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European Collaborators Define Dermcidin's Mode of Action

By BiotechDaily International staff writers
Posted on 06 Mar 2013
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A team of European molecular biologists have published the crystal structure and functional mechanism of the human antimicrobial peptide dermcidin.

Dermcidin (DCD) is a human antimicrobial peptide (AMP) that is constitutively expressed in sweat glands and secreted into sweat. By postsecretory proteolytic processing in human sweat, the precursor protein gives rise to several short DCD peptides varying in length from 25 to 48 amino acids and with net charges between minus two and plus two. Several DCD peptides show antimicrobial activity against pathogenic microorganisms such as Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Candida albicans, Staphylococcus epidermidis, Pseudomonas putida, and methicillin-resistant S. aureus as well as rifampin- and isoniazid-resistant Mycobacterium tuberculosis. DCD-derived peptides are active under high-salt conditions and in a buffer resembling human sweat. These peptides have diverse and overlapping spectra of activity that are independent of the net peptide charge, and previous studies showed that DCD peptides interacted with the bacterial cell envelope and killed gram-negative bacteria without forming pores in membranes.

Investigators at the University of Edinburgh (United Kingdom), the Max Planck Institute for Biophysical Chemistry (Goettingen, Germany), the Max Planck Institute for Developmental Biology (Tübingen, Germany), and the University of Strasbourg (France) collaborated in the effort to define the mode of action of DCD at the molecular and atomic levels.

In the February 20, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) they presented the X-ray crystal structure as well as solid-state NMR spectroscopy, electrophysiology, and molecular dynamic simulations of this major human antimicrobial.

The results demonstrated that dermcidin formed an architecture of high-conductance transmembrane channels, composed of zinc-connected trimers of antiparallel helix pairs. Molecular dynamics simulations elucidated the unusual membrane permeation pathway for ions and showed adjustment of the pore to various membranes. Water and charged particles were able to flow uncontrollably across the membrane, eventually killing harmful microbes.

The authors predicted that their findings may form a foundation for the structure-based design of a new generation of peptide antibiotics.

Related Links:
University of Edinburgh
Max Planck Institute for Biophysical Chemistry
Max Planck Institute for Developmental Biology



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