Expanding the Topological Landscape by a G-Column Flip of a Parallel G-Quadruplex.
Ontology highlight
ABSTRACT:
SUBMITTER: Mohr S
PROVIDER: S-EPMC8361731 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Circular dichroism and stopped-flow UV spectroscopies were used to investigate the thermodynamic stability and the folding pathway of d[TGAG3TG3TAG3TG3TA2] at 25 °C in solutions containing 25 mM KCl. Under these conditions the oligonucleotide adopts a thermally stable, all-parallel G-quadruplex topography containing three stacked quartets. K+-induced folding shows three resolved relaxation times, each with distinctive spectral changes. Folding is complete within 200 s. These data indicate a folding pathway that involves at least two populated intermediates, one of which seems to be an antiparallel structure that rearranges to the final all-parallel conformation. Molecular dynamics reveals a stereochemically plausible folding pathway that does not involve complete unfolding of the intermediate. The rate of unfolding was determined using complementary DNA to trap transiently unfolded states to form a stable duplex. As assessed by 1D-1H NMR and fluorescence spectroscopy, unfolding is extremely slow with only one observable rate-limiting relaxation time.
| S-EPMC6455816 | biostudies-literature
Project description:G-quadruplex-forming nucleic acids have evolved to have applications in biology, drug design, sensing, and nanotechnology, to name a few. Together with the structural understanding, several attempts have been made to discover and design new classes of chemical agents that target these structures in the hope of using them as future therapeutics. Here, we report the binding of aminoglycosides, in particular neomycin, to parallel G-quadruplexes that exist as G-quadruplex monomers, dimers, or compounds that have the propensity to form dimeric G-quadruplex structures. Using a combination of calorimetric and spectroscopic studies, we show that neomycin binds to the parallel G-quadruplex with affinities in the range of Ka ∼ 105-108 M-1, which depends on the base composition, ability to form dimeric G-quadruplex structures, salt, and pH of the buffer used. At pH 7.0, the binding of neomycin was found to be electrostatically driven potentially through the formation of ion pairs formed with the quadruplex. Lowering the pH resulted in neomycin's association constants in the range of Ka ∼ 106-107 M-1 in a salt dependent manner. Circular dichroism (CD) studies showed that neomycin's binding does not cause a change in the parallel conformation of the G-quadruplex, yet some binding-induced changes in the intensity of the CD signals were seen. A comparative binding study of neomycin and paromomycin using d(UG4T) showed paromomycin binding to be much weaker than neomycin, highlighting the importance of ring I in the recognition process. In toto, our results expanded the binding landscape of aminoglycosides where parallel G-quadruplexes have been discovered as one of the high-affinity sites. These results may offer a new understanding of some of the undesirable functions of aminoglycosides and help in the design of aminoglycoside-based G-quadruplex binders of high affinity.
| S-EPMC10475565 | biostudies-literature
Project description:The solution structure of a locked nucleic acid (LNA) quadruplex, formed by the oligomer d(TGGGT), containing only conformationally restricted LNA residues is reported. NMR and CD spectroscopy, as well as molecular dynamics and mechanic calculations, has been used to characterize the complex. The molecule adopts a parallel stranded conformation with a 4-fold rotational symmetry, showing a right-handed helicity and the guanine residues in an almost planar conformation with three well-defined G-tetrads. The thermal stability of Q-LNA has been found to be comparable with that of [r(UGGGU)]4, while a T(m) increment of 20 degrees C with respect to the corresponding DNA quadruplex structure [d(TGGGT)]4 has been observed. The structural features of the LNA quadruplex reported here may open new perspectives for the biological application of LNAs as novel versatile tools to design aptamer or catalyst oligonucleotides.
| S-EPMC434435 | biostudies-literature
Project description:Glioblastoma multiforme (GBM), a grade IV glioma, is a challenging disease for patients and clinicians, with an extremely poor prognosis. These tumours manifest a high molecular heterogeneity, with limited therapeutic options for patients. Since GBM is a rare disease, sufficient statistically strong evidence is often not available to explore the roles of lesser-known GBM proteins. We present a network-based approach using centrality measures to explore some key, topologically strategic proteins for the analysis of GBM. Since network-based analyses are sensitive to changes in network topology, we analysed nine different GBM networks, and show that small but well-curated networks consistently highlight a set of proteins, indicating their likely involvement in the disease. We propose 18 novel candidates which, based on differential expression, mutation analysis, and survival analysis, indicate that they may play a role in GBM progression. These should be investigated further for their functional roles in GBM, their clinical prognostic relevance, and their potential as therapeutic targets.
