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TitleTetracenomycin X sequesters peptidyl-tRNA during translation of QK motifs.
Journal, issue, pagesNat Chem Biol, Vol. 19, Issue 9, Page 1091-1096, Year 2023
Publish dateJun 15, 2023
AuthorsElodie C Leroy / Thomas N Perry / Thibaud T Renault / C Axel Innis /
PubMed AbstractAs antimicrobial resistance threatens our ability to treat common bacterial infections, new antibiotics with limited cross-resistance are urgently needed. In this regard, natural products that target ...As antimicrobial resistance threatens our ability to treat common bacterial infections, new antibiotics with limited cross-resistance are urgently needed. In this regard, natural products that target the bacterial ribosome have the potential to be developed into potent drugs through structure-guided design, provided their mechanisms of action are well understood. Here we use inverse toeprinting coupled to next-generation sequencing to show that the aromatic polyketide tetracenomycin X primarily inhibits peptide bond formation between an incoming aminoacyl-tRNA and a terminal Gln-Lys (QK) motif in the nascent polypeptide. Using cryogenic electron microscopy, we reveal that translation inhibition at QK motifs occurs via an unusual mechanism involving sequestration of the 3' adenosine of peptidyl-tRNA in the drug-occupied nascent polypeptide exit tunnel of the ribosome. Our study provides mechanistic insights into the mode of action of tetracenomycin X on the bacterial ribosome and suggests a path forward for the development of novel aromatic polyketide antibiotics.
External linksNat Chem Biol / PubMed:37322159
MethodsEM (single particle)
Resolution2.7 Å
Structure data

14956

7zta

EMDB-14956, PDB-7zta:
Structure of an Escherichia coli 70S ribosome stalled by Tetracenomycin X during translation of an MAAAPQK(C) peptide
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-K:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-OCW:
Tetracenomycin X

ChemComp-CYS:
CYSTEINE / Cysteine

ChemComp-GLN:
GLUTAMINE / Glutamine

ChemComp-HOH:
WATER / Water

Source
  • escherichia coli k-12 (bacteria)
KeywordsRIBOSOME / Antibiotic / Translation / Tetracenomycin X / Protein synthesis inhibitor

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