3zs0 | pdb_00003zs0

Human Myeloperoxidase inactivated by TX2

spinqualitylabelsall models 3zs0, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3zs0 is a 4 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 2.3Å Ligands: ACT, BMA, CA, CL, CSO, FUC, HEM, MAN, NAG, SO4, ZS0 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. 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 a prime candidate for promoting oxidative stress during inflammation. This abundant enzyme of neutrophils uses hydrogen peroxide to oxidize chloride to highly reactive and toxic chlorine bleach. We have identified 2-thioxanthines as potent mechanism-based inactivators of MPO. Mass spectrometry and x-ray crystal structures revealed that these inhibitors become covalently attached to the heme prosthetic groups of the enzyme. We propose a mechanism whereby 2-thioxanthines are oxidized, and their incipient free radicals react with the heme groups of the enzyme before they can exit the active site. 2-Thioxanthines inhibited MPO in plasma and decreased protein chlorination in a mouse model of peritonitis. They slowed but did not prevent neutrophils from killing bacteria and were poor inhibitors of thyroid peroxidase. Our study shows that MPO is susceptible to the free radicals it generates, and this Achilles' heel of the enzyme can be exploited to block oxidative stress during inflammation. 2-thioxanthines are mechanism-based inactivators of myeloperoxidase that block oxidative stress during inflammation.,Tiden AK, Sjogren T, Svensson M, Bernlind A, Senthilmohan R, Auchere F, Norman H, Markgren PO, Gustavsson S, Schmidt S, Lundquist S, Forbes LV, Magon NJ, Paton LN, Jameson GN, Eriksson H, Kettle AJ J Biol Chem. 2011 Oct 28;286(43):37578-89. Epub 2011 Aug 31. PMID:21880720 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Myeloperoxidase Sandbox WWC11

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