5uzu

Immune evasion by a Staphylococcal Peroxidase Inhibitor that blocks myeloperoxidase

spinqualitylabelsall models 5uzu, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5uzu is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BMA, CA, CL, NAG NonStd Res: CSO Activity: Myeloperoxidase, with EC number 1.11.2.2 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 Staphylococcus aureus is highly adapted to its host and has evolved many strategies to resist opsonization and phagocytosis. Even after uptake by neutrophils, S. aureus shows resistance to killing, which suggests the presence of phagosomal immune evasion molecules. With the aid of secretome phage display, we identified a highly conserved protein that specifically binds and inhibits human myeloperoxidase (MPO), a major player in the oxidative defense of neutrophils. We have named this protein "staphylococcal peroxidase inhibitor" (SPIN). To gain insight into inhibition of MPO by SPIN, we solved the cocrystal structure of SPIN bound to a recombinant form of human MPO at 2.4-A resolution. This structure reveals that SPIN acts as a molecular plug that prevents H2O2 substrate access to the MPO active site. In subsequent experiments, we observed that SPIN expression increases inside the neutrophil phagosome, where MPO is located, compared with outside the neutrophil. Moreover, bacteria with a deleted gene encoding SPIN showed decreased survival compared with WT bacteria after phagocytosis by neutrophils. Taken together, our results demonstrate that S. aureus secretes a unique proteinaceous MPO inhibitor to enhance survival by interfering with MPO-mediated killing. Immune evasion by a staphylococcal inhibitor of myeloperoxidase.,de Jong NWM, Ramyar KX, Guerra FE, Nijland R, Fevre C, Voyich JM, McCarthy AJ, Garcia BL, van Kessel KPM, van Strijp JAG, Geisbrecht BV, Haas PA Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):9439-9444. doi:, 10.1073/pnas.1707032114. Epub 2017 Aug 14. PMID:28808028 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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