5a0c: Difference between revisions

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 ==Crystal Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor==
 <StructureSection load='5a0c' size='340' side='right' caption='[[5a0c]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[5a0c]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5A0C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5A0C FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JJV:(6S)-6-(4-CYANO-2-METHYLSULFONYL-PHENYL)-4-METHYL-2-OXIDANYLIDENE-3-[3-(TRIFLUOROMETHYL)PHENYL]-1,6-DIHYDROPYRIMIDINE-5-CARBONITRILE'>JJV</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=XPE:3,6,9,12,15,18,21,24,27-NONAOXANONACOSANE-1,29-DIOL'>XPE</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=JJV:(6S)-6-(4-CYANO-2-METHYLSULFONYL-PHENYL)-4-METHYL-2-OXIDANYLIDENE-3-[3-(TRIFLUOROMETHYL)PHENYL]-1,6-DIHYDROPYRIMIDINE-5-CARBONITRILE'>JJV</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=XPE:3,6,9,12,15,18,21,24,27-NONAOXANONACOSANE-1,29-DIOL'>XPE</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5a09|5a09]], [[5a0a|5a0a]], [[5a0b|5a0b]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </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=5a0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a0c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5a0c RCSB], [http://www.ebi.ac.uk/pdbsum/5a0c PDBsum]</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=5a0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a0c OCA], [http://pdbe.org/5a0c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5a0c RCSB], [http://www.ebi.ac.uk/pdbsum/5a0c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5a0c ProSAT]</span></td></tr>
 </table>
 == Disease ==
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 == Function ==
 [[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.<ref>PMID:15140022</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease-anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluorometh yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.
+Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases.,von Nussbaum F, Li VM, Allerheiligen S, Anlauf S, Barfacker L, Bechem M, Delbeck M, Fitzgerald MF, Gerisch M, Gielen-Haertwig H, Haning H, Karthaus D, Lang D, Lustig K, Meibom D, Mittendorf J, Rosentreter U, Schafer M, Schafer S, Schamberger J, Telan LA, Tersteegen A ChemMedChem. 2015 Jul;10(7):1163-73. doi: 10.1002/cmdc.201500131. Epub 2015 Jun, 17. PMID:26083237<ref>PMID:26083237</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 5a0c" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>