Negamycin interferes with decoding and translocation by simultaneous interaction with rRNA and tRNA
Open accessAbstract
Negamycin (NEG) is a ribosome-targeting antibiotic that exhibits clinically promising activity. Its binding site and mode of action have remained unknown. We solved the structure of the Thermus thermophilus ribosome bound to mRNA and three tRNAs, in complex with NEG. The drug binds to both small and large ribosomal subunits at nine independent sites. Resistance mutations in the 16S rRNA unequivocally identified the binding site in the vicinity of the conserved helix 34 (h34) in the small subunit as the primary site of antibiotic action in the bacterial and, possibly, eukaryotic ribosome. At this site, NEG contacts 16S rRNA as well as the anticodon loop of the A-site tRNA. Although the NEG site of action overlaps with that of tetracycline (TET), the two antibiotics exhibit different activities: while TET sterically hinders binding of aminoacyl-tRNA to the ribosome, NEG stabilizes its binding, thereby inhibiting translocation and stimulating miscoding.
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The phosphate group of A1197 engages negamycin through a bound Mg2+ ion.
“The phosphate group of A1197 also engages negamycin through a bound Mg 2 + ion.”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [11]
In the T. thermophilus structure with a bound tRNA molecule, the phosphate oxygens of nucleotides U1052 and G1053 indirectly interact with negamycin and the tRNA molecule through a coordinated Mg2+ ion.
“In the T. thermophilus structure with a bound tRNA molecule, the phosphate oxygens of nucleotides U1052 and G1053 indirectly interact with negamycin and the tRNA molecule through a coordinated Mg 2 + ion (Fig. 1 E and Fig. S1).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [11]
Two previously identified negamycin resistance mutations, U1052G and U1060A, localize to the head domain of the 30S subunit positioned within helix 34 (h34) and are in close proximity to the negamycin binding site.
“Two previously identified negamycin resistance mutations, U1052G and U1060A, localize to the head domain of the 30S subunit positioned within helix 34 (h34) and are in close proximity to the negamycin binding site (Fig. 1 A and B ) (11, 12).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [11]
The mechanism of action for both negamycin and tetracycline is to interfere with tRNA binding to the aminoacyl-tRNA (aa-tRNA) site of the small 30S ribosomal subunit.
“The mechanism of action for both antibiotics is to interfere with tRNA binding to the aminoacyltRNA (aa-tRNA) site of the small 30S ribosomal subunit (11, 12).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [11]
Negamycin is a natural bactericidal antibiotic active against a broad spectrum of Gram-negative pathogens, including Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii.
“Negamycin is a natural bactericidal antibiotic that displays activity against a broad spectrum of Gram-negative pathogens, including Klebsiella pneumoniae , Pseudomonas aeruginosa , and Acinetobacter baumannii (11, 12).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [11]
Negamycin and tetracycline possess chemically distinct features that form different sets of electrostatic and van der Waals interactions, specifically with h31 and h34.
“Despite the overlapping binding sites, negamycin and tetracycline possess chemically distinct features (Fig. 2 B ) that form different sets of electrostatic and van der Waals interactions, specifically with h31 and h34 (11, 12, 17).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [11]
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- Authors
- Polikanov, Y. S., Szal, T., Jiang, F., Gupta, P., Matsuda, R., Shiozuka, M., Steitz, T. A., Vázquez-Laslop, N., & Mankin, A. S.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Illinois Chicago (US)
- The University of Tokyo (JP)
- Corresponding author
- Steitz, Thomas A.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 56
- Issue
- 4
- Pages
- 541-550
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4334386
- OpenAlex
- W2005480696
- Cited by
- 57
- References
- 54
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 1 · 2021: 7 · 2020: 5 · 2019: 4 · 2018: 6 · 2017: 2 · 2016: 8 · 2015: 6
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- National Center of Neurology and Psychiatry (25650106)
- National Institutes of Health (23-5, GM022778, GM106386)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- negamycin, ribosome-targeting antibiotics, ribosome structure, 16S rRNA, tRNA binding, A-site tRNA, anticodon loop, tetracycline, antibiotic binding sites, resistance mutations
- MeSH terms
- Amino Acids, Diamino, Anti-Bacterial Agents, Base Sequence, Binding Sites, Models, Molecular, Protein Synthesis Inhibitors, RNA, Bacterial, RNA, Messenger, RNA, Ribosomal, RNA, Transfer, Protein Biosynthesis, Thermus thermophilus, Crystallography, X-Ray, Amino Acid Motifs, RNA Stability, Ribosome Subunits, Small, Bacterial, Ribosome Subunits, Large, Bacterial
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