7U2H

Crystal structure of the Thermus thermophilus 70S ribosome in complex with mRNA, aminoacylated A-site Gly-NH-tRNAgly, aminoacylated P-site fMet-NH-tRNAmet, and deacylated E-site tRNAgly at 2.55A resolution

This is a non-PDB format compatible entry.

Summary for 7U2H

• Entry DOI: 10.2210/pdb7u2h/pdb
• Descriptor: 23S Ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (61 entities in total)
• Functional Keywords: chloramphenicol; antibiotic; glycine; non-hydrolyzable; aminoacyl-trna; peptidyl-trna; 70s ribosome; x-ray structure; pre-attack state; transpeptidation; peptidyl transferase center; context-specificity of drug action; inhibition of translation; uncompetitive inhibitor, ribosome
• Biological source: Escherichia coli; More
• Total number of polymer chains: 112
• Total formula weight: 4566191.36

Authors

Syroegin, E.A.,Aleksandrova, E.V.,Polikanov, Y.S. (deposition date: 2022-02-24, release date: 2022-07-13, Last modification date: 2023-11-15)

Primary citation

Syroegin, E.A.,Aleksandrova, E.V.,Polikanov, Y.S.
Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine.
Nucleic Acids Res., 50:7669-7679, 2022

PubMed Abstract: 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.

PubMed: 35766409
DOI: 10.1093/nar/gkac548

Experimental method

X-RAY DIFFRACTION (2.55 Å)