5NDK

Crystal structure of aminoglycoside TC007 co-crystallized with 70S ribosome from Thermus thermophilus, three tRNAs and mRNA

This is a non-PDB format compatible entry.

Summary for 5NDK

• Entry DOI: 10.2210/pdb5ndk/pdb
• Descriptor: 16S ribosomal RNA, 50S ribosomal protein L13, 50S ribosomal protein L24, ... (56 entities in total)
• Functional Keywords: translation, ribosome, 3s, 50s, 70s, trna, mrna, bacteria, rna-protein complex, inhibitor, antibiotic, aminoglycoside
• Biological source: Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579); More
• Total number of polymer chains: 108
• Total formula weight: 4521807.35

Authors

Prokhorova, I.,Djumagulov, M.,Urzhumtsev, A.,Yusupov, M.,Yusupova, G. (deposition date: 2017-03-08, release date: 2017-12-13, Last modification date: 2024-05-08)

Primary citation

Prokhorova, I.,Altman, R.B.,Djumagulov, M.,Shrestha, J.P.,Urzhumtsev, A.,Ferguson, A.,Chang, C.T.,Yusupov, M.,Blanchard, S.C.,Yusupova, G.
Aminoglycoside interactions and impacts on the eukaryotic ribosome.
Proc. Natl. Acad. Sci. U.S.A., 114:E10899-E10908, 2017

PubMed 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-Å 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.

PubMed: 29208708
DOI: 10.1073/pnas.1715501114

Experimental method

X-RAY DIFFRACTION (2.95 Å)