Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine

Ribosome serves as a universal molecular machine capable of synthesis of all the proteins in a cell. Small-molecule inhibitors, such as ribosome-targeting antibiotics, can compromise the catalytic versatility of the ribosome in a context-dependent fashion, preventing transpeptidation only between pa...

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Bibliographic Details
Published in:Nucleic acids research 2022-07, Vol.50 (13), p.7669-7679
Main Authors: Syroegin, Egor A, Aleksandrova, Elena V, Polikanov, Yury S
Format: Article
Language:English
Subjects:
Amino Acids - metabolism
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
BASIC BIOLOGICAL SCIENCES
Binding Sites
Chloramphenicol - pharmacology
Glycine
Peptides - chemistry
Peptidyl Transferases - metabolism
RNA, Transfer - metabolism
Structural Biology
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Summary:Ribosome serves as a universal molecular machine capable of synthesis of all the proteins in a cell. Small-molecule inhibitors, such as ribosome-targeting antibiotics, can compromise the catalytic versatility of the ribosome in a context-dependent fashion, preventing transpeptidation only between particular combinations of substrates. Classic peptidyl transferase center inhibitor chloramphenicol (CHL) fails to inhibit transpeptidation reaction when the incoming A site acceptor substrate is glycine, and the molecular basis for this phenomenon is unknown. Here, we present a set of high-resolution X-ray crystal structures that explain why CHL is unable to inhibit peptide bond formation between the incoming glycyl-tRNA and a nascent peptide that otherwise is conducive to the drug action. Our structures reveal that fully accommodated glycine residue can co-exist in the A site with the ribosome-bound CHL. Moreover, binding of CHL to a ribosome complex carrying glycyl-tRNA does not affect the positions of the reacting substrates, leaving the peptide bond formation reaction unperturbed. These data exemplify how small-molecule inhibitors can reshape the A-site amino acid binding pocket rendering it permissive only for specific amino acid residues and rejective for the other substrates extending our detailed understanding of the modes of action of ribosomal antibiotics.
ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/gkac548