Acta Crystallographica Section D

Biological Crystallography

Volume 69, Part 4 (April 2013)


research papers



Acta Cryst. (2013). D69, 520-533    [ doi:10.1107/S0907444912050469 ]

Structure of the complex between teicoplanin and a bacterial cell-wall peptide: use of a carrier-protein approach

N. J. Economou, I. J. Zentner, E. Lazo, J. Jakoncic, V. Stojanoff, S. D. Weeks, K. C. Grasty, S. Cocklin and P. J. Loll

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.

PDB references: 3vfj and 3vfk

Keywords: antibiotics; carrier proteins; glycopeptides; teicoplanin; radiation damage.


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