Structural basis for the context-specific action of the classic peptidyl transferase inhibitor chloramphenicol.

Publication Type:

Journal Article

Source:

Nat Struct Mol Biol, Volume 29, Issue 2, p.152-161 (2022)

Keywords:

Anti-Bacterial Agents, Binding Sites, Chloramphenicol, Enzyme Inhibitors, Kinetics, Models, Molecular, Peptidyl Transferases, Protein Conformation, Protein Synthesis Inhibitors, Ribosomes, RNA, Transfer, Amino Acyl, Static Electricity, Thermus thermophilus

Abstract:

<p>Ribosome-targeting antibiotics serve as powerful antimicrobials and as tools for studying the ribosome, the catalytic peptidyl transferase center (PTC) of which is targeted by many drugs. The classic PTC-acting antibiotic chloramphenicol (CHL) and the newest clinically significant linezolid (LZD) were considered indiscriminate inhibitors of protein synthesis that cause ribosome stalling at every codon of every gene being translated. However, recent discoveries have shown that CHL and LZD preferentially arrest translation when the ribosome needs to polymerize particular amino acid sequences. The molecular mechanisms that underlie the context-specific action of ribosome inhibitors are unknown. Here we present high-resolution structures of ribosomal complexes, with or without CHL, carrying specific nascent peptides that support or negate the drug action. Our data suggest that the penultimate residue of the nascent peptide directly modulates antibiotic affinity to the ribosome by either establishing specific interactions with the drug or by obstructing its proper placement in the binding site.</p>

PDB: 
7RQA for the T. thermophilus 70S ribosome in complex with protein Y, A-site aminoacyl-tRNA analog ACC-Pmn and P-site peptidyl-tRNA analog ACCA-ITM; 7RQB for the T. thermophilus 70S ribosome in complex with protein Y, A-site aminoacyl-tRNA analog ACC-Pmn and P-site peptidyl-tRNA analog ACCA-IAM; 7RQC for the T. thermophilus 70S ribosome in complex with protein Y, A-site aminoacyl-tRNA analog ACC-Pmn and P-site peptidyl-tRNA analog ACCA-IFM; 7RQD for the T. thermophilus 70S ribosome in complex with protein Y, A-site deacylated tRNA analog CACCA, P-site peptidyl-tRNA analog ACCA-ITM and chloramphenicol; 7RQE for the T. thermophilus 70S ribosome in complex with protein Y, A-site deacylated tRNA analog CACCA, P-site peptidyl-tRNA analog ACCA-IAM and chloramphenicol
Detector: 
EIGER
EIGER2
Beamline: 
24-ID-C
24-ID-E