Structural and functional studies of defensin-inspired peptides.
Mammals have evolved complex self-defence mechanisms to protect themselves from infection. This innate immune system comprises a large family of hundreds of peptides and proteins which have potent antibiotic activity at nanomolar concentrations. The defensins are a group of small cationic peptides which contain a high proportion of positively charged and hydrophobic amino acids. Their exact mechanism of antimicrobial action is unclear, but it is thought that the defensins bind to and disrupt the outer cell membrane which ultimately causes lysis and cell death. They are characterized by six conserved cysteine residues which oxidize to form three intramolecular disulphide (S-S) bonds. The human and mouse defensins have been subdivided into classes based on their sequence, site of expression and the S-S bond connectivity of the cysteine residues. Alpha-defensins are connected by cysteines 1 and 6, 2 and 4, and 3 and 5, whereas beta-defensins have a 1-5, 2-4 and 3-6 cysteine S-S connectivity. We present our structural and functional studies of a novel mouse beta-defensin-related peptide (Defr1) which contains only five cysteine residues. Synthetic Defr1 was more active than its six-cysteine analogue against a large panel of pathogens. High-resolution MS techniques revealed that Defr1 contains an unusual defensin structure. These studies have guided the design of novel peptides to explore the roles of defensins as antibiotics and as stimulants of the immune response.
Clarke
D J
DJ
School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, Scotland, UK.
Campopiano
D J
DJ
D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism; D023082:Defensins / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000378:metabolism
D000890:Anti-Infective Agents; D023082:Defensins; D008565:Membrane Proteins; D009363:Neoplasm Proteins