihydrocaffeic acid</scene> (<span style="color:royalblue;background-color:black;font-weight:bold;">colored in royalblue</span>), <scene name='Journal:JBSD:29/Cv/6'>isopraeroside IV</scene> (<font color='blueviolet'><b>colored in blueviolet</b></font>), and <scene name='Journal:JBSD:29/Cv/8'>scopolin</scene> (<span style="color:chocolate;background-color:black;font-weight:bold;">colored in chocolate</span>) had high binding affinity with IDE protein and formed hydrogen bonds with the key active residue, <font color='magenta'><b>Glu111 (colored in magenta)</b></font> and <span style="color:lime;background-color:black;font-weight:bold;">other residues in the IDE binding site (colored in green)</span>. As the top three TCM compounds had stable interactions with zinc cation and residues in the catalytic site of IDE, they may block binding of other substrates, such as insulin, to the catalytic site. This competitive binding may limit the degradation of insulin. The top TCM candidates, dihydrocaffeic acid, isopraeroside IV, and scopolin, may have potential to be lead compounds for controlling insulin degradation for type 2 diabetes mellitus.
Virtual screening of the IDE protein (PDB ID: [[2jg4]]) was conducted using the binding site defined by the catalytic site of IDE protein. In silico results indicate that traditional Chinese medicine compounds <scene name='Journal:JBSD:29/Cv/5'>dihydrocaffeic acid</scene> (<span style="color:royalblue;background-color:black;font-weight:bold;">colored in royalblue</span>), <scene name='Journal:JBSD:29/Cv/6'>isopraeroside IV</scene> (<font color='blueviolet'><b>colored in blueviolet</b></font>), and <scene name='Journal:JBSD:29/Cv/8'>scopolin</scene> (<span style="color:chocolate;background-color:black;font-weight:bold;">colored in chocolate</span>) had high binding affinity with IDE protein and formed hydrogen bonds with the key active residue, <font color='magenta'><b>Glu111 (colored in magenta)</b></font> and <span style="color:lime;background-color:black;font-weight:bold;">other residues in the IDE binding site (colored in green)</span>. As the top three TCM compounds had stable interactions with zinc cation and residues in the catalytic site of IDE, they may block binding of other substrates, such as insulin, to the catalytic site. This competitive binding may limit the degradation of insulin. The top TCM candidates, dihydrocaffeic acid, isopraeroside IV, and scopolin, may have potential to be lead compounds for controlling insulin degradation for type 2 diabetes mellitus.
</StructureSection>
__NOTOC__


==3D structures of insulin-degrading enzyme==
==3D structures of insulin-degrading enzyme==
[[Insulin-degrading enzyme 3D structures]]


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
</StructureSection>
{{#tree:id=OrganizedByTopic|openlevels=0|
__NOTOC__
 
*Insulin-degrading enzyme
 
**[[2jg4]] - hIDE (mutant) – human<br />
**[[3qz2]] - hIDE<br />
**[[6bf6]], [[6b7y]] – hIDE – Cryo EM<br />
**[[3p7l]] - rIDE  – rat<br />
 
*Insulin-degrading enzyme complexes
 
**[[3n56]], [[3n57]] – hIDE  (mutant) + B-type natriuretic peptide <br />
**[[3ofi]] - hIDE  + ubiquitin<br />
**[[3h44]] - hIDE  (mutant) + C-C motif chemokine 3<br />
**[[4ral]] - hIDE (mutant) + C-C motif chemokine 4<br />
**[[3hgz]], [[2g48]] - hIDE  (mutant) + amylin<br />
**[[3e4z]] - hIDE  (mutant) + insulin-like growth factor II<br />
**[[3e50]] - hIDE  (mutant) + Transforming growth factor α<br />
**[[3e4a]] – hIDE (mutant) + hydroxamate peptide II1<br />
**[[2wby]], [[2wc0]] - hIDE  (mutant) + insulin<br />
**[[3cww]] - hIDE  (mutant) + Bradykinin N terminal peptide<br />
**[[2jbu]] - hIDE  (mutant) + co-purified peptide<br />
**[[2g47]], [[2wk3]] - hIDE  (mutant) + amyloid β A4 residues 1-40<br />
**[[4m1c]] – hIDE + antibody + amyloid β A4 protein residues 1-40<br />
**[[2g49]] - hIDE  (mutant) + glucagons<br />
**[[2g54]] - hIDE (mutant) + insulin β chain + Zn<br />
**[[2g56]] - hIDE + insulin β chain <br />
**[[4dtt]], [[4dwk]], [[4nxo]], [[4qia]]  – hIDE + inhibitor<br />
**[[4gs8]], [[4gsc]], [[4gsf]], [[4ifh]], [[2ypu]], [[4lte]], [[4pf7]], [[4pf9]], [[4pfc]], [[4re9]] - hIDE (mutant) + inhibitor<br />
**[[3p7o]] - rIDE  (mutant) + peptide<br />
**[[4iof]] – hIDE + antibody<br />
**[[5uoe]] – hIDE (mutant) + antibody <br />
**[[6bf7]], [[6bf9]] – hIDE + antibody – Cryo EM<br />
**[[6bf8]], [[6bfc]], [[6b3q]] – hIDE + insulin – Cryo EM<br />
**[[6b70]] – hIDE + antibody + insulin – Cryo EM<br />
**[[5wob]] – hIDE + antibody + insulin<br />
**[[5cjo]] – hIDE (mutant) + antibody + insulin<br />
**[[3tuv]] - rIDE + peptide + ATP
}}


== References ==
== References ==

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Élodie Weider, Michal Harel, Alexander Berchansky, Joel L. Sussman, Jaime Prilusky, Karsten Theis
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