Loop residues of thrombin-binding DNA aptamer impact G-quadruplex stability and thrombin binding

Nagatoishi, Satoru; Isono, Noburu; Tsumoto, Kouhei; Sugimoto, Naoki

doi:10.1016/j.biochi.2011.03.013

Cited by 83 publications

(94 citation statements)

References 70 publications

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“…If TTA loops of hTel are replaced by AAA, the G-quadruplex stability decreases largely [5]. Similar results also found in TBA's TT loops, when thymine residues are substituted by adenine, the G-quadruplex is more stable or more unstable than that of wild-type base on the position of the thymine which is been replaced [6]. Besides, the loop length and loop sequence affect the folding topologies and stability of G-quadruplexes, which have been investigated by experimental and computational methods [7], [8].…”

Section: Introductionsupporting

confidence: 71%

Structural Dynamics of Human Telomeric G-Quadruplex Loops Studied by Molecular Dynamics Simulations

2013

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Loops which are linkers connecting G-strands and supporting the G-tetrad core in G-quadruplex are important for biological roles of G-quadruplexes. TTA loop is a common sequence which mainly resides in human telomeric DNA (hTel) G-quadruplex. A series of molecular dynamics (MD) simulations were carried out to investigate the structural dynamics of TTA loops. We found that (1) the TA base pair formed in TTA loops are very stable, the occupied of all hydrogen bonds are more than 0.95. (2) The TA base pair makes the adjacent G-quartet more stable than others. (3) For the edgewise loop and the diagonal loop, most loop bases are stacking with others, only few bases have considerable freedom. (4) The stabilities of these stacking structures are distinct. Part of the loops, especially TA base pairs, and bases stacking with the G-quartet, maintain certain stable conformations in the simulation, but other parts, like TT and TA stacking structures, are not stable enough. For the first time, spontaneous conformational switches of TTA edgewise loops were observed in our long time MD simulations. (5) For double chain reversal loop, it is really hard to maintain a stable conformation in the long time simulation under present force fields (parm99 and parmbsc0), as it has multiple conformations with similar free energies.

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Section: Introductionsupporting

confidence: 71%

Structural Dynamics of Human Telomeric G-Quadruplex Loops Studied by Molecular Dynamics Simulations

2013

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“…Although the roles of G-quadruplex loops and tail strands have not yet been clearly elucidated, until now, previous studies have indeed shown that the loops and tail strands are able to influence the G-quadruplex interactions with target molecules, including their stability and structural conformation and thus their target specificity 35, 36. Because the head and tail sequences of G-quartet motif are obviously required, only full-length aptamers were employed for all of the following experiments.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Selection of Cell-Internalizing DNA Aptamers in a Model System of Inflammatory Kidney Disease

Ranches

Lukasser

Schramek

et al. 2017

Molecular Therapy - Nucleic Acids

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Chronic kidney disease (CKD) is a progressive pathological condition marked by a gradual loss of kidney function. Treatment of CKD is most effective when diagnosed at an early stage and patients are still asymptomatic. However, current diagnostic biomarkers (e.g., serum creatinine and urine albumin) are insufficient for prediction of the pathogenesis of the disease. To address this need, we applied a cell-SELEX (systematic evolution of ligands by exponential enrichment) approach and identified a series of DNA aptamers, which exhibit high affinity and selectivity for cytokine-stimulated cells, resembling some aspects of a CKD phenotype. The cell-SELEX approach was driven toward the enrichment of aptamers that internalize via the endosomal pathway by isolating the endosomal fractions in each selection cycle. Indeed, we demonstrated co-localization of selected aptamers with lysosomal-associated membrane protein 1 (LAMP-1), a late endosomal and lysosomal marker protein, by fluorescence in situ hybridization. These findings are consistent with binding and subsequent internalization of the aptamers into cytokine-stimulated cells. Thus, our study sets the stage for applying selected DNA aptamers as theragnostic reagents for the development of targeted therapies to combat CKD.

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“…In Figure 2a , we showed the most probable secondary structures of these aptamers, taking into account the lower free energy (ΔG). Because many of the aptamers described in the literature contain G-quadruplex structures, 22,23,24 which strongly stabilize the tertiary structure, the capacity of apMNK2F and apMNK3R to form G-quadruplex structures was studied using the QGRS Mapper program. The analysis results indicated that the aptamer apMNK2F could form two of these structures, one with three and one with two flat planes, while apMNK3R could form a two plane G-quadruplex structure ( Figure 2a ).…”

Section: Resultsmentioning

confidence: 99%

Characterization of MNK1b DNA Aptamers That Inhibit Proliferation in MDA-MB231 Breast Cancer Cells

García-Recio

Pinto-Díez

Pérez-Morgado

et al. 2016

Molecular Therapy - Nucleic Acids

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Elevated expression levels of eukaryotic initiation factor 4E (eIF4E) promote cancer development and progression. MAP kinase interacting kinases (MNKs) modulate the function of eIF4E through the phosphorylation that is necessary for oncogenic transformation. Therefore, pharmacologic MNK inhibitors may provide a nontoxic and effective anticancer strategy. MNK1b is a truncated isoform of MNK1a that is active in the absence of stimuli. Using in vitro selection, high-affinity DNA aptamers to MNK1b were selected from a library of ssDNA. Selection was monitored using the enzyme-linked oligonucleotide assay (ELONA), and the selected aptamer population was cloned and sequenced. Four groups of aptamers were identified, and the affinities of one representative for rMNK1b were determined using ELONA and quantitative polymerase chain reaction. Two aptamers, named apMNK2F and apMNK3R, had a lower Kd in the nmol/l range. The secondary structure of the selected aptamers was predicted using mFold, and the QGRS Mapper indicated the presence of potential G-quadruplex structures in both aptamers. The selected aptamers were highly specific against MNK1, showing higher affinity to MNK1b than to MNK1a. Interestingly, both aptamers were able to produce significant translation inhibition and prevent tumor cell proliferation and migration and colony formation in breast cancer cells. These results indicate that MNK1 aptamers have an attractive therapeutic potential.

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Loop residues of thrombin-binding DNA aptamer impact G-quadruplex stability and thrombin binding

Cited by 83 publications

References 70 publications

Structural Dynamics of Human Telomeric G-Quadruplex Loops Studied by Molecular Dynamics Simulations

Structural Dynamics of Human Telomeric G-Quadruplex Loops Studied by Molecular Dynamics Simulations

In Vitro Selection of Cell-Internalizing DNA Aptamers in a Model System of Inflammatory Kidney Disease

Characterization of MNK1b DNA Aptamers That Inhibit Proliferation in MDA-MB231 Breast Cancer Cells

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