Identification and structural characterization of a novel myeloperoxidase inhibitor from Staphylococcus delphini

Ploscariu, Nicoleta T.; de Jong, Nienke W. M.; van Kessel, Kok P. M.; van Strijp, Jos A. G.; Geisbrecht, Brian V.

doi:10.1016/j.abb.2018.03.007

Title: Identification and structural characterization of a novel myeloperoxidase inhibitor from Staphylococcus delphini

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Abstract

Staphylococcus aureus and related species are highly adapted to their hosts and have evolved numerous strategies to evade the immune system. S. aureus shows resistance to killing following uptake into the phagosome, which suggests that the bacterium evades intracellular killing mechanisms used by neutrophils. We recently discovered an S. aureus protein (SPIN for Staphylococcal Peroxidase INhibitor) that binds to and inhibits myeloperoxidase (MPO), a major player in the oxidative defense of neutrophils. To allow for comparative studies between multiple SPIN sequences, we identified a panel of homologs from species closely related to S. aureus. Characterization of these proteins revealed that SPIN molecules from S. agnetis, S. delphini, S. schleiferi, and S. intermedius all bind human MPO with nanomolar affinities, and that those from S. delphini, S. schleiferi, and S. intermedius inhibit human MPO in a dose-dependent manner. A 2.4 Å resolution co-crystal structure of SPINdelphini bound to recombinant human MPO allowed us to identify conserved structural features of SPIN proteins, and to propose sequence-dependent physical explanations for why SPIN-aureus binds human MPO with higher affinity than SPIN-delphini. Overall, these studies expand our understanding of MPO binding and inhibition by a recently identified component of the staphylococcal innate immune evasion arsenal.

Authors:

Ploscariu, Nicoleta T. ^[1]; de Jong, Nienke W. M. ^[2]; van Kessel, Kok P. M. ^[2];

^[2]; Geisbrecht, Brian V. ^[1]

Kansas State Univ., Manhattan, KS (United States)
Utrecht Univ. (Netherlands)

Publication Date:: Wed Mar 07 00:00:00 EST 2018

Research Org.:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: ZonMw; Netherlands Organisation for Health Research and Development; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)

OSTI Identifier:: 1433718

Alternate Identifier(s):: OSTI ID: 1548601

Grant/Contract Number:: 205200004; AI111203; GM121511; W-31-109-Eng-38

Resource Type:: Accepted Manuscript

Journal Name:: Archives of Biochemistry and Biophysics

Additional Journal Information:: Journal Volume: 645; Journal Issue: C; Journal ID: ISSN 0003-9861

Publisher:: Elsevier

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Myeloperoxidase; Inhibitor; Staphylococcus aureus; Staphylococcus delphini; Immune evasion; X-ray crystallography

Citation Formats


                    Ploscariu, Nicoleta T., de Jong, Nienke W. M., van Kessel, Kok P. M., van Strijp, Jos A. G., and Geisbrecht, Brian V. Identification and structural characterization of a novel myeloperoxidase inhibitor from Staphylococcus delphini.  United States: N. p., 2018. 
Web.  doi:10.1016/j.abb.2018.03.007.

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                    Ploscariu, Nicoleta T., de Jong, Nienke W. M., van Kessel, Kok P. M., van Strijp, Jos A. G., & Geisbrecht, Brian V. Identification and structural characterization of a novel myeloperoxidase inhibitor from Staphylococcus delphini.  United States.  https://doi.org/10.1016/j.abb.2018.03.007

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                    Ploscariu, Nicoleta T., de Jong, Nienke W. M., van Kessel, Kok P. M., van Strijp, Jos A. G., and Geisbrecht, Brian V. Wed .  
"Identification and structural characterization of a novel myeloperoxidase inhibitor from Staphylococcus delphini".  United States.  https://doi.org/10.1016/j.abb.2018.03.007.  https://www.osti.gov/servlets/purl/1433718.

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@article{osti_1433718,

  title        = {Identification and structural characterization of a novel myeloperoxidase inhibitor from Staphylococcus delphini},

  author       = {Ploscariu, Nicoleta T. and de Jong, Nienke W. M. and van Kessel, Kok P. M. and van Strijp, Jos A. G. and Geisbrecht, Brian V.},

  abstractNote = {Staphylococcus aureus and related species are highly adapted to their hosts and have evolved numerous strategies to evade the immune system. S. aureus shows resistance to killing following uptake into the phagosome, which suggests that the bacterium evades intracellular killing mechanisms used by neutrophils. We recently discovered an S. aureus protein (SPIN for Staphylococcal Peroxidase INhibitor) that binds to and inhibits myeloperoxidase (MPO), a major player in the oxidative defense of neutrophils. To allow for comparative studies between multiple SPIN sequences, we identified a panel of homologs from species closely related to S. aureus. Characterization of these proteins revealed that SPIN molecules from S. agnetis, S. delphini, S. schleiferi, and S. intermedius all bind human MPO with nanomolar affinities, and that those from S. delphini, S. schleiferi, and S. intermedius inhibit human MPO in a dose-dependent manner. A 2.4 Å resolution co-crystal structure of SPINdelphini bound to recombinant human MPO allowed us to identify conserved structural features of SPIN proteins, and to propose sequence-dependent physical explanations for why SPIN-aureus binds human MPO with higher affinity than SPIN-delphini. Overall, these studies expand our understanding of MPO binding and inhibition by a recently identified component of the staphylococcal innate immune evasion arsenal.},

  doi          = {10.1016/j.abb.2018.03.007},

  journal      = {Archives of Biochemistry and Biophysics},

  number       = C,

  volume       = 645,

  place        = {United States},

  year         = {Wed Mar 07 00:00:00 EST 2018},

  month        = {Wed Mar 07 00:00:00 EST 2018}

}

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