| S-EPMC9965660 | biostudies-literature
Project description:Two bipyridine isomers (2,2'- and 4,4'-), used as coformers and ligands in coordination chemistry, were subjected to solid form screening and crystal structure prediction. One anhydrate and a formic acid disolvate were crystallized for 2,2'-bipyridine, whereas multiple solid-state forms, anhydrate, dihydrate, and eight solvates with carboxylic acids, including a polymorphic acetic acid disolvate, were found for the 4,4'-isomer. Seven of the solvates are reported for the first time, and structural information is provided for six of the new solvates. All twelve solid-state forms were investigated comprehensively using experimental [thermal analysis, isothermal calorimetry, X-ray diffraction, gravimetric moisture (de)sorption, and IR spectroscopy] and computational approaches. Lattice and interaction energy calculations confirmed the thermodynamic driving force for disolvate formation, mediated by the absence of H-bond donor groups of the host molecules. The exposed location of the N atoms in 4,4'-bipyridine facilitates the accommodation of bigger carboxylic acids and leads to higher conformational flexibility compared to 2,2'-bipyridine. For the 4,4'-bipyridine anhydrate ↔ hydrate interconversion hardly any hysteresis and a fast transformation kinetics are observed, with the critical relative humidity being at 35% at room temperature. The computed anhydrate crystal energy landscapes have the 2,2'-bipyridine as the lowest energy structure and the 4,4'-bipyridine among the low-energy structures and suggest a different crystallization behavior of the two compounds.
| S-EPMC8640990 | biostudies-literature
Project description:G-quadruplexes (G4s) are four-stranded, guanine-rich nucleic acid structures that can influence a variety of biological processes such as the transcription and translation of genes and DNA replication. In many cases, a single G4-forming nucleic acid sequence can adopt multiple different folded conformations that interconvert on biologically relevant timescales, entropically stabilizing the folded state. The coexistence of different folded conformations also suggests that there are multiple pathways leading from the unfolded to the folded state ensembles, potentially modulating the folding rate and biological activity. We have developed an experimental method for quantifying the contributions of individual pathways to the folding of conformationally heterogeneous G4s that is based on mutagenesis, thermal hysteresis kinetic experiments and global analysis, and validated our results using photocaged kinetic NMR experiments. We studied the regulatory Pu22 G4 from the c-myc oncogene promoter, which adopts at least four distinct folded isomers. We found that the presence of four parallel pathways leads to a 2.5-fold acceleration in folding; that is, the effective folding rate from the unfolded to folded ensembles is 2.5 times as large as the rate constant for the fastest individual pathway. Since many G4 sequences can adopt many more than four isomers, folding accelerations of more than an order of magnitude are possible via this mechanism.
| S-EPMC7897495 | biostudies-literature
Project description:This paper concerns the Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) structural studies of the quadruple helix arrangements adopted by three tailored oligodeoxyribonucleotide analogues, namely d(TG(Me)GGT), d(TGG(Me)GT) and d(TGGG(Me)T), where dG(Me) represents a 8-methyl-2'-deoxyguanosine residue. The results of this study clearly demonstrate that the effects of the incorporation of dG(Me) instead of a dG residue are strongly dependant upon the positioning of a single base replacement along the sequence. As such, d(TG(Me)GGT), d(TGG(Me)GT) have been found to form 4-fold symmetric quadruplexes with all strands parallel and equivalent to each other, each more stable than their natural counterpart. NMR experiments clearly indicate that [d(TG(Me)GGT)]4 possesses a G(Me)-tetrad with all dG(Me) residues in a syn-glycosidic conformation while an anti-arrangement is apparent for the four dG(Me) of [d(TGG(Me)GT)]4. As the two complexes show a quite different CD behaviour, a possible relationship between the presence of residues adopting syn-glycosidic conformations and CD profiles is briefly discussed. As far as d(TGGG(Me)T) is concerned, NMR data indicate that at 25 degrees C it exists primarily as a single-strand conformation in equilibrium with minor amounts of a quadruplex structure.
