title: Crystal structure and functional mechanism of a human antimicrobial membrane channel.
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.
authors: Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors: Chen
authors: C
authors: Song
authors: Conrad
authors: C
authors: Weichbrodt
authors: Evgeniy S
authors: ES
authors: Salnikov
authors: Marek
authors: M
authors: Dynowski
authors: Björn O
authors: BO
authors: Forsberg
authors: Burkhard
authors: B
authors: Bechinger
authors: Claudia
authors: C
authors: Steinem
authors: Bert L
authors: BL
authors: de Groot
authors: Ulrich
authors: U
authors: Zachariae
authors: Kornelius
authors: K
authors: Zeth
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006801:Humans; D007473:Ion Channels / Q000737:chemistry* / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000254:growth & development*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
chemical_list: D000890:Anti-Infective Agents; D007473:Ion Channels; D010455:Peptides; C442243:dermcidin