title: Structure of the complex between teicoplanin and a bacterial cell-wall peptide: use of a carrier-protein approach.
abstract: Multidrug-resistant bacterial infections are commonly treated with glycopeptide antibiotics such as teicoplanin. This drug inhibits bacterial cell-wall biosynthesis by binding and sequestering a cell-wall precursor: a D-alanine-containing peptide. A carrier-protein strategy was used to crystallize the complex of teicoplanin and its target peptide by fusing the cell-wall peptide to either MBP or ubiquitin via native chemical ligation and subsequently crystallizing the protein-peptide-antibiotic complex. The 2.05 Å resolution MBP-peptide-teicoplanin structure shows that teicoplanin recognizes its ligand through a combination of five hydrogen bonds and multiple van der Waals interactions. Comparison of this teicoplanin structure with that of unliganded teicoplanin reveals a flexibility in the antibiotic peptide backbone that has significant implications for ligand recognition. Diffraction experiments revealed an X-ray-induced dechlorination of the sixth amino acid of the antibiotic; it is shown that teicoplanin is significantly more radiation-sensitive than other similar antibiotics and that ligand binding increases radiosensitivity. Insights derived from this new teicoplanin structure may contribute to the development of next-generation antibacterials designed to overcome bacterial resistance.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Nicoleta J
authors.initials: NJ
authors.lastname: Economou
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Zentner
authors.forename: Edwin
authors.initials: E
authors.lastname: Lazo
authors.forename: Jean
authors.initials: J
authors.lastname: Jakoncic
authors.forename: Vivian
authors.initials: V
authors.lastname: Stojanoff
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weeks
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Grasty
authors.forename: Simon
authors.initials: S
authors.lastname: Cocklin
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Loll
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D002473:Cell Wall / Q000737:chemistry*; D003460:Crystallization; D018360:Crystallography, X-Ray; D006020:Glycopeptides / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008848:Micromonosporaceae; D011485:Protein Binding; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism; D017334:Teicoplanin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D006020:Glycopeptides; D008024:Ligands; D011498:Protein Precursors; D017334:Teicoplanin
keywords: antibiotics; carrier proteins; glycopeptides; radiation damage; teicoplanin