4c1m: Difference between revisions

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-{{STRUCTURE_4c1m|  PDB=4c1m  |  SCENE=  }}
-===Myeloperoxidase in complex with the revesible inhibitor HX1===
-==Disease==
+==Myeloperoxidase in complex with the revesible inhibitor HX1==
-[[http://www.uniprot.org/uniprot/PERM_HUMAN PERM_HUMAN]] Defects in MPO are the cause of myeloperoxidase deficiency (MPOD) [MIM:[http://omim.org/entry/254600 254600]]. A disorder characterized by decreased myeloperoxidase activity in neutrophils and monocytes that results in disseminated candidiasis.<ref>PMID:8142659</ref> <ref>PMID:7904599</ref> <ref>PMID:8621627</ref> <ref>PMID:9637725</ref> <ref>PMID:9354683</ref>
+<StructureSection load='4c1m' size='340' side='right'caption='[[4c1m]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4c1m]] is a 4 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=4C1M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C1M 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=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NIH:2-{[3,5-BIS(TRIFLUOROMETHYL)BENZYL]AMINO}-N-HYDROXY-6-OXO-1,6-DIHYDROPYRIMIDINE-5-CARBOXAMIDE'>NIH</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=4c1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c1m OCA], [https://pdbe.org/4c1m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c1m RCSB], [https://www.ebi.ac.uk/pdbsum/4c1m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c1m ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/PERM_HUMAN PERM_HUMAN] Defects in MPO are the cause of myeloperoxidase deficiency (MPOD) [MIM:[https://omim.org/entry/254600 254600]. A disorder characterized by decreased myeloperoxidase activity in neutrophils and monocytes that results in disseminated candidiasis.<ref>PMID:8142659</ref> <ref>PMID:7904599</ref> <ref>PMID:8621627</ref> <ref>PMID:9637725</ref> <ref>PMID:9354683</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/PERM_HUMAN PERM_HUMAN] Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The neutrophil enzyme myeloperoxidase (MPO) promotes oxidative stress in numerous inflammatory pathologies by producing hypohalous acids. Its inadvertent activity is a prime target for pharmacological control. Previously, salicylhydroxamic acid (SHA) was reported to be a weak reversible inhibitor of MPO. We aimed to identify related hydroxamates that are good inhibitors of the enzyme. We report on three hydroxamates as the first potent reversible inhibitors of MPO. The chlorination activity of purified MPO was inhibited by 50% by 5 nM of a trifluoromethyl-substituted aromatic hydroxamate, HX1. The hydroxamates were specific for MPO in neutrophils and more potent toward MPO compared to a broad range of redox enzymes and alternative targets. Surface plasmon resonance measurements showed the strength of binding of hydroxamates to MPO correlated with the degree of enzyme inhibition. The crystal structure of MPO-HX1 revealed the inhibitor was bound within the active site cavity above the heme and blocked the substrate channel. HX1 was a mixed-type inhibitor of the halogenation activity of MPO with respect to both hydrogen peroxide and halide. Spectral analyses demonstrated that hydroxamates can act variably as substrates for MPO and convert the enzyme to a nitrosyl ferrous intermediate. This property was unrelated to their ability to inhibit MPO. We propose that aromatic hydroxamates bind tightly to the active site of MPO and prevent it from producing hypohalous acids. This mode of reversible inhibition has potential for blocking the activity of MPO and limiting oxidative stress during inflammation.
-==Function==
+Potent Reversible Inhibition of Myeloperoxidase by Aromatic Hydroxamates.,Forbes LV, Sjogren T, Auchere F, Jenkins DW, Thong B, Laughton D, Hemsley P, Pairaudeau G, Turner R, Eriksson H, Unitt JF, Kettle AJ J Biol Chem. 2013 Nov 5. PMID:24194519<ref>PMID:24194519</ref>
-[[http://www.uniprot.org/uniprot/PERM_HUMAN PERM_HUMAN]] Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity.
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[4c1m]] is a 4 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=4C1M OCA].
+</div>
+<div class="pdbe-citations 4c1m" style="background-color:#fffaf0;"></div>
-==Reference==
+==See Also==
-<references group="xtra"/><references/>
+*[[Myeloperoxidase|Myeloperoxidase]]
+*[[Sandbox WWC11|Sandbox WWC11]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Auchere, F.]]
+[[Category: Large Structures]]
-[[Category: Eriksson, H.]]
+[[Category: Auchere F]]
-[[Category: Forbes, L V.]]
+[[Category: Eriksson H]]
-[[Category: Hemsley, P.]]
+[[Category: Forbes LV]]
-[[Category: Jenkins, D W.]]
+[[Category: Hemsley P]]
-[[Category: Kettle, A J.]]
+[[Category: Jenkins DW]]
-[[Category: Laughton, D.]]
+[[Category: Kettle AJ]]
-[[Category: Pairaudeau, G.]]
+[[Category: Laughton D]]
-[[Category: Sjogren, T.]]
+[[Category: Pairaudeau G]]
-[[Category: Thong, B.]]
+[[Category: Sjogren T]]
-[[Category: Unitt, J F.]]
+[[Category: Thong B]]
-[[Category: Hydroxamate]]
+[[Category: Unitt JF]]
-[[Category: Oxidoreductase]]