Aminoglycoside interactions and impacts on the eukaryotic ribosome.

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Prokhorova I, Altman RB, Djumagulov M, Shrestha JP, Urzhumtsev A, Ferguson A, Chang CT, Yusupov M, Blanchard SC, Yusupova G

Aminoglycoside interactions and impacts on the eukaryotic ribosome.

Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):E10899-E10908. doi: 10.1073/pnas.1715501114. Epub 2017 Dec 5.

PubMed ID

29208708 [ View in PubMed

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Abstract

Aminoglycosides are chemically diverse, broad-spectrum antibiotics that target functional centers within the bacterial ribosome to impact all four principle stages (initiation, elongation, termination, and recycling) of the translation mechanism. The propensity of aminoglycosides to induce miscoding errors that suppress the termination of protein synthesis supports their potential as therapeutic interventions in human diseases associated with premature termination codons (PTCs). However, the sites of interaction of aminoglycosides with the eukaryotic ribosome and their modes of action in eukaryotic translation remain largely unexplored. Here, we use the combination of X-ray crystallography and single-molecule FRET analysis to reveal the interactions of distinct classes of aminoglycosides with the 80S eukaryotic ribosome. Crystal structures of the 80S ribosome in complex with paromomycin, geneticin (G418), gentamicin, and TC007, solved at 3.3- to 3.7-A resolution, reveal multiple aminoglycoside-binding sites within the large and small subunits, wherein the 6'-hydroxyl substituent in ring I serves as a key determinant of binding to the canonical eukaryotic ribosomal decoding center. Multivalent binding interactions with the human ribosome are also evidenced through their capacity to affect large-scale conformational dynamics within the pretranslocation complex that contribute to multiple aspects of the translation mechanism. The distinct impacts of the aminoglycosides examined suggest that their chemical composition and distinct modes of interaction with the ribosome influence PTC read-through efficiency. These findings provide structural and functional insights into aminoglycoside-induced impacts on the eukaryotic ribosome and implicate pleiotropic mechanisms of action beyond decoding.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Paromomycin	40S ribosomal protein SA	Protein	Humans	Yes	Inhibitor	Details
Paromomycin	60S ribosomal protein L10-like	Protein	Humans	Yes	Inhibitor	Details