4pf9: Difference between revisions
New page: '''Unreleased structure''' The entry 4pf9 is ON HOLD until Paper Publication Authors: Wang, Y., Guo, S. Description: |
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==Crystal structure of insulin degrading enzyme complexed with inhibitor== | |||
<StructureSection load='4pf9' size='340' side='right'caption='[[4pf9]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4pf9]] is a 2 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=4PF9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PF9 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]] 2.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2Q6:METHYL+[(2S)-2-[4-({5-[4-({(2S)-2-[(3S)-3-AMINO-2-OXOPIPERIDIN-1-YL]-2-CYCLOHEXYLACETYL}AMINO)PHENYL]PENTYL}OXY)PHENYL]-3-(QUINOLIN-3-YL)PROPYL]CARBAMATE'>2Q6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4pf9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pf9 OCA], [https://pdbe.org/4pf9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pf9 RCSB], [https://www.ebi.ac.uk/pdbsum/4pf9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pf9 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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Insulin-degrading enzyme (IDE, insulysin) is the best characterized catabolic enzyme implicated in proteolysis of insulin. Recently, a peptide inhibitor of IDE has been shown to affect levels of insulin, amylin, and glucagon in vivo. However, IDE-/- mice display variable phenotypes relating to fasting plasma insulin levels, glucose tolerance, and insulin sensitivity depending on the cohort and age of animals. Here, we interrogated the importance of IDE-mediated catabolism on insulin clearance in vivo. Using structure-based design, we linked two newly identified ligands binding at unique IDE exosites together to construct a potent series of novel inhibitors. These compounds do not interact with the catalytic zinc of the protease. Since one of these inhibitors (NTE-1) was determined to have pharmacokinetic properties sufficient to sustain plasma levels >50x its IDE IC50, studies in rodents were conducted. In oral glucose tolerance tests with diet-induced obese (DIO) mice, NTE-1 treatment improved glucose clearance. Yet, in insulin tolerance tests and euglycemic clamp experiments, NTE-1 did not improve insulin action or increase plasma insulin levels. Importantly, IDE inhibition with NTE-1 did result in elevated plasma amylin levels, suggesting the in vivo role of IDE action on amylin may be more significant than an effect on insulin. Further, using the inhibitors described in this report, we demonstrate that in HEK cells IDE has little impact on insulin clearance. In total, evidence from our studies supports a minimal role for IDE in insulin clearance in vivo and suggest IDE may be more important in helping regulate amylin clearance in vivo. | |||
Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in vivo.,Durham TB, Toth JL, Klimkowski VJ, Cao JX, Siesky AM, Alexander-Chacko J, Wu GY, Dixon JT, McGee JE, Wang Y, Guo SY, Cavitt RN, Schindler J, Thibodeaux SJ, Calvert NA, Coghlan MJ, Sindelar DK, Christe M, Kiselyov VV, Michael MD, Sloop KW J Biol Chem. 2015 Jun 17. pii: jbc.M115.638205. PMID:26085101<ref>PMID:26085101</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4pf9" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Insulin-degrading enzyme 3D structures|Insulin-degrading enzyme 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Guo S]] | |||
[[Category: Wang Y]] | |||
Latest revision as of 10:16, 27 September 2023
Crystal structure of insulin degrading enzyme complexed with inhibitorCrystal structure of insulin degrading enzyme complexed with inhibitor
Structural highlights
FunctionIDE_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 PubMedInsulin-degrading enzyme (IDE, insulysin) is the best characterized catabolic enzyme implicated in proteolysis of insulin. Recently, a peptide inhibitor of IDE has been shown to affect levels of insulin, amylin, and glucagon in vivo. However, IDE-/- mice display variable phenotypes relating to fasting plasma insulin levels, glucose tolerance, and insulin sensitivity depending on the cohort and age of animals. Here, we interrogated the importance of IDE-mediated catabolism on insulin clearance in vivo. Using structure-based design, we linked two newly identified ligands binding at unique IDE exosites together to construct a potent series of novel inhibitors. These compounds do not interact with the catalytic zinc of the protease. Since one of these inhibitors (NTE-1) was determined to have pharmacokinetic properties sufficient to sustain plasma levels >50x its IDE IC50, studies in rodents were conducted. In oral glucose tolerance tests with diet-induced obese (DIO) mice, NTE-1 treatment improved glucose clearance. Yet, in insulin tolerance tests and euglycemic clamp experiments, NTE-1 did not improve insulin action or increase plasma insulin levels. Importantly, IDE inhibition with NTE-1 did result in elevated plasma amylin levels, suggesting the in vivo role of IDE action on amylin may be more significant than an effect on insulin. Further, using the inhibitors described in this report, we demonstrate that in HEK cells IDE has little impact on insulin clearance. In total, evidence from our studies supports a minimal role for IDE in insulin clearance in vivo and suggest IDE may be more important in helping regulate amylin clearance in vivo. Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in vivo.,Durham TB, Toth JL, Klimkowski VJ, Cao JX, Siesky AM, Alexander-Chacko J, Wu GY, Dixon JT, McGee JE, Wang Y, Guo SY, Cavitt RN, Schindler J, Thibodeaux SJ, Calvert NA, Coghlan MJ, Sindelar DK, Christe M, Kiselyov VV, Michael MD, Sloop KW J Biol Chem. 2015 Jun 17. pii: jbc.M115.638205. PMID:26085101[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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