Crystal structure and functional mechanism of a human antimicrobial membrane channel

Chen Song, Conrad Weichbrodt, Evgeniy S. Salnikov, Marek Dynowski, Bjorn O. Forsberg, Burkhard Bechinger, Claudia Steinem, Bert L. De Groot, Ulrich Zachariae, Kornelius Zeth

    Research output: Contribution to journalArticle

    63 Citations (Scopus)

    Abstract

    Multicellular organisms fight bacterial and fungal infections by producing peptide-derived broad-spectrum antibiotics. These hostdefense peptides compromise the integrity of microbial cell membranes and thus evade pathways by which bacteria develop rapid antibiotic resistance. Although more than 1,700 host-defense peptides have been identified, the structural and mechanistic basis of their action remains speculative. This impedes the desired rational development of these agents into next-generation antibiotics. We present the X-ray crystal structure as well as solid-state NMR spectroscopy, electrophysiology, and MD simulations of human dermcidin in membranes that reveal the antibiotic mechanism of this major human antimicrobial, found to suppress Staphylococcus aureus growth on the epidermal surface. Dermcidin forms an architecture of high-conductance transmembrane channels, composed of zinc-connected trimers of antiparallel helix pairs. Molecular dynamics simulations elucidate the unusual membrane permeation pathway for ions and show adjustment of the pore to various membranes. Our study unravels the comprehensive mechanism for the membrane-disruptive action of this mammalian host-defense peptide at atomistic level. The results may form a foundation for the structure-based design of peptide antibiotics.
    Original languageEnglish
    Pages (from-to)4586-4591
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume110
    Issue number12
    DOIs
    Publication statusPublished - 2013

    Fingerprint

    Ion Channels
    Peptides
    Anti-Bacterial Agents
    Membranes
    Mycoses
    Electrophysiology
    Molecular Dynamics Simulation
    Microbial Drug Resistance
    Bacterial Infections
    Staphylococcus aureus
    Zinc
    Magnetic Resonance Spectroscopy
    Cell Membrane
    X-Rays
    Ions
    Bacteria
    Growth
    dermcidin

    Cite this

    Song, Chen ; Weichbrodt, Conrad ; Salnikov, Evgeniy S. ; Dynowski, Marek ; Forsberg, Bjorn O. ; Bechinger, Burkhard ; Steinem, Claudia ; De Groot, Bert L. ; Zachariae, Ulrich ; Zeth, Kornelius. / Crystal structure and functional mechanism of a human antimicrobial membrane channel. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 12. pp. 4586-4591.
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    abstract = "Multicellular organisms fight bacterial and fungal infections by producing peptide-derived broad-spectrum antibiotics. These hostdefense peptides compromise the integrity of microbial cell membranes and thus evade pathways by which bacteria develop rapid antibiotic resistance. Although more than 1,700 host-defense peptides have been identified, the structural and mechanistic basis of their action remains speculative. This impedes the desired rational development of these agents into next-generation antibiotics. We present the X-ray crystal structure as well as solid-state NMR spectroscopy, electrophysiology, and MD simulations of human dermcidin in membranes that reveal the antibiotic mechanism of this major human antimicrobial, found to suppress Staphylococcus aureus growth on the epidermal surface. Dermcidin forms an architecture of high-conductance transmembrane channels, composed of zinc-connected trimers of antiparallel helix pairs. Molecular dynamics simulations elucidate the unusual membrane permeation pathway for ions and show adjustment of the pore to various membranes. Our study unravels the comprehensive mechanism for the membrane-disruptive action of this mammalian host-defense peptide at atomistic level. The results may form a foundation for the structure-based design of peptide antibiotics.",
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    Song, C, Weichbrodt, C, Salnikov, ES, Dynowski, M, Forsberg, BO, Bechinger, B, Steinem, C, De Groot, BL, Zachariae, U & Zeth, K 2013, 'Crystal structure and functional mechanism of a human antimicrobial membrane channel', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 12, pp. 4586-4591. https://doi.org/10.1073/pnas.1214739110

    Crystal structure and functional mechanism of a human antimicrobial membrane channel. / Song, Chen; Weichbrodt, Conrad; Salnikov, Evgeniy S.; Dynowski, Marek; Forsberg, Bjorn O.; Bechinger, Burkhard; Steinem, Claudia; De Groot, Bert L.; Zachariae, Ulrich; Zeth, Kornelius.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 12, 2013, p. 4586-4591.

    Research output: Contribution to journalArticle

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    AU - Bechinger, Burkhard

    AU - Steinem, Claudia

    AU - De Groot, Bert L.

    AU - Zachariae, Ulrich

    AU - Zeth, Kornelius

    N1 - Copyright 2013 Elsevier B.V., All rights reserved.

    PY - 2013

    Y1 - 2013

    N2 - Multicellular organisms fight bacterial and fungal infections by producing peptide-derived broad-spectrum antibiotics. These hostdefense peptides compromise the integrity of microbial cell membranes and thus evade pathways by which bacteria develop rapid antibiotic resistance. Although more than 1,700 host-defense peptides have been identified, the structural and mechanistic basis of their action remains speculative. This impedes the desired rational development of these agents into next-generation antibiotics. We present the X-ray crystal structure as well as solid-state NMR spectroscopy, electrophysiology, and MD simulations of human dermcidin in membranes that reveal the antibiotic mechanism of this major human antimicrobial, found to suppress Staphylococcus aureus growth on the epidermal surface. Dermcidin forms an architecture of high-conductance transmembrane channels, composed of zinc-connected trimers of antiparallel helix pairs. Molecular dynamics simulations elucidate the unusual membrane permeation pathway for ions and show adjustment of the pore to various membranes. Our study unravels the comprehensive mechanism for the membrane-disruptive action of this mammalian host-defense peptide at atomistic level. The results may form a foundation for the structure-based design of peptide antibiotics.

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