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Structure paper

TitleStructural basis for context-specific inhibition of translation by oxazolidinone antibiotics.
Journal, issue, pagesNat Struct Mol Biol, Vol. 29, Issue 2, Page 162-171, Year 2022
Publish dateFeb 14, 2022
AuthorsKaitlyn Tsai / Vanja Stojković / D John Lee / Iris D Young / Teresa Szal / Dorota Klepacki / Nora Vázquez-Laslop / Alexander S Mankin / James S Fraser / Danica Galonić Fujimori /
PubMed AbstractThe antibiotic linezolid, the first clinically approved member of the oxazolidinone class, inhibits translation of bacterial ribosomes by binding to the peptidyl transferase center. Recent work has ...The antibiotic linezolid, the first clinically approved member of the oxazolidinone class, inhibits translation of bacterial ribosomes by binding to the peptidyl transferase center. Recent work has demonstrated that linezolid does not inhibit peptide bond formation at all sequences but rather acts in a context-specific manner, namely when alanine occupies the penultimate position of the nascent chain. However, the molecular basis for context-specificity has not been elucidated. Here we show that the second-generation oxazolidinone radezolid also induces stalling with a penultimate alanine, and we determine high-resolution cryo-EM structures of linezolid- and radezolid-stalled ribosome complexes to explain their mechanism of action. These structures reveal that the alanine side chain fits within a small hydrophobic crevice created by oxazolidinone, resulting in improved ribosome binding. Modification of the ribosome by the antibiotic resistance enzyme Cfr disrupts stalling due to repositioning of the modified nucleotide. Together, our findings provide molecular understanding for the context-specificity of oxazolidinones.
External linksNat Struct Mol Biol / PubMed:35165456 / PubMed Central
MethodsEM (single particle)
Resolution2.35 - 2.48 Å
Structure data

EMDB-24800, PDB-7s1g:
wild-type Escherichia coli stalled ribosome with antibiotic linezolid
Method: EM (single particle) / Resolution: 2.48 Å

EMDB-24801, PDB-7s1h:
Wild-type Escherichia coli ribosome with antibiotic linezolid
Method: EM (single particle) / Resolution: 2.35 Å

EMDB-24802, PDB-7s1i:
Wild-type Escherichia coli stalled ribosome with antibiotic radezolid
Method: EM (single particle) / Resolution: 2.48 Å

EMDB-24803, PDB-7s1j:
Wild-type Escherichia coli ribosome with antibiotic radezolid
Method: EM (single particle) / Resolution: 2.47 Å

EMDB-24804, PDB-7s1k:
Cfr-modified Escherichia coli stalled ribosome with antibiotic radezolid
Method: EM (single particle) / Resolution: 2.42 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ZLD:
N-{[(5S)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide / antibiotic*YM / Linezolid

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER / Water

ChemComp-RD8:
Radezolid / antibiotic*YM / Radezolid

Source
  • escherichia coli (E. coli)
KeywordsRIBOSOME/ANTIBIOTIC / Escherichia coli stalled ribosome / oxazolidinone / linezolid / RIBOSOME-ANTIBIOTIC complex / Escherichia coli ribosome / RIBOSOME / stalled ribosome / radezolid / Cfr-modified

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