Structural basis for the context-specific action of the classic peptidyl transferase inhibitor chloramphenicol.
Anti-Bacterial Agents
/ chemistry
Binding Sites
Chloramphenicol
/ chemistry
Enzyme Inhibitors
/ chemistry
Kinetics
Models, Molecular
Peptidyl Transferases
/ antagonists & inhibitors
Protein Conformation
Protein Synthesis Inhibitors
/ chemistry
RNA, Transfer, Amino Acyl
/ chemistry
Ribosomes
/ drug effects
Static Electricity
Thermus thermophilus
/ drug effects
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
11
06
2021
accepted:
23
12
2021
pubmed:
16
2
2022
medline:
26
2
2022
entrez:
15
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35165455
doi: 10.1038/s41594-022-00720-y
pii: 10.1038/s41594-022-00720-y
pmc: PMC9071271
mid: NIHMS1791601
doi:
Substances chimiques
Anti-Bacterial Agents
0
Enzyme Inhibitors
0
Protein Synthesis Inhibitors
0
RNA, Transfer, Amino Acyl
0
tRNA, peptidyl-
0
Chloramphenicol
66974FR9Q1
Peptidyl Transferases
EC 2.3.2.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
152-161Subventions
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM132302
Pays : United States
Organisme : NIH HHS
ID : S10 OD021527
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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