Insulin-Degrading Enzyme - Revision history

Michal Harel at 08:22, 11 February 2021

Michal Harel — Thu, 11 Feb 2021 08:22:03 GMT

←Older revision		Revision as of 08:22, 11 February 2021
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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? ==

Michal Harel at 08:25, 29 August 2019

Michal Harel — Thu, 29 Aug 2019 08:25:12 GMT

←Older revision		Revision as of 08:25, 29 August 2019
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	</StructureSection>		</StructureSection>
	__NOTOC__		__NOTOC__
-
-	==3D structures of insulin-degrading enzyme==
-
-	Updated on {{REVISIONDAY2}}-{{MONTHNAME\|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
-	{{#tree:id=OrganizedByTopic\|openlevels=0\|
-
-	*Insulin-degrading enzyme
-
-	**[[2jg4]] - hIDE (mutant) – human<br />
-	**[[3qz2]] - hIDE<br />
-	**[[6bf6]], [[6b7y]] – hIDE – Cryo EM<br />
-	**[[3p7l]] - rIDE – rat<br />
-
-	*Insulin-degrading enzyme binary 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 />
-	**[[2g49]] - hIDE (mutant) + glucagons<br />
-	**[[2g56]] - hIDE + insulin β chain <br />
-	**[[4dtt]], [[4dwk]], [[4nxo]], [[4qia]] – hIDE + inhibitor<br />
-	**[[4gs8]], [[4gsc]], [[4gsf]], [[4ifh]], [[2ypu]], [[4lte]], [[4pf7]], [[4pf9]], [[4pfc]], [[4re9]], [[6mq3]] - hIDE (mutant) + inhibitor<br />
-	**[[3p7o]] - rIDE (mutant) + peptide<br />
-	**[[4iof]] – hIDE + antibody<br />
-	**[[5uoe]] – hIDE (mutant) + antibody <br />
-	**[[6bf7]], [[6bf9]], [[6b7z]] – hIDE + antibody – Cryo EM<br />
-	**[[6bf8]], [[6bfc]], [[6b3q]] – hIDE + insulin – Cryo EM<br />
-
-	*Insulin-degrading enzyme ternary complexes
-
-	**[[4m1c]] – hIDE + antibody + amyloid β A4 protein residues 1-40<br />
-	**[[6eds]] - hIDE (mutant) + glucagon + inhibitor<br />
-	**[[2g54]] - hIDE (mutant) + insulin chain + Zn<br />
-	**[[4pes]], [[6byz]] - hIDE (mutant) + inhibitor + tripeptide<br />
-	**[[6b70]] – hIDE + antibody + insulin – Cryo EM<br />
-	**[[4q5z]] – hIDE + antibody + insulin<br />
-	**[[5cjo]] – hIDE (mutant) + antibody + insulin<br />
-	**[[3tuv]] - rIDE + peptide + ATP
-
-	}}

	== References ==		== References ==

Michal Harel at 08:23, 29 August 2019

Michal Harel — Thu, 29 Aug 2019 08:23:59 GMT

←Older revision		Revision as of 08:23, 29 August 2019
Line 44:		Line 44:

	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.
		+
		+	==3D structures of insulin-degrading enzyme==
		+	[[Insulin-degrading enzyme 3D structures]]
		+
	</StructureSection>		</StructureSection>
	__NOTOC__		__NOTOC__
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	**[[3p7l]] - rIDE – rat<br />		**[[3p7l]] - rIDE – rat<br />

-	*Insulin-degrading enzyme complexes	+	*Insulin-degrading enzyme binary complexes

