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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303264/ https://www.ncbi.nlm.nih.gov/pubmed/35766409 http://dx.doi.org/10.1093/nar/gkac548 |
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author | Syroegin, Egor A Aleksandrova, Elena V Polikanov, Yury S |
author_facet | Syroegin, Egor A Aleksandrova, Elena V Polikanov, Yury S |
author_sort | Syroegin, Egor A |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9303264 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-93032642022-07-22 Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine Syroegin, Egor A Aleksandrova, Elena V Polikanov, Yury S Nucleic Acids Res Structural Biology 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. Oxford University Press 2022-06-29 /pmc/articles/PMC9303264/ /pubmed/35766409 http://dx.doi.org/10.1093/nar/gkac548 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Structural Biology Syroegin, Egor A Aleksandrova, Elena V Polikanov, Yury S Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine |
title | Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine |
title_full | Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine |
title_fullStr | Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine |
title_full_unstemmed | Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine |
title_short | Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine |
title_sort | structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of a-site glycine |
topic | Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303264/ https://www.ncbi.nlm.nih.gov/pubmed/35766409 http://dx.doi.org/10.1093/nar/gkac548 |
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