Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria

@article{Schluenzen2001StructuralBF,
  title={Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria},
  author={F. Schluenzen and R. Zarivach and J. Harms and A. Bashan and A. Tocilj and Renate Albrecht and A. Yonath and Franc{\"E}ois Franceschi},
  journal={Nature},
  year={2001},
  volume={413},
  pages={814-821}
}
Ribosomes, the site of protein synthesis, are a major target for natural and synthetic antibiotics. Detailed knowledge of antibiotic binding sites is central to understanding the mechanisms of drug action. Conversely, drugs are excellent tools for studying the ribosome function. To elucidate the structural basis of ribosome–antibiotic interactions, we determined the high-resolution X-ray structures of the 50S ribosomal subunit of the eubacterium Deinococcus radiodurans, complexed with the… Expand
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References

SHOWING 1-10 OF 57 REFERENCES
Fine structure of the peptidyl transferase centre on 23 S-like rRNAs deduced from chemical probing of antibiotic-ribosome complexes.
TLDR
It is proposed that the putative sub-sites of the peptidyl transferase centre are physically separated, that some drugs bind to more than one of them, and that they are conformationally interdependent. Expand
Inhibition of the ribosomal peptidyl transferase reaction by the mycarose moiety of the antibiotics carbomycin, spiramycin and tylosin.
TLDR
Data are presented to argue that a disaccharide at position 5 in the lactone ring of macrolides is essential for inhibition of peptide bond formation and that the mycarose moiety is placed near the conserved U2506 in the central loop region of domain V 23 S rRNA. Expand
Interaction of the antibiotics clindamycin and lincomycin with Escherichia coli 23S ribosomal RNA.
TLDR
In vitro, the results show that in vitro the drugs are equally potent in blocking their ribosomal target site and their inhibitory effects on peptide bond formation could, however, be subtly different. Expand
Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3
TLDR
The crystal structure analysis of the complex with tetracycline revealed the functionally important site responsible for the blockage of the A‐site and implies that the anti‐association activity of IF3 is due to its influence on the conformational dynamics of the small ribosomal subunit. Expand
The macrolide–ketolide antibiotic binding site is formed by structures in domains II and V of 23S ribosomal RNA
TLDR
Findings indicate how drug derivatization can improve the inhibition of bacteria that have macrolide resistance conferred by changes in the peptidyl transferase loop. Expand
Structural basis for selectivity and toxicity of ribosomal antibiotics
TLDR
Analysis of resistance mutations in bacteria allows the prediction of whether cytoplasmic or mitochondrial ribosomes in eukaryotic cells will be sensitive to the drug, which has important implications for drug specificity and toxicity. Expand
The structural basis of ribosome activity in peptide bond synthesis.
TLDR
It is established that the ribosome is a ribozyme and the catalytic properties of its all-RNA active site are addressed and the mechanism of peptide bond synthesis appears to resemble the reverse of the acylation step in serine proteases. Expand
Ribosomal peptidyl transferase can withstand mutations at the putative catalytic nucleotide
TLDR
It is reported that large ribosomal subunits with mutated A2451 showed significant peptidyl transferase activity in several independent assays, and the ribosome apparently promotes transpeptidation not through chemical catalysis, but by properly positioning the substrates of protein synthesis. Expand
Mutational analysis of the donor substrate binding site of the ribosomal peptidyltransferase center.
TLDR
Results with a modified "fragment" assay using the minimal donor substrate pA-fMet are consistent with a model where the nucleotides psiGG2582 form a binding pocket for C75 of the tRNA. Expand
The importance of highly conserved nucleotides in the binding region of chloramphenicol at the peptidyl transfer centre of Escherichia coli 23S ribosomal RNA.
TLDR
The results establish the critical structural and functional importance of highly conserved nucleotides in the chloramphenicol binding region and a mechanistic model is presented to explain the disruptive effect of chlorampshenicol on peptide bond formation at the ribosomal subunit interface. Expand
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1
2
3
4
5
...