| Structural highlights
9sds is a 6 chain structure with sequence from Homo sapiens and Staphylococcus aureus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.49Å |
| 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
The heme enzyme myeloperoxidase is a key player in the innate immune defense. It uses hydrogen peroxide to produce bactericidal hypohalous acids from (pseudo)halides, foremost chloride, and thiocyanate in the neutrophil phagosome. However, the available structural data on the halide-binding site, the marked pH dependence of halide oxidation, and the atypical pK(a) of an active-site histidine 261 fail to fully account for the mechanism of halide oxidation by myeloperoxidase. In the present study, crystal structures of myeloperoxidase-halide complexes show that halides can integrate into the hydrogen-bonding network formed by conserved water molecules, without directly interacting with the deprotonated histidine at both acidic and neutral pH. Molecular dynamics simulations reveal that protonation of histidine 261 decreases active site rigidity and increases the flexibility of arginine 405. Together with the terminal residues of the myeloperoxidase heavy and light chains, arginine 405 contributes to halide transport into the active site. Kinetic analyses and simulations further demonstrate that sodium ions play a critical role as charge shields, enabling halides to traverse the negatively charged access channel, which represents a key bottleneck for halide binding. Thus, halide access to the active site is governed by a complex interplay of electrostatic interactions involving both solvent ions and charged amino acid residues.
Halide binding by myeloperoxidase is regulated by access channel dynamics and charge interactions.,Leitgeb U, Crha R, Fegerl I, Furtmuller PG, Oostenbrink C, Pfanzagl V Int J Biol Macromol. 2025 Oct 4;330(Pt 2):148038. doi: , 10.1016/j.ijbiomac.2025.148038. PMID:41043752[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Leitgeb U, Crha R, Fegerl I, Furtmüller PG, Oostenbrink C, Pfanzagl V. Halide binding by myeloperoxidase is regulated by access channel dynamics and charge interactions. Int J Biol Macromol. 2025 Oct 4;330(Pt 2):148038. PMID:41043752 doi:10.1016/j.ijbiomac.2025.148038
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