==Crystal structure of human neutrophil elastase complexed with an inhibitor (GW475151)==

<StructureSection load='1h1b' size='340' side='right'caption='[[1h1b]], [[Resolution|resolution]] 2.00&Aring;' scene=''>

<table><tr><td colspan='2'>[[1h1b]] 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=1H1B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1H1B FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=151:(2S)-3-METHYL-2-((2R,3S)-3-[(METHYLSULFONYL)AMINO]-1-{[2-(PYRROLIDIN-1-YLMETHYL)-1,3-OXAZOL-4-YL]CARBONYL}PYRROLIDIN-2-YL)BUTANOIC+ACID'>151</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [http://pdbe.org/1h1b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [http://www.ebi.ac.uk/pdbsum/1h1b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1h1b ProSAT]</span></td></tr>

== Disease ==

[[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>

== 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 ==

Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a suitable candidate for development. Described here is the discovery of three further derivatives of pyrrolidine trans-lactams, which fulfill the criteria required for back-up candidates 28, 29, and 32. These include increased activity in inhibiting HNE in human whole blood (HWB) and comparable pharmacokinetic properties, in particular clearance, in two species. To provide a rapid assessment of clearance, cassette dosing in dog was used. Modern array techniques, including the synthesis of mixtures, were used to synthesize compounds rapidly. Having selected three potential compounds as back-up candidates, they were prepared as single enantiomers and profiled in in vitro and in vivo assays and evaluated pharmacokinetically in rat and dog. These compounds are highly potent and selective HNE inhibitors, with a prolonged pharmacodynamic action. Pharmacokinetically, these compounds are comparable with 1 while they are more potent in HWB. Compound 28, however, has a higher clearance. One of these compounds, 32, was cocrystallized with HNE, and features of this structure are described and compared with the cocrystal structure of 1 in porcine pancreatic elastase.

Discovery of further pyrrolidine trans-lactams as inhibitors of human neutrophil elastase (HNE) with potential as development candidates and the crystal structure of HNE complexed with an inhibitor (GW475151).,Macdonald SJ, Dowle MD, Harrison LA, Clarke GD, Inglis GG, Johnson MR, Shah P, Smith RA, Amour A, Fleetwood G, Humphreys DC, Molloy CR, Dixon M, Godward RE, Wonacott AJ, Singh OM, Hodgson ST, Hardy GW J Med Chem. 2002 Aug 29;45(18):3878-90. PMID:12190311<ref>PMID:12190311</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

</div>

<div class="pdbe-citations 1h1b" style="background-color:#fffaf0;"></div>

==See Also==

*[[Elastase|Elastase]]

== References ==

<references/>

[[Category: Homo sapiens]]

[[Category: Leukocyte elastase]]

[[Category: Serine protease]]