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Chemically related 4,5-linked aminoglycoside antibiotics drive subunit rotation in opposite directions.

<div class='caption-title'>Investigation of the neomycin family of aminoglycosides.</div>
<div class='caption-title'>Neomycin-induced effects on intersubunit rotation in wild-type and A1408G aminoglycoside-resistant ribosomes.</div>
<div class='caption-title'>Paromomycin effects on intersubunit rotation in wild-type and A1408G aminoglycoside-resistant ribosomes.</div>
Wasserman MR, Pulk A, Zhou Z, Altman RB, Zinder JC, Green KD, Garneau-Tsodikova S, Cate JH, Blanchard SC
OpenAccess logo Nat Commun 6 7896 (2015)
Cited: 40 times
EuropePMC logo PMID: 26224058

Abstract

Dynamic remodelling of intersubunit bridge B2, a conserved RNA domain of the bacterial ribosome connecting helices 44 (h44) and 69 (H69) of the small and large subunit, respectively, impacts translation by controlling intersubunit rotation. Here we show that aminoglycosides chemically related to neomycin-paromomycin, ribostamycin and neamine-each bind to sites within h44 and H69 to perturb bridge B2 and affect subunit rotation. Neomycin and paromomycin, which only differ by their ring-I 6'-polar group, drive subunit rotation in opposite directions. This suggests that their distinct actions hinge on the 6'-substituent and the drug's net positive charge. By solving the crystal structure of the paromomycin-ribosome complex, we observe specific contacts between the apical tip of H69 and the 6'-hydroxyl on paromomycin from within the drug's canonical h44-binding site. These results indicate that aminoglycoside actions must be framed in the context of bridge B2 and their regulation of subunit rotation.

Articles - 4woi mentioned but not cited (5)

  1. Chemically related 4,5-linked aminoglycoside antibiotics drive subunit rotation in opposite directions. Wasserman MR, Pulk A, Zhou Z, Altman RB, Zinder JC, Green KD, Garneau-Tsodikova S, Cate JH, Blanchard SC. Nat Commun 6 7896 (2015)
  2. Structural analysis of 70S ribosomes by cross-linking/mass spectrometry reveals conformational plasticity. Tüting C, Iacobucci C, Ihling CH, Kastritis PL, Sinz A. Sci Rep 10 12618 (2020)
  3. Further Characterization of the Pseudo-Symmetrical Ribosomal Region. Rivas M, Fox GE. Life (Basel) 10 E201 (2020)
  4. Geometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decoding. Girodat D, Wieden HJ, Blanchard SC, Sanbonmatsu KY. Nat Commun 14 5582 (2023)
  5. DrugPred_RNA-A Tool for Structure-Based Druggability Predictions for RNA Binding Sites. Rekand IH, Brenk R. J Chem Inf Model 61 4068-4081 (2021)


Reviews citing this publication (6)

  1. Antibiotic Combination Therapy: A Strategy to Overcome Bacterial Resistance to Aminoglycoside Antibiotics. Wang N, Luo J, Deng F, Huang Y, Zhou H. Front Pharmacol 13 839808 (2022)
  2. Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities. Thamban Chandrika N, Garneau-Tsodikova S. Chem Soc Rev 47 1189-1249 (2018)
  3. Aminoglycoside Resistance: Updates with a Focus on Acquired 16S Ribosomal RNA Methyltransferases. Wachino JI, Doi Y, Arakawa Y. Infect Dis Clin North Am 34 887-902 (2020)
  4. Destination of aminoglycoside antibiotics in the 'post-antibiotic era'. Takahashi Y, Igarashi M. J Antibiot (Tokyo) (2017)
  5. Identifying targets to prevent aminoglycoside ototoxicity. Kim J, Hemachandran S, Cheng AG, Ricci AJ. Mol Cell Neurosci 120 103722 (2022)
  6. Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective. Pellegrino S, Terrosu S, Yusupova G, Yusupov M. Cancers (Basel) 13 4392 (2021)

Articles citing this publication (29)



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