Aminoglycoside Antibiotics Are Able To Specifically Bind the 5‘-Untranslated Region of Thymidylate Synthase Messenger RNA

Tok, Jeffrey B.‐H.; Cho, Junhyeong; Rando, Robert R.

doi:10.1021/bi9819428

Cited by 68 publications

(87 citation statements)

References 35 publications

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“…It is likely a common property of paromomycin, a polycation, to display both high affinity and low affinity binding to a single RNA target. Our ITC-derived average affinity of 0.5 6 0.3 mM for the high affinity TSMCparomomycin interaction is similar to the previously measured value of 2.241 6 0.210 mM (Tok et al 1999). The small difference between our measurement and that of Tok and Rando may be a reflection of different buffer conditions used for the two measurements.…”

Section: Comparison With Other Rna-aminoglycoside Interactionssupporting

confidence: 89%

“…Another RNA motif known to bind aminoglycosides, and the focus of this paper, is a cytosine-cytosine (CC) mismatch found in a hairpin structure in the mRNA that codes for the human thymidylate synthase (TS) protein, TS mRNA construct (TSMC) RNA (Fig. 1;Tok et al 1999). Recently, a combinatorial screening study of internal loop structures for aminoglycoside binding pulled out a CC mismatch in many RNA constructs (Disney et al 2008).…”

Section: Introductionmentioning

confidence: 99%

“…In order to better understand and potentially influence the TS interaction with its mRNA, Tok and co-workers have investigated the interaction between members of the aminoglycoside molecular family and the CC mismatch containing mRNA hairpin (Tok et al 1999). However, structural information for this therapeutically important interaction is not known.…”

Section: Introductionmentioning

confidence: 99%

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Structure of the cytosine–cytosine mismatch in the thymidylate synthase mRNA binding site and analysis of its interaction with the aminoglycoside paromomycin

Tavares¹,

Beribisky²,

Johnson³

2009

RNA

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The structure of a cytosine-cytosine (CC) mismatch-containing RNA molecule derived from a hairpin structure in the thymidylate synthase mRNA that binds the aminoglycoside paromomycin with high affinity was determined using nuclear magnetic resonance (NMR) spectroscopy. The cytosines in the mismatch form a noncanonical base pair where both cytosines are uncharged and stack within the stem of the RNA structure. Binding to paromomycin was analyzed using isothermal titration calorimetry (ITC) to demonstrate the necessity of the CC mismatch and to determine the affinity dissociation constant of this RNA to paromomycin to be 0.5 6 0.3 mM. The CC mismatch, and the neighboring GC base pairs experienced the highest degree of chemical shift changes in their H6 and H5 resonances indicating that paromomycin binds in the major groove at the CC mismatch site. In comparing the structure of CC mismatch RNA with a fully Watson-Crick GC base paired stem, the CC mismatch is shown to confer a widening of the major groove. This widening, combined with the dynamic nature of the CC mismatch, enables binding of paromomycin to this RNA molecule.

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Section: Comparison With Other Rna-aminoglycoside Interactionssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structure of the cytosine–cytosine mismatch in the thymidylate synthase mRNA binding site and analysis of its interaction with the aminoglycoside paromomycin

Tavares¹,

Beribisky²,

Johnson³

2009

RNA

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“…This was initially shown in short RNA molecules (aptamers) (Wang and Rando 1995) and subsequently in messenger RNA (Voeller et al 1995;Tok et al 1999;Walter et al 1999). Aminoglycoside-RNA interaction has been implicated in gene expression regulation (Suess et al 2003).…”

Section: Discussionmentioning

confidence: 98%

Aminoglycoside-Induced Premature Stop Codon Read-Through of Mucopolysaccharidosis Type I Patient Q70X and W402X Mutations in Cultured Cells

et al. 2013

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The premature stop codon mutations, Q70X and W402X, are the most common a-L-iduronidase gene (IDUA) mutations in mucopolysaccharidosis type I (MPS I) patients. Read-through drugs have been used to suppress premature stop codons, and this can potentially be used to treat patients who have this type of mutation. We examined the effects of aminoglycoside treatment on the IDUA mutations Q70X and W402X in cultured cells and show that 4,5-disubstituted aminoglycosides induced more readthrough for the W402X mutation, while 4,6-disubstituted aminoglycosides promoted more read-through for the Q70X mutation: lividomycin (4,5-disubstituted) induced a 7.8-fold increase in a-L-iduronidase enzyme activity for the W402X mutation; NB54 (4,5-disubstituted) induced a 3.7 fold increase in the amount of a-L-iduronidase enzyme activity for the W402X mutation, but had less effect on the Q70X mutation, whereas gentamicin (4,6-disubstituted) had the reverse effect on read-through for both mutations. The predicted mRNA secondary structural changes for both mutations were markedly different, which may explain these different effects on read-through for these two premature stop codons.

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“…Besides binding to these RNA folds, aminoglycosides also specifically recognize some motifs such as an internal loop in the 5'-UTR of the human thymidylate synthase (TS) mRNA (Fig. (1a)) [47] and regulatory domains in the RNA genome of HIV (Fig. (1a)), namely TAR [48] and RRE [49].…”

Section: Definition and Explorationmentioning

confidence: 99%

Rational Drug Design and High-Throughput Techniques for RNA Targets

Hermann

Westhof²

2000

CCHTS

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RNA molecules are the only known molecules which possess the double property of being depository of genetic information, like DNA, and of displaying catalytic activities, like protein enzymes. RNA molecules intervene in all steps of gene expression and in many other biological activities. Like proteins, RNAs achieve those biological functions by adopting intricate three-dimensional folds and architectures. Further, as in protein sequences, RNA sequences contain signatures specific for threedimensional motifs which participate in recognition and binding. In regulatory pathways, RNA molecules exist in equilibria between transient structures differentially stabilized by effectors such as proteins or cofactors. Therefore, RNA molecules display their potential as drug targets on different levels, namely in three-dimensional folds, in structural equilibria and in RNA-protein interfaces. Several examples will be described together with the already available techniques for combinatorial synthesis and high-throughput screening of potential drug and target RNA molecules.

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Aminoglycoside Antibiotics Are Able To Specifically Bind the 5‘-Untranslated Region of Thymidylate Synthase Messenger RNA

Cited by 68 publications

References 35 publications

Structure of the cytosine–cytosine mismatch in the thymidylate synthase mRNA binding site and analysis of its interaction with the aminoglycoside paromomycin

Structure of the cytosine–cytosine mismatch in the thymidylate synthase mRNA binding site and analysis of its interaction with the aminoglycoside paromomycin

Aminoglycoside-Induced Premature Stop Codon Read-Through of Mucopolysaccharidosis Type I Patient Q70X and W402X Mutations in Cultured Cells

Rational Drug Design and High-Throughput Techniques for RNA Targets

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