	**[[3n56]], [[3n57]] – hIDE (mutant) + B-type natriuretic peptide <br />		**[[3n56]], [[3n57]] – hIDE (mutant) + B-type natriuretic peptide <br />
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	**[[2jbu]] - hIDE (mutant) + co-purified peptide<br />		**[[2jbu]] - hIDE (mutant) + co-purified peptide<br />
	**[[2g47]], [[2wk3]] - hIDE (mutant) + amyloid β A4 residues 1-40<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 />		**[[2g49]] - hIDE (mutant) + glucagons<br />
-	**[[2g54]] - hIDE (mutant) + insulin β chain + Zn<br />
	**[[2g56]] - hIDE + insulin β chain <br />		**[[2g56]] - hIDE + insulin β chain <br />
	**[[4dtt]], [[4dwk]], [[4nxo]], [[4qia]] – hIDE + inhibitor<br />		**[[4dtt]], [[4dwk]], [[4nxo]], [[4qia]] – hIDE + inhibitor<br />
-	**[[4gs8]], [[4gsc]], [[4gsf]], [[4ifh]], [[2ypu]], [[4lte]], [[4pf7]], [[4pf9]], [[4pfc]], [[4re9]] - hIDE (mutant) + inhibitor<br />	+	**[[4gs8]], [[4gsc]], [[4gsf]], [[4ifh]], [[2ypu]], [[4lte]], [[4pf7]], [[4pf9]], [[4pfc]], [[4re9]], [[6mq3]] - hIDE (mutant) + inhibitor<br />
	**[[3p7o]] - rIDE (mutant) + peptide<br />		**[[3p7o]] - rIDE (mutant) + peptide<br />
	**[[4iof]] – hIDE + antibody<br />		**[[4iof]] – hIDE + antibody<br />
	**[[5uoe]] – hIDE (mutant) + antibody <br />		**[[5uoe]] – hIDE (mutant) + antibody <br />
-	**[[6bf7]], [[6bf9]] – hIDE + antibody – Cryo EM<br />	+	**[[6bf7]], [[6bf9]], [[6b7z]] – hIDE + antibody – Cryo EM<br />
	**[[6bf8]], [[6bfc]], [[6b3q]] – hIDE + insulin – Cryo EM<br />		**[[6bf8]], [[6bfc]], [[6b3q]] – hIDE + insulin – Cryo EM<br />
		+
		+	*Insulin-degrading enzyme ternary complexes
		+
		+	**[[4m1c]] – hIDE + antibody + amyloid β A4 protein residues 1-40<br />
		+	**[[6eds]] - hIDE (mutant) + glucagon + inhibitor<br />
		+	**[[2g54]] - hIDE (mutant) + insulin chain + Zn<br />
		+	**[[4pes]], [[6byz]] - hIDE (mutant) + inhibitor + tripeptide<br />
	**[[6b70]] – hIDE + antibody + insulin – Cryo EM<br />		**[[6b70]] – hIDE + antibody + insulin – Cryo EM<br />
-	**[[~~5wob~~]] – hIDE + antibody + insulin<br />	+	**[[4q5z]] – hIDE + antibody + insulin<br />
	**[[5cjo]] – hIDE (mutant) + antibody + insulin<br />		**[[5cjo]] – hIDE (mutant) + antibody + insulin<br />
	**[[3tuv]] - rIDE + peptide + ATP		**[[3tuv]] - rIDE + peptide + ATP
		+
	}}		}}

Karsten Theis at 17:23, 20 July 2019

Karsten Theis — Sat, 20 Jul 2019 17:23:08 GMT

←Older revision		Revision as of 17:23, 20 July 2019
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-	<StructureSection load='' size='350' side='right' scene='42/428052/Cv/1' caption='Human insulin-degrading enzyme (grey and green) complex with glucagon preproprotein peptide (pink and yellow) and diethylene dioxide (PDB code [[2g49]])'>	+	<StructureSection load='' size='350' side='right' scene='42/428052/Cv/2' caption='Human insulin-degrading enzyme (grey and green) complex with glucagon preproprotein peptide (pink and yellow) and diethylene dioxide (PDB code [[2g49]])'>
	== Function ==		== Function ==
	[[Insulin-Degrading Enzyme]] (PDB entry [[2g49]]) is a highly conserved 2*113 kDa homodimeric zinc metalloprotease. It belongs to the M16A family of metalloproteases within the ME clan. It hydrolyses [[insulin]] and several amyloidogenic peptides like amyloid-β (Aβ).		[[Insulin-Degrading Enzyme]] (PDB entry [[2g49]]) is a highly conserved 2*113 kDa homodimeric zinc metalloprotease. It belongs to the M16A family of metalloproteases within the ME clan. It hydrolyses [[insulin]] and several amyloidogenic peptides like amyloid-β (Aβ).

