6sma

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(Difference between revisions)

Revision as of 07:05, 29 April 2020

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

Structural highlights

6sma is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Related:	6qbu, 6qen, 6qeo
Gene:	ELANE, ELA2 (HUMAN)
Activity:	Leukocyte elastase, with EC number 3.4.21.37
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[ELNE_HUMAN] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM: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.^[1] ^[2] Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM: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.^[3]

Function

[ELNE_HUMAN] Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.^[4]

Publication Abstract from PubMed

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.

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Duan Z, Li FQ, Wechsler J, Meade-White K, Williams K, Benson KF, Horwitz M. A novel notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia. Mol Cell Biol. 2004 Jan;24(1):58-70. PMID:14673143
↑ Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet. 1999 Dec;23(4):433-6. PMID:10581030 doi:10.1038/70544
↑ Germeshausen M, Zeidler C, Stuhrmann M, Lanciotti M, Ballmaier M, Welte K. Digenic mutations in severe congenital neutropenia. Haematologica. 2010 Jul;95(7):1207-10. doi: 10.3324/haematol.2009.017665. Epub, 2010 Mar 10. PMID:20220065 doi:10.3324/haematol.2009.017665
↑ Tralau T, Meyer-Hoffert U, Schroder JM, Wiedow O. Human leukocyte elastase and cathepsin G are specific inhibitors of C5a-dependent neutrophil enzyme release and chemotaxis. Exp Dermatol. 2004 May;13(5):316-25. PMID:15140022 doi:10.1111/j.0906-6705.2004.00145.x
↑ Carvalho LAR, Almeida VT, Brito JA, Lum KM, Oliveira TF, Guedes RC, Goncalves LM, Lucas SD, Cravatt BF, Archer M, Moreira R. 3-Oxo-beta-sultam as a Sulfonylating Chemotype for Inhibition of Serine Hydrolases and Activity-Based Protein Profiling. ACS Chem Biol. 2020 Mar 20. doi: 10.1021/acschembio.0c00090. PMID:32176480 doi:http://dx.doi.org/10.1021/acschembio.0c00090

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6sma"

@@ Line 3: / Line 3: @@
 <StructureSection load='6sma' size='340' side='right'caption='[[6sma]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
 == Structural highlights ==
-<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>
+<table><tr><td colspan='2'>[[6sma]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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>
 </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>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6qbu|6qbu]], [[6qen|6qen]], [[6qeo|6qeo]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ELANE, ELA2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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://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>
@@ Line 26: / Line 27: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Leukocyte elastase]]

6sma

From Proteopedia

Revision as of 07:05, 29 April 2020

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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