6sma

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'''Unreleased structure'''
 
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The entry 6sma is ON HOLD until Paper Publication
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==Crystal structure of Human Neutrophil Elastase (HNE) in complex with the 3-Oxo-beta-Sultam inhibitor LMC249==
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<StructureSection load='6sma' size='340' side='right'caption='[[6sma]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6sma]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SMA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6SMA FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=LKK:3-[[1-[(4-bromophenyl)methyl]-1,2,3-triazol-4-yl]methylcarbamoyl]pentane-3-sulfonic+acid'>LKK</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6qbu|6qbu]], [[6qen|6qen]], [[6qeo|6qeo]]</td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6sma FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6sma OCA], [http://pdbe.org/6sma PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6sma RCSB], [http://www.ebi.ac.uk/pdbsum/6sma PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6sma ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:[http://omim.org/entry/162800 162800]]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency.<ref>PMID:14673143</ref> <ref>PMID:10581030</ref> Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:[http://omim.org/entry/202700 202700]]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.<ref>PMID:20220065</ref>
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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3-Oxo-beta-sultams are four-membered ring ambident electrophiles that can react with nucleophiles either at the carbonyl carbon or at the sulfonyl sulfur atoms, and that have been reported to inhibit serine hydrolases via acylation of the active-site serine residue. We have developed a panel of 3-oxo-beta-sultam inhibitors and show, through crystallographic data, that they are regioselective sulfonylating electrophiles, covalently binding to the catalytic serine of human and porcine elastases through the sulfur atom. Application of 3-oxo-beta-sultam-derived activity-based probes in a human proteome revealed their potential to label disease-related serine hydrolases and proteasome subunits. Activity-based protein profiling applications of 3-oxo-beta-sultams should open up new opportunities to investigate these classes of enzymes in complex proteomes and expand the toolbox of available sulfur-based covalent protein modifiers in chemical biology.
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Authors:
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3-Oxo-beta-sultam as a Sulfonylating Chemotype for Inhibition of Serine Hydrolases and Activity-Based Protein Profiling.,Carvalho LAR, Almeida VT, Brito JA, Lum KM, Oliveira TF, Guedes RC, Goncalves LM, Lucas SD, Cravatt BF, Archer M, Moreira R ACS Chem Biol. 2020 Mar 20. doi: 10.1021/acschembio.0c00090. PMID:32176480<ref>PMID:32176480</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 6sma" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Leukocyte elastase]]
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[[Category: Almeida, V T]]
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[[Category: Archer, M]]
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[[Category: Brito, J A]]
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[[Category: Carvalho, L M]]
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[[Category: Moreira, R]]
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[[Category: 3-oxo-beta-sultam]]
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[[Category: Human neutrophil elastase]]
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[[Category: Hydrolase]]
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[[Category: Inhibitor]]
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[[Category: Serine hydrolase]]
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[[Category: Sulfonylation]]

Revision as of 06:54, 8 April 2020

Crystal structure of Human Neutrophil Elastase (HNE) in complex with the 3-Oxo-beta-Sultam inhibitor LMC249

PDB ID 6sma

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