4ym9: Difference between revisions
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==Crystal structure of Porcine Pancreatic Elastase (PPE) in complex with the novel inhibitor JM102== | |||
<StructureSection load='4ym9' size='340' side='right'caption='[[4ym9]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ym9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YM9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YM9 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]] 1.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4E4:2-ETHYL-2-(HYDROXYMETHYL)-N-(6-METHYLPYRIDIN-3-YL)BUTANAMIDE'>4E4</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4ym9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ym9 OCA], [https://pdbe.org/4ym9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ym9 RCSB], [https://www.ebi.ac.uk/pdbsum/4ym9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ym9 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CELA1_PIG CELA1_PIG] Acts upon elastin. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Human neutrophil elastase (HNE) is a serine protease associated with several inflammatory processes such as chronic obstructive pulmonary disease (COPD). The precise involvement of HNE in COPD and other inflammatory disease mechanisms has yet to be clarified. Herein we report a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC, or 'click' chemistry) approach based on the 4-oxo-beta-lactam warhead that yielded potent HNE inhibitors containing a triazole moiety. The resulting structure-activity relationships set the basis to develop fluorescent and biotinylated activity-based probes as tools for molecular functional analysis. Attaching the tags to the 4-oxo-beta-lactam scaffold did not affect HNE inhibitory activity, as revealed by the IC50 values in the nanomolar range (56-118 nm) displayed by the probes. The nitrobenzoxadiazole (NBD)-based probe presented the best binding properties (ligand efficiency (LE)=0.31) combined with an excellent lipophilic ligand efficiency (LLE=4.7). Moreover, the probes showed adequate fluorescence properties, internalization in human neutrophils, and suitable detection of HNE in the presence of a large excess of cell lysate proteins. This allows the development of activity-based probes with promising applications in target validation and identification, as well as diagnostic tools. | |||
Clickable 4-Oxo-beta-lactam-Based Selective Probing for Human Neutrophil Elastase Related Proteomes.,Ruivo EF, Goncalves LM, Carvalho LA, Guedes RC, Hofbauer S, Brito JA, Archer M, Moreira R, Lucas SD ChemMedChem. 2016 Sep 20;11(18):2037-42. doi: 10.1002/cmdc.201600258. Epub 2016, Jul 28. PMID:27465595<ref>PMID:27465595</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 4ym9" style="background-color:#fffaf0;"></div> | ||
[[Category: Brito | |||
[[Category: | ==See Also== | ||
[[Category: Moreira | *[[Elastase 3D structures|Elastase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Sus scrofa]] | |||
[[Category: Archer M]] | |||
[[Category: Brito JA]] | |||
[[Category: Hofbauer S]] | |||
[[Category: Moreira R]] | |||
[[Category: Mulchande J]] | |||
[[Category: Nogly P]] | |||
[[Category: Pessanha M]] | |||
Latest revision as of 13:55, 10 January 2024
Crystal structure of Porcine Pancreatic Elastase (PPE) in complex with the novel inhibitor JM102Crystal structure of Porcine Pancreatic Elastase (PPE) in complex with the novel inhibitor JM102
Structural highlights
FunctionCELA1_PIG Acts upon elastin. Publication Abstract from PubMedHuman neutrophil elastase (HNE) is a serine protease associated with several inflammatory processes such as chronic obstructive pulmonary disease (COPD). The precise involvement of HNE in COPD and other inflammatory disease mechanisms has yet to be clarified. Herein we report a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC, or 'click' chemistry) approach based on the 4-oxo-beta-lactam warhead that yielded potent HNE inhibitors containing a triazole moiety. The resulting structure-activity relationships set the basis to develop fluorescent and biotinylated activity-based probes as tools for molecular functional analysis. Attaching the tags to the 4-oxo-beta-lactam scaffold did not affect HNE inhibitory activity, as revealed by the IC50 values in the nanomolar range (56-118 nm) displayed by the probes. The nitrobenzoxadiazole (NBD)-based probe presented the best binding properties (ligand efficiency (LE)=0.31) combined with an excellent lipophilic ligand efficiency (LLE=4.7). Moreover, the probes showed adequate fluorescence properties, internalization in human neutrophils, and suitable detection of HNE in the presence of a large excess of cell lysate proteins. This allows the development of activity-based probes with promising applications in target validation and identification, as well as diagnostic tools. Clickable 4-Oxo-beta-lactam-Based Selective Probing for Human Neutrophil Elastase Related Proteomes.,Ruivo EF, Goncalves LM, Carvalho LA, Guedes RC, Hofbauer S, Brito JA, Archer M, Moreira R, Lucas SD ChemMedChem. 2016 Sep 20;11(18):2037-42. doi: 10.1002/cmdc.201600258. Epub 2016, Jul 28. PMID:27465595[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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