期刊
NUCLEIC ACIDS RESEARCH
卷 45, 期 16, 页码 9573-9582出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkx673
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资金
- National Institutes of Health (NIH) [R01 GM106386]
- NIH [R35 GM118101, R01 106386]
- Hans W. Vahlteich Professorship
- University of Illinois startup funds
- King Saud University Scholarship for Graduate Studies
- University of Michigan Rackham Merit Pre-doctoral Fellowship
- National Institute of General Medical Sciences from the NIH [P41 GM103403]
- NIH-ORIPHEI [S10 RR029205]
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
Antibiotics methymycin (MTM) and pikromycin (PKM), co-produced by Streptomyces venezuelae, represent minimalist macrolide protein synthesis inhibitors. Unlike other macrolides, which carry several side chains, a single desosamine sugar is attached to the macrolactone ring of MTM and PKM. In addition, the macrolactone scaffold of MTM is smaller than in other macrolides. The unusual structure of MTM and PKM and their simultaneous secretion by S. venezuelae bring about the possibility that two compounds would bind to distinct ribosomal sites. However, by combining genetic, biochemical and crystallographic studies, we demonstrate that MTM and PKM inhibit translation by binding to overlapping sites in the ribosomal exit tunnel. Strikingly, while MTM and PKM readily arrest the growth of bacteria, similar to 40% of cellular proteins continue to be synthesized even at saturating concentrations of the drugs. Gel electrophoretic analysis shows that compared to other ribosomal antibiotics, MTM and PKM prevent synthesis of a smaller number of cellular polypeptides illustrating a unique mode of action of these antibiotics.
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