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.

doi:10.1093/nar/gkac548

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

Journal Article · Wed Jun 29 00:00:00 EDT 2022 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkac548· OSTI ID:1878375

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Univ. of Illinois, Chicago, IL (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1878375

Alternate ID(s):: OSTI ID: 1879738

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 13 Vol. 50; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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