title: Conformational investigation of antibiotic proximicin by X-ray structure analysis and quantum studies suggest a stretched conformation of this type of γ-peptide.
abstract: The proximicins A-C are naturally occurring cytotoxic γ-peptides that contain the unique 4-amino-furan-carboxylic acid. In contrast to the structurally related cytotoxic natural DNA binder netropsin and distamycin, both exhibiting as core building block N-methyl-4-amino-pyrrol-carboxylic acid, no DNA binding was observed for the procimicins. X-ray analysis of crystals of a protected 4-amino-furan-2-carboxylic acid dipeptide revealed a stretched conformation. In contrast, for netropsin and distamycin, sickle-shaped crystal conformations were observed. DFT-calculations elegantly confirm these conformational arrangements. The most stable conformers of the proximicins are linear whereas sickle-shaped conformations are less stable, having higher Gibbs energies. For netropsin, distamycin and the netropsin-proximicin-hybrid a sickle shaped conformation appears energetically favored. The reported results are consistent with the observations that the proximicins A-C do not bind to the DNA and have a different mode of action concerning their cytotoxic activity with respect to netropsin and distamycin.
authors.affiliation: Institut für Chemie, Technische Universität Berlin, Strasse des 17, Juni 124, 10623 Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Denisiuk
authors.forename: Vivien
authors.initials: V
authors.lastname: Schubert
authors.forename: Falko E
authors.initials: FE
authors.lastname: Wolter
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Irran
authors.forename: Patrick
authors.initials: P
authors.lastname: Trouillas
authors.forename: Roderich D
authors.initials: RD
authors.lastname: Süssmuth
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D009429:Netropsin / Q000031:analogs & derivatives / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D011789:Quantum Theory
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; C529559:proximicin A; C529560:proximicin B; C529561:proximicin C; D009429:Netropsin