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| | ==Crystal structure of an activity-based probe HNE complex== | | ==Crystal structure of an activity-based probe HNE complex== |
| - | <StructureSection load='4wvp' size='340' side='right' caption='[[4wvp]], [[Resolution|resolution]] 1.63Å' scene=''> | + | <StructureSection load='4wvp' size='340' side='right'caption='[[4wvp]], [[Resolution|resolution]] 1.63Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wvp]] 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=4WVP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WVP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wvp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WVP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WVP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.63Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=3V2:[(1R)-1-AMINOPROPYL]PHOSPHONIC+ACID'>3V2</scene>, <scene name='pdbligand=3V3:1-AMINO-3,6,9,12-TETRAOXAPENTADECAN-15-OIC+ACID'>3V3</scene>, <scene name='pdbligand=BTN:BIOTIN'>BTN</scene>, <scene name='pdbligand=NLB:6-(BENZYLOXY)-L-NORLEUCINE'>NLB</scene>, <scene name='pdbligand=OIC:OCTAHYDROINDOLE-2-CARBOXYLIC+ACID'>OIC</scene>, <scene name='pdbligand=OMT:S-DIOXYMETHIONINE'>OMT</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3V2:[(1R)-1-AMINOPROPYL]PHOSPHONIC+ACID'>3V2</scene>, <scene name='pdbligand=3V3:1-AMINO-3,6,9,12-TETRAOXAPENTADECAN-15-OIC+ACID'>3V3</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=BTN:BIOTIN'>BTN</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NLB:6-(BENZYLOXY)-L-NORLEUCINE'>NLB</scene>, <scene name='pdbligand=OIC:OCTAHYDROINDOLE-2-CARBOXYLIC+ACID'>OIC</scene>, <scene name='pdbligand=OMT:S-DIOXYMETHIONINE'>OMT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4wvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wvp OCA], [https://pdbe.org/4wvp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wvp RCSB], [https://www.ebi.ac.uk/pdbsum/4wvp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wvp ProSAT]</span></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=4wvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wvp OCA], [http://pdbe.org/4wvp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wvp RCSB], [http://www.ebi.ac.uk/pdbsum/4wvp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wvp ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == 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> | + | [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 == | | == 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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4wvp" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4wvp" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Elastase 3D structures|Elastase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Leukocyte elastase]] | + | [[Category: Large Structures]] |
| - | [[Category: Drag, M]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Kasperkiewicz, P]] | + | [[Category: Drag M]] |
| - | [[Category: Lechtenberg, B C]] | + | [[Category: Kasperkiewicz P]] |
| - | [[Category: Riedl, S J]] | + | [[Category: Lechtenberg BC]] |
| - | [[Category: Robinson, H R]] | + | [[Category: Riedl SJ]] |
| - | [[Category: Acitivity-based probe]]
| + | [[Category: Robinson HR]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Hne]]
| + | |
| - | [[Category: Hycosul]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Neutrophil elastase]]
| + | |
| - | [[Category: Protease]]
| + | |
| Structural highlights
4wvp is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.63Å |
| Ligands: | , , , , , , , , , , |
| 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
Human neutrophil elastase (HNE) plays a central role in neutrophil host defense, but its broad specificity makes HNE a difficult target for both inhibitor and probe development. Recently, we identified the unnatural amino acid containing activity-based probe PK101, which exhibits astounding sensitivity and selectivity for HNE, yet completely lacks mechanistic explanation for its unique characteristics. Here, we present the crystal structure of the HNE-PK101 complex which not only reveals the basis for PK101 ultrasensitivity but also uncovers so far unrecognized HNE features. Strikingly, the Nle(O-Bzl) function in the P4 position of PK101 reveals and leverages an "exo-pocket" on HNE as a critical factor for selectivity. Furthermore, the PK101 P3 position harbors a methionine dioxide function, which mimics a post-translationally oxidized methionine residue and forms a critical hydrogen bond to the backbone amide of Gly219 of HNE. Gly219 resides in a Gly-Gly motif that is unique to HNE, yet compulsory for this interaction. Consequently, this feature enables HNE to accommodate substrates that have undergone methionine oxidation, which constitutes a hallmark post-translational modification of neutrophil signaling.
The Elastase-PK101 Structure: Mechanism of an Ultrasensitive Activity-based Probe Revealed.,Lechtenberg BC, Kasperkiewicz P, Robinson H, Drag M, Riedl SJ ACS Chem Biol. 2015 Jan 22. PMID:25581168[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Lechtenberg BC, Kasperkiewicz P, Robinson H, Drag M, Riedl SJ. The Elastase-PK101 Structure: Mechanism of an Ultrasensitive Activity-based Probe Revealed. ACS Chem Biol. 2015 Jan 22. PMID:25581168 doi:http://dx.doi.org/10.1021/cb500909n
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