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

  title={Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria},
  author={Frank Schluenzen and Raz Zarivach and J Harms and Anat Bashan and Ante Tocilj and Renate Albrecht and Ada E. Yonath and Franc{\"E}ois Franceschi},
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… 

Species-specific antibiotic-ribosome interactions: implications for drug development

Revisiting the structural data for the bacterial D50S-antibiotic complexes reveals that the mode of binding of the macrolides, ketolides, streptogramins and lincosamides is generally similar to that observed in the archaeal H50S structures.

On the specificity of antibiotics targeting the large ribosomal subunit

  • Daniel N. Wilson
  • Biology, Chemistry
    Annals of the New York Academy of Sciences
  • 2011
A picture is emerging defining the specific functional states of the ribosome that antibiotics preferentially target, and mechanistic insight into antibiotic inhibition will be important for the development of the next generation of antimicrobial agents.

The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics

At least two pairs of structurally dissimilar compounds have been selected in the course of evolution to act synergistically by targeting neighboring sites in the ribosome by binding at the peptidyl transferase center of the eubacterial large ribosomal subunit.

Macrolide antibiotic interaction and resistance on the bacterial ribosome.

The information is now available to understand, at atomic resolution, how macrolide antibiotics interact with their ribosomal target, how the target is altered to confer resistance, and in which directions the authors need to look to rationally design better drugs to overcome the extant resistance mechanisms.

Context-specific inhibition of translation by ribosomal antibiotics targeting the peptidyl transferase center

It is shown that the activity of chloramphenicol and linezolid critically depends on the nature of specific amino acids of the nascent chain carried by the ribosome and by the identity of the residue entering the A site, which indicates that the nascent protein modulates the properties of the Ribosomal catalytic center and affects binding of its ligands.

Antibiotics that target protein synthesis

The major classes of antibiotics that target the bacterial ribosome are discussed and classified according to their respective target.

Context-Specific Action of Ribosomal Antibiotics.

These findings demonstrate that the protein residing in the exit tunnel influences the properties of the PTC, including its ability to bind inhibitors of translation, and the mechanism of action of antibiotics is directly affected by the functional link between the exit Tunnel and the catalytic core of the ribosome.

Structures of the Escherichia coli ribosome with antibiotics bound near the peptidyl transferase center explain spectra of drug action

X-ray crystal structures of the Escherichia coli ribosome in complexes with clinically important antibiotics of four major classes are reported, arguing that the identity of nucleotides 752, 2609, and 2055 of 23S ribosomal RNA explain in part the spectrum and selectivity of antibiotic action.

The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning

The crystal structure of the oxazolidinone linezolid bound to the Deinococcus radiodurans 50S ribosomal subunit is determined and a model whereby oxazolicinones impart their inhibitory effect by perturbing the correct positioning of tRNAs on the ribosome is presented.

Structure-based drug design meets the ribosome.




Fine structure of the peptidyl transferase centre on 23 S-like rRNAs deduced from chemical probing of antibiotic-ribosome complexes.

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.

Inhibition of the ribosomal peptidyl transferase reaction by the mycarose moiety of the antibiotics carbomycin, spiramycin and tylosin.

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.

Interaction of the antibiotics clindamycin and lincomycin with Escherichia coli 23S ribosomal RNA.

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.

Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3

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.

The macrolide–ketolide antibiotic binding site is formed by structures in domains II and V of 23S ribosomal RNA

Findings indicate how drug derivatization can improve the inhibition of bacteria that have macrolide resistance conferred by changes in the peptidyl transferase loop.

The structural basis of ribosome activity in peptide bond synthesis.

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.

Ribosomal peptidyl transferase can withstand mutations at the putative catalytic nucleotide

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.

Mutational analysis of the donor substrate binding site of the ribosomal peptidyltransferase center.

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.

The importance of highly conserved nucleotides in the binding region of chloramphenicol at the peptidyl transfer centre of Escherichia coli 23S ribosomal RNA.

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.

A ketolide resistance mutation in domain II of 23S rRNA reveals the proximity of hairpin 35 to the peptidyl transferase centre

Ketolides represent a new generation of macrolide antibiotics. In order to identify the ketolide‐binding site on the ribosome, a library of Escherichia coli clones, transformed with a plasmid