Solution NMR determination of hydrogen bonding and base pairing between the <i>glyQS</i> T box riboswitch Specifier domain and the anticodon loop of tRNA<sup>Gly</sup>

Chang, Andrew; Nikonowicz, Edward P.

doi:10.1016/j.febslet.2013.09.003

Cited by 16 publications

(25 citation statements)

References 25 publications

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“…This position was protected by both tRNAs (albeit lower in NP2) and could indicate a wobblepairing with U33. This interaction possibly facilitates the anticodon reading and also contributes to the orientation and binding of all tRNAs, as has been also suggested by the recent structures (Chang and Nikonowicz 2013;Grigg et al 2013;Grigg and Ke 2013b;Zhang and Ferré-D'Amaré 2013). Since all the tRNAs contain anticodon loops with characteristic flexibility, it is possible that this interaction may be needed to stabilize the local structure, which in turn favors an induced fit (Chang and Nikonowicz 2013;Zhang and Ferré-D'Amaré 2015).…”

Section: Trna Gly Binding Induces Structural Changes On S Aureus Glymentioning

confidence: 59%

“…Instead, the third position of the SL codon (C111) remained accessible, at least in part, an observation that was quite intriguing and raised questions, given the specificity of the interaction between SL and both tRNAs. A previous study investigating the interaction of a tyrS mRNA leader in which the UAC specifier triplet was replaced by the glycyl GGC failed to detect binding when tRNA Gly(UCC) was used (Chang and Nikonowicz 2013). This binding inability is very likely observed due to the nature of the hybrid T-box sequence that was tested and also possibly due to different conformational changes that were induced.…”

Section: Trna Gly Binding Induces Structural Changes On S Aureus Glymentioning

confidence: 97%

“…Due to its conservation, it is easily recognizable by the available bioinformatics tools and plays a role in the recognition and binding of tRNA's discriminator base and universal 3 ′ CCA end (Vitreschak et al 2008;Wels et al 2008;Chang and Nikonowicz 2013). This interaction is equally critical for the correct positioning of tRNAs and moreover, it is important for sensing uncharged or charged tRNAs (Zhang and Ferré-D'Amaré 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Recent structural studies, focused mainly on stem I, have provided a more detailed illustration of the conformation changes that occur during the interaction of the T-box with the tRNA (Chang and Nikonowicz 2013;Grigg et al 2013;Grigg and Ke 2013b;Zhang and Ferré-D'Amaré 2013). In addition, the important role of tRNA's elbow for efficient interaction also became evident (Lehmann et al 2013).…”

Section: Introductionmentioning

confidence: 99%

“…This domain is quite flexible and it has been proposed to facilitate interaction with tRNA via an "induced fit" model (Zhang and Ferré-D'Amaré 2013). Although bioinformatics tools are able to identify numerous T-boxes, the secondary structures from only a few species were experimentally verified (Vitreschak et al 2008;Gutiér-rez-Preciado et al 2009;Chang and Nikonowicz 2013;Sun and Rodionov 2014). Despite the recent progress (Miao et al 2015), it is even more difficult to reliably predict the tertiary structure of T-boxes.…”

Section: Introductionmentioning

confidence: 99%

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A glyS T-box riboswitch with species-specific structural features responding to both proteinogenic and nonproteinogenic tRNA^Gly isoacceptors

Apostolidi

Saad

Drainas

et al. 2015

RNA

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In Staphylococcus aureus, a T-box riboswitch exists upstream of the glyS gene to regulate transcription of the sole glycyl-tRNA synthetase, which aminoacylates five tRNA Gly isoacceptors bearing GCC or UCC anticodons. Subsequently, the glycylated tRNAs serve as substrates for decoding glycine codons during translation, and also as glycine donors for exoribosomal synthesis of pentaglycine peptides during cell wall formation. Probing of the predicted T-box structure revealed a long stem I, lacking features previously described for similar T-boxes. Moreover, the antiterminator stem includes a 42-nt long intervening sequence, which is staphylococci-specific. Finally, the terminator conformation adopts a rigid two-stem structure, where the intervening sequence forms the first stem followed by the second stem, which includes the more conserved residues. Interestingly, all five tRNA Gly isoacceptors interact with S. aureus glyS T-box with different binding affinities and they all induce transcription readthrough at different levels. The ability of both GCC and UCC anticodons to interact with the specifier loop indicates ambiguity during the specifier triplet reading, similar to the unconventional reading of glycine codons during protein synthesis. The S. aureus glyS T-box structure is consistent with the recent crystallographic and NMR studies, despite apparent differences, and highlights the phylogenetic variability of T-boxes when studied in a genome-dependent context. Our data suggest that the S. aureus glyS T-box exhibits differential tRNA selectivity, which possibly contributes toward the regulation and synchronization of ribosomal and exoribosomal peptide synthesis, two essential but metabolically unrelated pathways.

