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{{Large structure}}
{{STRUCTURE_4dl1|  PDB=4dl1  |  SCENE=  }}
===Crystal Structure of human Myeloperoxidase with covalent thioxanthine analog===
{{ABSTRACT_PUBMED_22352991}}


==Disease==
==Crystal Structure of human Myeloperoxidase with covalent thioxanthine analog==
[[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='4dl1' size='340' side='right'caption='[[4dl1]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4dl1]] is a 16 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=4DL1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DL1 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=0KY:3-[(2R)-2-ETHOXYPROPYL]-2-THIOXO-1,2,3,9-TETRAHYDRO-6H-PURIN-6-ONE'>0KY</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=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></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=4dl1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dl1 OCA], [https://pdbe.org/4dl1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dl1 RCSB], [https://www.ebi.ac.uk/pdbsum/4dl1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dl1 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 ==
Myeloperoxidase (MPO) is known to be inactivated and covalently modified by treatment with hydrogen peroxide and agents similar to 3-(2-ethoxypropyl)-2-thioxo-2,3-dihydro-1H-purin-6(9H)-one (1), a 254.08 Da derivative of 2-thioxanthine. Peptide mapping by liquid chromatography and mass spectrometry detected modification by 1 in a labile peptide-heme-peptide fragment of the enzyme, accompanied by a mass increase of 252.08 Da. The loss of two hydrogen atoms was consistent with mechanism-based oxidative coupling. Multistage mass spectrometry (MS(4)) of the modified fragment in an ion trap/Orbitrap spectrometer demonstrated that 1 was coupled directly to heme. Use of a 10 amu window delivered the full isotopic envelope of each precursor ion to collision-induced dissociation, preserving definitive isotopic profiles for iron-containing fragments through successive steps of multistage mass spectrometry. Iron isotope signatures and accurate mass measurements supported the structural assignments. Crystallographic analysis confirmed linkage between the methyl substituent of the heme pyrrole D ring and the sulfur atom of 1. The final orientation of 1 perpendicular to the plane of the heme ring suggested a mechanism consisting of two consecutive one-electron oxidations of 1 by MPO. Multistage mass spectrometry using stage-specific collision energies permits stepwise deconstruction of modifications of heme enzymes containing covalent links between the heme group and the polypeptide chain.


==Function==
Deconstruction of Activity-Dependent Covalent Modification of Heme in Human Neutrophil Myeloperoxidase by Multistage Mass Spectrometry (MS(4)).,Geoghegan KF, Varghese AH, Feng X, Bessire AJ, Conboy JJ, Ruggeri RB, Ahn K, Spath SN, Filippov SV, Conrad SJ, Carpino PA, Guimaraes CR, Vajdos FF Biochemistry. 2012 Mar 13;51(10):2065-77. Epub 2012 Mar 1. PMID:22352991<ref>PMID:22352991</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>
[[4dl1]] is a 16 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=4DL1 OCA].
</div>
<div class="pdbe-citations 4dl1" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
<ref group="xtra">PMID:022352991</ref><references group="xtra"/><references/>
*[[Myeloperoxidase|Myeloperoxidase]]
*[[Sandbox WWC11|Sandbox WWC11]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Myeloperoxidase]]
[[Category: Large Structures]]
[[Category: Vajdos, F.]]
[[Category: Vajdos F]]
[[Category: Varghese, A.]]
[[Category: Varghese A]]
[[Category: Heme-dependent peroxidase]]
[[Category: Oxidoreductase]]

Latest revision as of 12:49, 25 December 2024

Crystal Structure of human Myeloperoxidase with covalent thioxanthine analogCrystal Structure of human Myeloperoxidase with covalent thioxanthine analog

Structural highlights

4dl1 is a 16 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2Å
Ligands:, , , , , , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PERM_HUMAN Defects in MPO are the cause of myeloperoxidase deficiency (MPOD) [MIM:254600. A disorder characterized by decreased myeloperoxidase activity in neutrophils and monocytes that results in disseminated candidiasis.[1] [2] [3] [4] [5]

Function

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.

