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4qia

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Revision as of 08:59, 24 April 2019

Crystal structure of human insulin degrading enzyme (ide) in complex with inhibitor N-benzyl-N-(carboxymethyl)glycyl-L-histidine

Structural highlights

4qia is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	IDE (HUMAN)
Activity:	Insulysin, with EC number 3.4.24.56
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-a and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-a clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role.

Structure-activity relationships of imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme.,Charton J, Gauriot M, Totobenazara J, Hennuyer N, Dumont J, Bosc D, Marechal X, Elbakali J, Herledan A, Wen X, Ronco C, Gras-Masse H, Heninot A, Pottiez V, Landry V, Staels B, Liang WG, Leroux F, Tang WJ, Deprez B, Deprez-Poulain R Eur J Med Chem. 2015 Jan 27;90:547-67. doi: 10.1016/j.ejmech.2014.12.005. Epub, 2014 Dec 4. PMID:25489670^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ. Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci. 2000 Mar 1;20(5):1657-65. PMID:10684867
↑ Im H, Manolopoulou M, Malito E, Shen Y, Zhao J, Neant-Fery M, Sun CY, Meredith SC, Sisodia SS, Leissring MA, Tang WJ. Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. J Biol Chem. 2007 Aug 31;282(35):25453-63. Epub 2007 Jul 5. PMID:17613531 doi:10.1074/jbc.M701590200
↑ Malito E, Ralat LA, Manolopoulou M, Tsay JL, Wadlington NL, Tang WJ. Molecular Bases for the Recognition of Short Peptide Substrates and Cysteine-Directed Modifications of Human Insulin-Degrading Enzyme. Biochemistry. 2008 Nov 6. PMID:18986166 doi:10.1021/bi801192h
↑ Charton J, Gauriot M, Totobenazara J, Hennuyer N, Dumont J, Bosc D, Marechal X, Elbakali J, Herledan A, Wen X, Ronco C, Gras-Masse H, Heninot A, Pottiez V, Landry V, Staels B, Liang WG, Leroux F, Tang WJ, Deprez B, Deprez-Poulain R. Structure-activity relationships of imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme. Eur J Med Chem. 2015 Jan 27;90:547-67. doi: 10.1016/j.ejmech.2014.12.005. Epub, 2014 Dec 4. PMID:25489670 doi:http://dx.doi.org/10.1016/j.ejmech.2014.12.005

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4qia"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human insulin degrading enzyme (ide) in complex with inhibitor N-benzyl-N-(carboxymethyl)glycyl-L-histidine==
-<StructureSection load='4qia' size='340' side='right' caption='[[4qia]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
+<StructureSection load='4qia' size='340' side='right'caption='[[4qia]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4qia]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QIA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QIA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4qia]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QIA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QIA FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=33K:N-BENZYL-N-(CARBOXYMETHYL)GLYCYL-L-HISTIDINE'>33K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IDE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qia OCA], [http://pdbe.org/4qia PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qia RCSB], [http://www.ebi.ac.uk/pdbsum/4qia PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qia ProSAT]</span></td></tr>
@@ Line 19: / Line 20: @@
 </div>
 <div class="pdbe-citations 4qia" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Insulin-Degrading Enzyme|Insulin-Degrading Enzyme]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Insulysin]]
+[[Category: Large Structures]]
 [[Category: Deprez, B]]
 [[Category: Deprez-Poulain, R]]

4qia

From Proteopedia

Revision as of 08:59, 24 April 2019

Crystal structure of human insulin degrading enzyme (ide) in complex with inhibitor N-benzyl-N-(carboxymethyl)glycyl-L-histidine

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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