Karsten Theis at 17:17, 20 July 2019

Karsten Theis — Sat, 20 Jul 2019 17:17:48 GMT

←Older revision		Revision as of 17:17, 20 July 2019
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	<StructureSection load='' size='350' side='right' scene='42/428052/Cv/1' caption='Human insulin-degrading enzyme (grey and green) complex with glucagon preproprotein peptide (pink and yellow) and diethylene dioxide (PDB code [[2g49]])'>		<StructureSection load='' size='350' side='right' scene='42/428052/Cv/1' caption='Human insulin-degrading enzyme (grey and green) complex with glucagon preproprotein peptide (pink and yellow) and diethylene dioxide (PDB code [[2g49]])'>
	== Function ==		== Function ==
-	[[Insulin-Degrading Enzyme]] (PDB entry [[2g49]]) is a highly conserved 2*113 kDa homodimeric zinc metalloprotease. It belongs to the M16A family of metalloproteases within the ME clan. It hydrolyses insulin and several amyloidogenic peptides like amyloid-β (Aβ).	+	[[Insulin-Degrading Enzyme]] (PDB entry [[2g49]]) is a highly conserved 2*113 kDa homodimeric zinc metalloprotease. It belongs to the M16A family of metalloproteases within the ME clan. It hydrolyses [[insulin]] and several amyloidogenic peptides like amyloid-β (Aβ).
	Aβ is the main component of brain and of the amyloid islets found in Alzheimer’s disease.		Aβ is the main component of brain and of the amyloid islets found in Alzheimer’s disease.
-	Insulin is a peptide associated with ~~diabete~~. The gene encoding IDE is located on human chromosome 10q and is in a region linked to type 2 ~~diabete~~ and Alzheimer’s disease.	+	Insulin is a peptide associated with [[diabetes]]. The gene encoding IDE is located on human chromosome 10q and is in a region linked to type 2 diabetes and Alzheimer’s disease.
	The deletion of IDE in mice leads to hyperinsulinemia, glucose intolerance and increases cerebral Aβ accumulation. Conversely, enhancement of IDE activity in neurons significantly reduces Aβ levels in the brain.		The deletion of IDE in mice leads to hyperinsulinemia, glucose intolerance and increases cerebral Aβ accumulation. Conversely, enhancement of IDE activity in neurons significantly reduces Aβ levels in the brain.
	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.

Michal Harel at 08:22, 22 July 2018

Michal Harel — Sun, 22 Jul 2018 08:22:02 GMT

←Older revision		Revision as of 08:22, 22 July 2018
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	**[[2jg4]] - hIDE (mutant) – human<br />		**[[2jg4]] - hIDE (mutant) – human<br />
	**[[3qz2]] - hIDE<br />		**[[3qz2]] - hIDE<br />
		+	**[[6bf6]], [[6b7y]] – hIDE – Cryo EM<br />
	**[[3p7l]] - rIDE – rat<br />		**[[3p7l]] - rIDE – rat<br />

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	**[[3p7o]] - rIDE (mutant) + peptide<br />		**[[3p7o]] - rIDE (mutant) + peptide<br />
	**[[4iof]] – hIDE + antibody<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 />		**[[5wob]] – hIDE + antibody + insulin<br />
	**[[5cjo]] – hIDE (mutant) + antibody + insulin<br />		**[[5cjo]] – hIDE (mutant) + antibody + insulin<br />

Jaime Prilusky at 08:30, 18 April 2018

Jaime Prilusky — Wed, 18 Apr 2018 08:30:28 GMT

←Older revision		Revision as of 08:30, 18 April 2018
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	**[[3p7o]] - rIDE (mutant) + peptide<br />		**[[3p7o]] - rIDE (mutant) + peptide<br />
	**[[4iof]] – hIDE + antibody<br />		**[[4iof]] – hIDE + antibody<br />
-	**[[~~4q5z~~]] – hIDE + antibody + insulin<br />	+	**[[5wob]] – hIDE + antibody + insulin<br />
	**[[5cjo]] – hIDE (mutant) + antibody + insulin<br />		**[[5cjo]] – hIDE (mutant) + antibody + insulin<br />
	**[[3tuv]] - rIDE + peptide + ATP		**[[3tuv]] - rIDE + peptide + ATP