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Section: Trna Gly Binding Induces Structural Changes On S Aureus Glymentioning

confidence: 59%

Section: Trna Gly Binding Induces Structural Changes On S Aureus Glymentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A glyS T-box riboswitch with species-specific structural features responding to both proteinogenic and nonproteinogenic tRNA^Gly isoacceptors

Apostolidi

Saad

Drainas

et al. 2015

RNA

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Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

et al. 2019

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The emergence of multidrug‐resistant bacteria necessitates the identification of unique targets of intervention and compounds that inhibit their function. Gram‐positive bacteria use a well‐conserved tRNA‐responsive transcriptional regulatory element in mRNAs, known as the T‐box, to regulate the transcription of multiple operons that control amino acid metabolism. T‐box regulatory elements are found only in the 5′‐untranslated region (UTR) of mRNAs of Gram‐positive bacteria, not Gram‐negative bacteria or the human host. Using the structure of the 5′UTR sequence of the Bacillus subtilis tyrosyl‐tRNA synthetase mRNA T‐box as a model, in silico docking of 305 000 small compounds initially yielded 700 as potential binders that could inhibit the binding of the tRNA ligand. A single family of compounds inhibited the growth of Gram‐positive bacteria, but not Gram‐negative bacteria, including drug‐resistant clinical isolates at minimum inhibitory concentrations (MIC 16–64 μg mL−1). Resistance developed at an extremely low mutational frequency (1.21×10−10). At 4 μg mL−1, the parent compound PKZ18 significantly inhibited in vivo transcription of glycyl‐tRNA synthetase mRNA. PKZ18 also inhibited in vivo translation of the S. aureus threonyl‐tRNA synthetase protein. PKZ18 bound to the Specifier Loop in vitro (Kd≈24 μm). Its core chemistry necessary for antibacterial activity has been identified. These findings support the T‐box regulatory mechanism as a new target for antibiotic discovery that may impede the emergence of resistance.

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Structure and mechanism of the T‐box riboswitches

Zhang

Ferré-D′Amaré

2015

WIREs RNA

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In most Gram-positive bacteria, including many clinically devastating pathogens from genera such as Bacillus, Clostridium, Listeria and Staphylococcus, T-box riboswitches sense and regulate intracellular availability of amino acids through a multipartite mRNA-tRNA interaction. The T-box mRNA leaders respond to nutrient starvation by specifically binding cognate tRNAs and sensing whether the bound tRNA is aminoacylated, as a proxy for amino acid availability. Based on this readout, T-boxes direct a transcriptional or translational switch to control the expression of downstream genes involved in various aspects of amino acid metabolism: biosynthesis, transport, aminoacylation, transamidation, etc. Two decades after its discovery, the structural and mechanistic underpinnings of the T-box riboswitch were recently elucidated, producing a wealth of insights into how two structured RNAs can recognize each other with robust affinity and exquisite selectivity. The T-box paradigm exemplifies how natural non-coding RNAs can interact not just through sequence complementarity, but can add molecular specificity by precisely juxtaposing RNA structural motifs, exploiting inherently flexible elements and the biophysical properties of post-transcriptional modifications, ultimately achieving a high degree of shape complementarity through mutually induced fit. The T-box also provides a proof-of-principle that compact RNA domains can recognize minute chemical changes (such as tRNA aminoacylation) on another RNA. The unveiling of the structure and mechanism of the T-box system thus expands our appreciation of the range of capabilities and modes of action of structured non-coding RNAs, and hints at the existence of networks of non-coding RNAs that communicate through both, structural and sequence specificity.

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Solution NMR determination of hydrogen bonding and base pairing between the glyQS T box riboswitch Specifier domain and the anticodon loop of tRNA^Gly

Cited by 16 publications

References 25 publications

A glyS T-box riboswitch with species-specific structural features responding to both proteinogenic and nonproteinogenic tRNA^Gly isoacceptors

A glyS T-box riboswitch with species-specific structural features responding to both proteinogenic and nonproteinogenic tRNA^Gly isoacceptors

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

Structure and mechanism of the T‐box riboswitches

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Solution NMR determination of hydrogen bonding and base pairing between the glyQS T box riboswitch Specifier domain and the anticodon loop of tRNAGly

Cited by 16 publications

References 25 publications

A glyS T-box riboswitch with species-specific structural features responding to both proteinogenic and nonproteinogenic tRNAGly isoacceptors

A glyS T-box riboswitch with species-specific structural features responding to both proteinogenic and nonproteinogenic tRNAGly isoacceptors

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

Structure and mechanism of the T‐box riboswitches

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Solution NMR determination of hydrogen bonding and base pairing between the glyQS T box riboswitch Specifier domain and the anticodon loop of tRNA^Gly

A glyS T-box riboswitch with species-specific structural features responding to both proteinogenic and nonproteinogenic tRNA^Gly isoacceptors

A glyS T-box riboswitch with species-specific structural features responding to both proteinogenic and nonproteinogenic tRNA^Gly isoacceptors