Interactions between Flavins and Quadruplex Nucleic Acids

Merkle, Tobias; Sinn, Malte; Hartig, Jörg S.

doi:10.1002/cbic.201500463

Cited by 4 publications

(4 citation statements)

References 35 publications

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“…For instance, G4 structures formed by G 4 C 2 repeats were shown to sequester and activate hemes, which enhanced their oxidative processes upon formation of G4-heme complexes . On the other hand, the binding of natural cell metabolites, such as flavin, was speculated to affect G4 functionality, which might translate into gene expressions . With the establishment of the complex formation between G4s and cGAMP, the above concepts could therefore be extended to cyclic dinucleotides, as well as other guanine-containing metabolites.…”

Section: Discussionmentioning

confidence: 99%

“…75 On the other hand, the binding of natural cell metabolites, such as flavin, was speculated to affect G4 functionality, which might translate into gene expressions. 76 With the establishment of the complex formation between G4s and cGAMP, the above concepts could therefore be extended to cyclic dinucleotides, as well as other guanine-containing metabolites.…”

Section: ■ Discussionmentioning

confidence: 99%

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Solution Structures of a G-Quadruplex Bound to Linear- and Cyclic-Dinucleotides

et al. 2019

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Cyclic dinucleotides have emerged as important secondary messengers and cell signalling molecules that regulates several cell responses. A guanine-deficit G-quadruplex structure formation by a sequence containing (4n-1) guaninesn denoting the number of G-tetrad layer-was previously reported. Here, a (4n-1) G-quadruplex structure is shown to be capable of binding guanine-containing dinucleotides in micromolar affinity. The guanine base of the dinucleotides interacts with a vacant G-triad, forming four additional Hoogsteen hydrogen bonds to complete a G-tetrad. Solution structures of two complexes, both comprised of a (4n-1) G-quadruplex structure-one bound to a linear dinucleotide and the other to a cyclic dinucleotide (cGAMP)-are solved using NMR spectroscopy. The latter suggests sufficiently strong interaction between the guanine base of the dinucleotide and the vacant G-triad, which acts as an anchor point of binding. The detailed binding interfaces from the two solution structures provide useful information for specific ligand and/or drug design. The results also infer that other guanine-containing metabolites of a similar size have the capability of binding G-quadruplexes, potentially affecting the expression of the metabolites and functionality of the bound G-quadruplexes.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

Solution Structures of a G-Quadruplex Bound to Linear- and Cyclic-Dinucleotides

et al. 2019

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“…More than 30 proteins have been identified that specifically interact with G-quadruplexes in various ways, including examples that bind G-quadruplexes, mediate the folding of G-quadruplexes, and promote the unfolding of G-quadruplexes (13–14). A handful of cellular cofactors that bind G-quadruplexes have also been identified (15–18). G-quadruplexes that promote several types of peroxidase reactions in the presence of hemin and hydrogen peroxide have also been reported (19–20).…”

Section: Introductionmentioning

confidence: 99%

Altered biochemical specificity of G-quadruplexes with mutated tetrads

et al. 2016

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A fundamental motif in canonical nucleic acid structure is the base pair. Mutations that disrupt base pairs are typically destabilizing, but stability can often be restored by a second mutation that replaces the original base pair with an isosteric variant. Such concerted changes are a way to identify helical regions in secondary structures and to identify new functional motifs in sequenced genomes. In principle, such analysis can be extended to non-canonical nucleic acid structures, but this approach has not been utilized because the sequence requirements of such structures are not well understood. Here we investigate the sequence requirements of a G-quadruplex that can both bind GTP and promote peroxidase reactions. Characterization of all 256 variants of the central tetrad in this structure indicates that certain mutations can compensate for canonical G-G-G-G tetrads in the context of both GTP-binding and peroxidase activity. Furthermore, the sequence requirements of these two motifs are significantly different, indicating that tetrad sequence plays a role in determining the biochemical specificity of G-quadruplex activity. Our results provide insight into the sequence requirements of G-quadruplexes, and should facilitate the analysis of such motifs in sequenced genomes.

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“…For instance, bacterial and viral quadruplexes are now considered as valuable targets for therapeutic interventions aiming at harnessing pathogenic virulence 7 , as demonstrated by recent and elegant works from research teams of J.S. Hartig 40 41 42 and S. Richter 43 44 45 46 for instance.…”

Section: Discussionmentioning

confidence: 99%

Computational understanding and experimental characterization of twice-as-smart quadruplex ligands as chemical sensors of bacterial nucleotide second messengers

Zhou

Roembke

Paragi

et al. 2016

Sci Rep

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A twice-as-smart ligand is a small molecule that experiences a structural switch upon interaction with its target (i.e., smart ligand) that concomitantly triggers its fluorescence (i.e., smart probe). Prototypes of twice-as-smart ligands were recently developed to track and label G-quadruplexes: these higher-order nucleic acid structures originate in the assembly of four guanine(G)-rich DNA or RNA strands, whose stability is imparted by the formation and the self-assembly of G-quartets. The first prototypes of twice-as-smart quadruplex ligands were designed to exploit the self-association of quartets, being themselves synthetic G-quartets. While their quadruplex recognition capability has been thoroughly documented, some doubts remain about the precise photophysical mechanism that underlies their peculiar spectroscopic properties. Here, we uncovered this mechanism via complete theoretical calculations. Collected information was then used to develop a novel application of twice-as-smart ligands, as efficient chemical sensors of bacterial signaling pathways via the fluorescent detection of naturally occurring extracellular quadruplexes formed by cyclic dimeric guanosine monophosphate (c-di-GMP).

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Interactions between Flavins and Quadruplex Nucleic Acids

Cited by 4 publications

References 35 publications

Solution Structures of a G-Quadruplex Bound to Linear- and Cyclic-Dinucleotides

Solution Structures of a G-Quadruplex Bound to Linear- and Cyclic-Dinucleotides

Altered biochemical specificity of G-quadruplexes with mutated tetrads

Computational understanding and experimental characterization of twice-as-smart quadruplex ligands as chemical sensors of bacterial nucleotide second messengers

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