7oup: Difference between revisions
New page: '''Unreleased structure''' The entry 7oup is ON HOLD until Paper Publication Authors: Kumar, P., Reithofer, V., Gruber, K. Description: Structure of human DPP3 in complex with a hydrox... |
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==Structure of human DPP3 in complex with a hydroxyethylene transition state peptidomimetic== | |||
<StructureSection load='7oup' size='340' side='right'caption='[[7oup]], [[Resolution|resolution]] 2.65Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7oup]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OUP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OUP 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]] 2.65Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1QI:(2~{R},4~{S},5~{S})-5-azanyl-6-methyl-4-oxidanyl-2-(phenylmethyl)heptanoic+acid'>1QI</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=7oup FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oup OCA], [https://pdbe.org/7oup PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oup RCSB], [https://www.ebi.ac.uk/pdbsum/7oup PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oup ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DPP3_HUMAN DPP3_HUMAN] Cleaves Arg-Arg-beta-naphthylamide. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Dipeptidyl peptidase III (DPP3) is a ubiquitously expressed Zn-dependent protease, which plays an important role in regulating endogenous peptide hormones, such as enkephalins or angiotensins. In previous biophysical studies, it could be shown that substrate binding is driven by a large entropic contribution due to the release of water molecules from the closing binding cleft. Here, the design, synthesis and biophysical characterization of peptidomimetic inhibitors is reported, using for the first time an hydroxyethylene transition-state mimetic for a metalloprotease. Efficient routes for the synthesis of both stereoisomers of the pseudopeptide core were developed, which allowed the synthesis of peptidomimetic inhibitors mimicking the VVYPW-motif of tynorphin. The best inhibitors inhibit DPP3 in the low muM range. Biophysical characterization by means of ITC measurement and X-ray crystallography confirm the unusual entropy-driven mode of binding. Stability assays demonstrated the desired stability of these inhibitors, which efficiently inhibited DPP3 in mouse brain homogenate. | |||
Efficient Entropy-Driven Inhibition of Dipeptidyl Peptidase III by Hydroxyethylene Transition-State Peptidomimetics.,Ivkovic J, Jha S, Lembacher-Fadum C, Puschnig J, Kumar P, Reithofer V, Gruber K, Macheroux P, Breinbauer R Chemistry. 2021 Oct 7;27(56):14108-14120. doi: 10.1002/chem.202102204. Epub 2021 , Aug 31. PMID:34314529<ref>PMID:34314529</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7oup" style="background-color:#fffaf0;"></div> | ||
[[Category: Gruber | == References == | ||
[[Category: Reithofer | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Gruber K]] | |||
[[Category: Kumar P]] | |||
[[Category: Reithofer V]] | |||
Latest revision as of 12:31, 9 October 2024
Structure of human DPP3 in complex with a hydroxyethylene transition state peptidomimeticStructure of human DPP3 in complex with a hydroxyethylene transition state peptidomimetic
Structural highlights
FunctionDPP3_HUMAN Cleaves Arg-Arg-beta-naphthylamide. Publication Abstract from PubMedDipeptidyl peptidase III (DPP3) is a ubiquitously expressed Zn-dependent protease, which plays an important role in regulating endogenous peptide hormones, such as enkephalins or angiotensins. In previous biophysical studies, it could be shown that substrate binding is driven by a large entropic contribution due to the release of water molecules from the closing binding cleft. Here, the design, synthesis and biophysical characterization of peptidomimetic inhibitors is reported, using for the first time an hydroxyethylene transition-state mimetic for a metalloprotease. Efficient routes for the synthesis of both stereoisomers of the pseudopeptide core were developed, which allowed the synthesis of peptidomimetic inhibitors mimicking the VVYPW-motif of tynorphin. The best inhibitors inhibit DPP3 in the low muM range. Biophysical characterization by means of ITC measurement and X-ray crystallography confirm the unusual entropy-driven mode of binding. Stability assays demonstrated the desired stability of these inhibitors, which efficiently inhibited DPP3 in mouse brain homogenate. Efficient Entropy-Driven Inhibition of Dipeptidyl Peptidase III by Hydroxyethylene Transition-State Peptidomimetics.,Ivkovic J, Jha S, Lembacher-Fadum C, Puschnig J, Kumar P, Reithofer V, Gruber K, Macheroux P, Breinbauer R Chemistry. 2021 Oct 7;27(56):14108-14120. doi: 10.1002/chem.202102204. Epub 2021 , Aug 31. PMID:34314529[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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