View source for 5a8z


==Crystal Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor==
<StructureSection load='5a8z' size='340' side='right'caption='[[5a8z]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5a8z]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5A8Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5A8Z 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]] 2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=IUL:4-[(4R)-7-METHYL-2,5-BIS(OXIDANYLIDENE)-1-[3-(TRIFLUOROMETHYL)PHENYL]-3,4,6,8-TETRAHYDROPYRIMIDO[4,5-D]PYRIDAZIN-4-YL]BENZENECARBONITRILE'>IUL</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'>[https://proteopedia.org/fgij/fg.htm?mol=5a8z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a8z OCA], [https://pdbe.org/5a8z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5a8z RCSB], [https://www.ebi.ac.uk/pdbsum/5a8z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5a8z ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:[https://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:[https://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 ==
[https://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 driver of inflammation in many cardiopulmonary and systemic inflammatory and autoimmune conditions. Overshooting high HNE activity is the consequence of a disrupted protease-antiprotease balance. Accordingly, there has been an intensive search for potent and selective HNE inhibitors with suitable pharmacokinetics that would allowing oral administration in patients. Based on the chemical probe BAY-678 and the clinical candidate BAY 85-8501 we explored further ring topologies along the equator of the parent pyrimidinone lead series. Novel ring systems were annulated in the east, yielding imidazolo-, triazolo-, and tetrazolopyrimidines in order to ensure additional inhibitor-HNE contacts beyond the S1 and the S2 pocket of HNE. The western annulation of pyridazines led to the polar pyrimidopyridazine BAY-8040, which combines excellent potency and selectivity with a promising pharmacokinetic profile. In vivo efficacy with regard to decreasing cardiac remodeling and amelioration of cardiac function was shown in a monocrotaline-induced rat model for pulmonary arterial hypertension. This demonstrated in vivo proof of concept in animals.

Potent and Selective Human Neutrophil Elastase Inhibitors with Novel Equatorial Ring Topology: in vivo Efficacy of the Polar Pyrimidopyridazine BAY-8040 in a Pulmonary Arterial Hypertension Rat Model.,von Nussbaum F, Li VM, Meibom D, Anlauf S, Bechem M, Delbeck M, Gerisch M, Harrenga A, Karthaus D, Lang D, Lustig K, Mittendorf J, Schafer M, Schafer S, Schamberger J ChemMedChem. 2016 Jan 19;11(2):199-206. doi: 10.1002/cmdc.201500269. Epub 2015, Sep 3. PMID:26333652<ref>PMID:26333652</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5a8z" style="background-color:#fffaf0;"></div>

==See Also==
*[[Elastase 3D structures|Elastase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Anlauf S]]
[[Category: Bechem M]]
[[Category: Delbeck M]]
[[Category: Gerisch M]]
[[Category: Harrenga A]]
[[Category: Karthaus D]]
[[Category: Lang D]]
[[Category: Li VM]]
[[Category: Lustig K]]
[[Category: Meibom D]]
[[Category: Mittendorf J]]
[[Category: Schaefer M]]
[[Category: Schaefer S]]
[[Category: Schamberger J]]
[[Category: Von Nussbaum F]]