| S-EPMC1275585 | biostudies-literature
Project description:Diminazene, DMZ, (or berenil) has been reported as a tight binder of G-quadruplexes. G-Quadruplex structures are often located in the promotor regions of oncogenes and may play a regulatory role in gene expression based on the stability of the folding topology. In this study, attempts have been made to characterize the specificity of DMZ binding toward multiple G-quadruplex topologies or foldamers. Mutant sequences of the G-quadruplex forming promotor regions of several oncogenes were designed to exhibit restricted loop lengths and folding topologies. Circular dichroism was used to confirm the quadruplex topology of mutant BCL2, KRAS, and c-MYC sequences, human telomere (Na+ and K+) G-quadruplexes and their complexes with DMZ and analogs thereof. Isothermal titration calorimetry was used to generate a complete thermodynamic profile (ΔG, ΔH, -TΔS) for the formation of DMZ and analog complexes with the target G-quadruplexes. DMZ binds to parallel and/or mixed parallel/antiparallel quadruplex DNA motifs with stoichiometries up to 8:1 and via three binding modes with varying affinities. In the case of the parallel G-quadruplexes, with the exception of the long-looped c-MYC mutant, the highest affinity binding event (mode 1) is driven by enthalpy. DMZ binding to the long-looped c-MYC mutant exhibits a very favorable entropy change in addition to a moderately favorable enthalpy change. Mode 1 binding to the antiparallel and mixed parallel/antiparallel hTel quadruplexes is also driven by favorable enthalpy changes. In all cases, the intermediate DMZ affinity binding (mode 2) is driven almost entirely by entropy, with small or unfavorable enthalpic contributions. The weakest binding event (mode 3) is also entropically driven with small or moderate enthalpic contributions.
| S-EPMC6173502 | biostudies-literature
Project description:Keystone mutualisms, such as corals, lichens or mycorrhizae, sustain fundamental ecosystem functions. Range dynamics of these symbioses are, however, inherently difficult to predict because host species may switch between different symbiont partners in different environments, thereby altering the range of the mutualism as a functional unit. Biogeographic models of mutualisms thus have to consider both the ecological amplitudes of various symbiont partners and the abiotic conditions that trigger symbiont replacement. To address this challenge, we here investigate 'symbiont turnover zones'--defined as demarcated regions where symbiont replacement is most likely to occur, as indicated by overlapping abundances of symbiont ecotypes. Mapping the distribution of algal symbionts from two species of lichen-forming fungi along four independent altitudinal gradients, we detected an abrupt and consistent β-diversity turnover suggesting parallel niche partitioning. Modelling contrasting environmental response functions obtained from latitudinal distributions of algal ecotypes consistently predicted a confined altitudinal turnover zone. In all gradients this symbiont turnover zone is characterized by approximately 12°C average annual temperature and approximately 5°C mean temperature of the coldest quarter, marking the transition from Mediterranean to cool temperate bioregions. Integrating the conditions of symbiont turnover into biogeographic models of mutualisms is an important step towards a comprehensive understanding of biodiversity dynamics under ongoing environmental change.
| S-EPMC7209069 | biostudies-literature
Project description:Mutations in epigenetic pathways are common oncogenic drivers. Histones, the fundamental substrates for chromatin-modifying and remodelling enzymes, are mutated in tumours including gliomas, sarcomas, head and neck cancers, and carcinosarcomas. Classical 'oncohistone' mutations occur in the N-terminal tail of histone H3 and affect the function of polycomb repressor complexes 1 and 2 (PRC1 and PRC2). However, the prevalence and function of histone mutations in other tumour contexts is unknown. Here we show that somatic histone mutations occur in approximately 4% (at a conservative estimate) of diverse tumour types and in crucial regions of histone proteins. Mutations occur in all four core histones, in both the N-terminal tails and globular histone fold domains, and at or near residues that contain important post-translational modifications. Many globular domain mutations are homologous to yeast mutants that abrogate the need for SWI/SNF function, occur in the key regulatory 'acidic patch' of histones H2A and H2B, or are predicted to disrupt the H2B-H4 interface. The histone mutation dataset and the hypotheses presented here on the effect of the mutations on important chromatin functions should serve as a resource and starting point for the chromatin and cancer biology fields in exploring an expanding role of histone mutations in cancer.
| S-EPMC6512987 | biostudies-literature