Joel L. Sussman at 18:29, 28 December 2017

Joel L. Sussman — Thu, 28 Dec 2017 18:29:37 GMT

←Older revision		Revision as of 18:29, 28 December 2017
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-	<StructureSection load='~~2g49~~' size='350' side='right' scene='42/428052/Cv/1' caption='Human insulin-degrading enzyme (grey and green) complex with glucagon preproprotein peptide (pink and yellow) and diethylene dioxide (PDB code [[2g49]])'>	+	<StructureSection load='' size='350' side='right' scene='42/428052/Cv/1' caption='Human insulin-degrading enzyme (grey and green) complex with glucagon preproprotein peptide (pink and yellow) and diethylene dioxide (PDB code [[2g49]])'>
	== Function ==		== Function ==
	[[Insulin-Degrading Enzyme]] (PDB entry [[2g49]]) is a highly conserved 2*113 kDa homodimeric zinc metalloprotease. It belongs to the M16A family of metalloproteases within the ME clan. It hydrolyses insulin and several amyloidogenic peptides like amyloid-β (Aβ).		[[Insulin-Degrading Enzyme]] (PDB entry [[2g49]]) is a highly conserved 2*113 kDa homodimeric zinc metalloprotease. It belongs to the M16A family of metalloproteases within the ME clan. It hydrolyses insulin and several amyloidogenic peptides like amyloid-β (Aβ).

Joel L. Sussman at 18:29, 28 December 2017

Joel L. Sussman — Thu, 28 Dec 2017 18:29:15 GMT

←Older revision		Revision as of 18:29, 28 December 2017
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	**[[2g54]] - hIDE (mutant) + insulin β chain + Zn<br />		**[[2g54]] - hIDE (mutant) + insulin β chain + Zn<br />
	**[[2g56]] - hIDE + insulin β chain <br />		**[[2g56]] - hIDE + insulin β chain <br />
-	**~~[[2ypu]],~~ [[4dtt]], [[4dwk]], [[4nxo]], [[4qia]] – hIDE + inhibitor<br />	+	**[[4dtt]], [[4dwk]], [[4nxo]], [[4qia]] – hIDE + inhibitor<br />
-	**[[4gs8]], [[4gsc]], [[4gsf]], [[4ifh]], [[~~2yb3~~]], [[4lte]], [[4pf7]], [[4pf9]], [[4pfc]], [[4re9]] - hIDE (mutant) + inhibitor<br />	+	**[[4gs8]], [[4gsc]], [[4gsf]], [[4ifh]], [[2ypu]], [[4lte]], [[4pf7]], [[4pf9]], [[4pfc]], [[4re9]] - hIDE (mutant) + inhibitor<br />
	**[[3p7o]] - rIDE (mutant) + peptide<br />		**[[3p7o]] - rIDE (mutant) + peptide<br />
	**[[4iof]] – hIDE + antibody<br />		**[[4iof]] – hIDE + antibody<br />

Michal Harel at 07:58, 19 June 2017

Michal Harel — Mon, 19 Jun 2017 07:58:59 GMT

←Older revision		Revision as of 07:58, 19 June 2017
Line 76:		Line 76:
	**[[2g54]] - hIDE (mutant) + insulin β chain + Zn<br />		**[[2g54]] - hIDE (mutant) + insulin β chain + Zn<br />
	**[[2g56]] - hIDE + insulin β chain <br />		**[[2g56]] - hIDE + insulin β chain <br />
-	**[[2ypu]], [[4dtt]], [[4dwk]] – hIDE + inhibitor<br />	+	**[[2ypu]], [[4dtt]], [[4dwk]], [[4nxo]], [[4qia]] – hIDE + inhibitor<br />
-	**[[4gs8]], [[4gsc]], [[4gsf]], [[4ifh]], [[2yb3]] - hIDE (mutant) + inhibitor<br />	+	**[[4gs8]], [[4gsc]], [[4gsf]], [[4ifh]], [[2yb3]], [[4lte]], [[4pf7]], [[4pf9]], [[4pfc]], [[4re9]] - hIDE (mutant) + inhibitor<br />
	**[[3p7o]] - rIDE (mutant) + peptide<br />		**[[3p7o]] - rIDE (mutant) + peptide<br />
	**[[4iof]] – hIDE + antibody<br />		**[[4iof]] – hIDE + antibody<br />
		+	**[[4q5z]] – hIDE + antibody + insulin<br />
		+	**[[5cjo]] – hIDE (mutant) + antibody + insulin<br />
	**[[3tuv]] - rIDE + peptide + ATP		**[[3tuv]] - rIDE + peptide + ATP
	}}		}}