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1 Lehrstuhl für Biopolymere, Universität Bayreuth, D-95440 Bayreuth, Germany
2 IPF PharmaCeuticals GmbH, D-30625 Hannover, Germany
Reprint requests to: Heinrich Sticht, Lehrstuhl für Biopolymere, Universität Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany; e-mail: Heinrich.Sticht{at}Uni-Bayreuth.de; fax: +49-921-553544.
Defensins are cationic and cysteine-rich peptides that play a crucial role in the host defense against microorganisms of many organisms by their capability to permeabilize bacterial membranes. The low sequence similarity among the members of the large mammalian ß-defensin family suggests that their antimicrobial activity is largely independent of their primary structure. To investigate to what extent these defensins share a similar fold, the structures of the two human ß-defensins, hBD-1 and hBD-2, as well as those of two novel murine defensins, termed mBD-7 and mBD-8, were determined by nuclear magnetic resonance spectroscopy. All four defensins investigated share a striking similarity on the level of secondary and tertiary structure including the lack of a distinct hydrophobic core, suggesting that the fold is mainly stabilized by the presence of three disulfide bonds. In addition to the overall shape of the molecules, the ratio of solvent-exposed polar and hydrophobic side chains is also very similar among the four defensins investigated. It is significant that ß-defensins do not exhibit a common pattern of charged and hydrophobic residues on the protein surface and that the ß-defensin-specific fold appears to accommodate a wide range of different amino acids at most sequence positions. In addition to the implications for the mode of biological defensin actions, these findings are of particular interest because ß-defensins have been suggested as lead compounds for the development of novel peptide antibiotics for the therapy of infectious diseases.
Keywords: ß-defensin; NMR structure; peptide fold; antimicrobial peptide; chemotaxis; chemokine receptor
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