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Journal Article

Crystal structure and functional mechanism of a human antimicrobial membrane channel.

MPS-Authors
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Song,  C.
Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society;

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de Groot,  B. L.
Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society;

Fulltext (public)

1703486.pdf
(Publisher version), 964KB

1703486_SI.pdf
(Publisher version), 2MB

Supplementary Material (public)

1703486_sm01.avi
(Supplementary material), 8MB

1703486_sm02.avi
(Supplementary material), 6MB

Citation

Song, C., Weichbrodt, C., Salnikov, E., Dynowski, M., Forsberg, B., Bechinger, B., et al. (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, 110(12), 4586-4591. doi:10.1073/pnas.1214739110.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-EB45-D
Abstract
Multicellular organisms fight bacterial and fungal infections by producing peptide-derived broad-spectrum antibiotics. These host-defense 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.