View source for 6f5m


==Crystal structure of highly glycosylated human leukocyte elastase in complex with a thiazolidinedione inhibitor==
<StructureSection load='6f5m' size='340' side='right'caption='[[6f5m]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6f5m]] is a 2 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=6F5M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6F5M 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]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CQH:5-[[4-[[(2~{S})-4-methyl-1-oxidanylidene-1-[(2-propylphenyl)amino]pentan-2-yl]carbamoyl]phenyl]methyl]-2-oxidanylidene-1,3-thiazol-1-ium-4-olate'>CQH</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6f5m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f5m OCA], [https://pdbe.org/6f5m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6f5m RCSB], [https://www.ebi.ac.uk/pdbsum/6f5m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6f5m 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 ==
Glycosylated human leukocyte elastase (HLE) was crystallized and structurally analysed in complex with a 1,3-thiazolidine-2,4-dione derivative that had been identified as an HLE inhibitor in preliminary studies. In contrast to previously described HLE structures with small-molecule inhibitors, in this structure the inhibitor does not bind to the S1 and S2 substrate-recognition sites; rather, this is the first HLE structure with a synthetic inhibitor in which the S2' site is blocked that normally binds the second side chain at the C-terminal side of the scissile peptide bond in a substrate protein. The inhibitor also induces the formation of crystalline HLE dimers that block access to the active sites and that are also predicted to be stable in solution. Neither such HLE dimers nor the corresponding crystal packing have been observed in previous HLE crystal structures. This novel crystalline environment contributes to the observation that comparatively large parts of the N-glycan chains of HLE are defined by electron density. The final HLE structure contains the largest structurally defined carbohydrate trees among currently available HLE structures.

Crystal structure of highly glycosylated human leukocyte elastase in complex with an S2' site binding inhibitor.,Hochscherf J, Pietsch M, Tieu W, Kuan K, Abell AD, Gutschow M, Niefind K Acta Crystallogr F Struct Biol Commun. 2018 Aug 1;74(Pt 8):480-489. doi:, 10.1107/S2053230X1800537X. Epub 2018 Jul 26. PMID:30084397<ref>PMID:30084397</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6f5m" style="background-color:#fffaf0;"></div>

==See Also==
*[[Elastase 3D structures|Elastase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Abell A]]
[[Category: Guetschow M]]
[[Category: Hautmann S]]
[[Category: Hochscherf J]]
[[Category: Kuan K]]
[[Category: Niefind K]]
[[Category: Pietsch M]]
[[Category: Tieu W]]