Publication Abstract from PubMed

Myeloperoxidase (MPO) is known to be inactivated and covalently modified by treatment with hydrogen peroxide and agents similar to 3-(2-ethoxypropyl)-2-thioxo-2,3-dihydro-1H-purin-6(9H)-one (1), a 254.08 Da derivative of 2-thioxanthine. Peptide mapping by liquid chromatography and mass spectrometry detected modification by 1 in a labile peptide-heme-peptide fragment of the enzyme, accompanied by a mass increase of 252.08 Da. The loss of two hydrogen atoms was consistent with mechanism-based oxidative coupling. Multistage mass spectrometry (MS(4)) of the modified fragment in an ion trap/Orbitrap spectrometer demonstrated that 1 was coupled directly to heme. Use of a 10 amu window delivered the full isotopic envelope of each precursor ion to collision-induced dissociation, preserving definitive isotopic profiles for iron-containing fragments through successive steps of multistage mass spectrometry. Iron isotope signatures and accurate mass measurements supported the structural assignments. Crystallographic analysis confirmed linkage between the methyl substituent of the heme pyrrole D ring and the sulfur atom of 1. The final orientation of 1 perpendicular to the plane of the heme ring suggested a mechanism consisting of two consecutive one-electron oxidations of 1 by MPO. Multistage mass spectrometry using stage-specific collision energies permits stepwise deconstruction of modifications of heme enzymes containing covalent links between the heme group and the polypeptide chain.

Deconstruction of Activity-Dependent Covalent Modification of Heme in Human Neutrophil Myeloperoxidase by Multistage Mass Spectrometry (MS(4)).,Geoghegan KF, Varghese AH, Feng X, Bessire AJ, Conboy JJ, Ruggeri RB, Ahn K, Spath SN, Filippov SV, Conrad SJ, Carpino PA, Guimaraes CR, Vajdos FF Biochemistry. 2012 Mar 13;51(10):2065-77. Epub 2012 Mar 1. PMID:22352991[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Kizaki M, Miller CW, Selsted ME, Koeffler HP. Myeloperoxidase (MPO) gene mutation in hereditary MPO deficiency. Blood. 1994 Apr 1;83(7):1935-40. PMID:8142659
  2. ↑ Nauseef WM, Brigham S, Cogley M. Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan. J Biol Chem. 1994 Jan 14;269(2):1212-6. PMID:7904599
  3. ↑ Nauseef WM, Cogley M, McCormick S. Effect of the R569W missense mutation on the biosynthesis of myeloperoxidase. J Biol Chem. 1996 Apr 19;271(16):9546-9. PMID:8621627
  4. ↑ DeLeo FR, Goedken M, McCormick SJ, Nauseef WM. A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation. J Clin Invest. 1998 Jun 15;101(12):2900-9. PMID:9637725 doi:10.1172/JCI2649
  5. ↑ Romano M, Dri P, Dadalt L, Patriarca P, Baralle FE. Biochemical and molecular characterization of hereditary myeloperoxidase deficiency. Blood. 1997 Nov 15;90(10):4126-34. PMID:9354683
  6. ↑ Geoghegan KF, Varghese AH, Feng X, Bessire AJ, Conboy JJ, Ruggeri RB, Ahn K, Spath SN, Filippov SV, Conrad SJ, Carpino PA, Guimaraes CR, Vajdos FF. Deconstruction of Activity-Dependent Covalent Modification of Heme in Human Neutrophil Myeloperoxidase by Multistage Mass Spectrometry (MS(4)). Biochemistry. 2012 Mar 13;51(10):2065-77. Epub 2012 Mar 1. PMID:22352991 doi:10.1021/bi201872j

4dl1, resolution 2.00Å

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