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Sequence selectivity of macrolide-induced translational attenuation
Open accessAbstract
Significance: By globally mapping the position of stalled ribosomes in macrolide-treated Staphylococcus aureus , we identified the proteins whose synthesis is affected by this antibiotic. Rather than acting as a nonselective inhibitor, the binding of macrolides to the ribosome tunnel only induces stalling at a few unique sites that are enriched in proline and charged residues. The sequences that flank the stalling sites are highly variable but are essential for efficient stalling. Although it has long been assumed that macrolides inhibit translation after the synthesis of a few residues, we found that stalling could occur at any point during translation. Our results reveal a striking conservation of stalling motifs among all known arrest peptides that strongly suggests a universal ribosome stalling mechanism.
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“Recent studies on NPET binding translation inhibitors like macrolides and Tetracenomycin X have established that the sequence of the nascent peptide plays a crucial role in the binding affinity and efficacy of these inhibitors14,26,27.”
From Dual site targeting of the bacterial 70S ribosome by tetracyclines (2026) · cites this paper as [26]
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Metadata
- Authors
- Davis, A. R., Gohara, D. W., & Yap, M.-N. F.
- Affiliations
- Saint Louis University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-10-13
- Volume
- 111
- Issue
- 43
- Pages
- 15379-15384
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4217412
- OpenAlex
- W2165035045
- Cited by
- 123
- References
- 46
- Citations by year
- 2026: 13 · 2025: 10 · 2024: 10 · 2023: 6 · 2022: 8 · 2021: 14 · 2020: 12 · 2019: 8 · 2018: 11 · 2017: 18 · 2016: 10 · 2015: 3
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Saint Louis University
- National Institutes of Health
- National Institute of General Medical Sciences (R00GM094212)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
- Keywords
- macrolide antibiotics, azithromycin, translational attenuation, ribosome stalling, Staphylococcus aureus, proline-rich sequences, charged residues, translational arrest
- MeSH terms
- Peptides, Proline, Ribosomes, Staphylococcus aureus, Protein Biosynthesis, Open Reading Frames, Azithromycin, Macrolides, Sequence Analysis, Protein
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