title: Structure determination of human and murine beta-defensins reveals structural conservation in the absence of significant sequence similarity.
abstract: 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 beta-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 beta-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 beta-defensins do not exhibit a common pattern of charged and hydrophobic residues on the protein surface and that the beta-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 beta-defensins have been suggested as lead compounds for the development of novel peptide antibiotics for the therapy of infectious diseases.
authors.affiliation: Lehrstuhl für Biopolymere, Universität Bayreuth, D-95440 Bayreuth, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Bauer
authors.forename: K
authors.initials: K
authors.lastname: Schweimer
authors.forename: E
authors.initials: E
authors.lastname: Klüver
authors.forename: J R
authors.initials: JR
authors.lastname: Conejo-Garcia
authors.forename: W G
authors.initials: WG
authors.lastname: Forssmann
authors.forename: P
authors.initials: P
authors.lastname: Rösch
authors.forename: K
authors.initials: K
authors.lastname: Adermann
authors.forename: H
authors.initials: H
authors.lastname: Sticht
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002845:Chromatography; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004220:Disulfides; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D023083:beta-Defensins / Q000737:chemistry*
chemical_list: C406407:DEFB1 protein, human; C106641:DEFB4A protein, human; C446440:Defb7 protein, mouse; C446439:Defb8 protein, mouse; D004220:Disulfides; D010455:Peptides; D023083:beta-Defensins