期刊
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
卷 69, 期 -, 页码 520-533出版社
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S0907444912050469
关键词
antibiotics; carrier proteins; glycopeptides; teicoplanin; radiation damage
资金
- NIH/NIGMS [R01GM079508]
- Office of Biological and Environmental Research of the US Department of Energy
- Office of Basic Energy Sciences of the US Department of Energy
- National Institute of General Medical Sciences of the National Institutes of Health
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 proteinpeptideantibiotic complex. The 2.05 angstrom resolution MBPpeptideteicoplanin 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.
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