1. Structure of the complex between teicoplanin and a bacterial cell-wall peptide: use of a carrier-protein approach
- Author
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Edwin Lazo, Patrick J. Loll, Nicoleta J. Economou, Simon Cocklin, Stephen D. Weeks, Vivian Stojanoff, Kimberly C. Grasty, Isaac Zentner, and Jean Jakoncic
- Subjects
Stereochemistry ,Target peptide ,Peptide ,Plasma protein binding ,Crystallography, X-Ray ,Ligands ,Structural Biology ,Cell Wall ,medicine ,polycyclic compounds ,Protein Precursors ,chemistry.chemical_classification ,Chemistry ,Teicoplanin ,Glycopeptides ,Micromonosporaceae ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,Native chemical ligation ,Ligand (biochemistry) ,bacterial infections and mycoses ,Research Papers ,Glycopeptide ,Amino acid ,Anti-Bacterial Agents ,carbohydrates (lipids) ,Biochemistry ,bacteria ,Carrier Proteins ,Crystallization ,medicine.drug ,Protein Binding - 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 A 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.
- Published
- 2012