The Determination of Quadruplex Structures

Neidle, Stephen

doi:10.1016/b978-0-12-375138-6.00010-8

Cited by 21 publications

(32 citation statements)

References 36 publications

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“…19,20 The topology of the AIM by sc-xrd is similar to that observed in our computational docking study of the AIMs with human telomeric G4; Figure 1.B illustrates AIM 3a docked with coordinates from PDB accession 1KF1, 21 whereas Figure 1.C shows the low energy interaction calculated for the solution conformation of the G4, PDB accession number 2JSM, 22–24 docked with 3c. We considered a number of potential G4 coordinates and ligand binding modes; however, the lowest energy was calculated for a unique edge-to-face interaction of the AIM isoxazolyl-3-aryl moiety with the G-tetrad in both cases, which is in contrast to our predictions calculated with earlier programs, which suggested face-to-face π-stacking.…”

supporting

confidence: 64%

AIMing towards improved antitumor efficacy

Weaver¹,

Kearns²,

Stump³

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Using the structure-activity relationship emerging from previous reports, and guided by pharmacokinetic properties, new AIMs have been prepared with both improved efficacy against human glioblastoma cells and cell permeability as determined by fluorescent confocal microscopy. We present our first unambiguous evidence for telomeric G4-forming oligonucleotide anisotropy by NMR resulting from direct interaction with AIMs, which is consistent with both our G4 melting studies by CD, and our working hypothesis. Finally, we show that AIMs induce apoptosis in SNB-19 cells.

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supporting

confidence: 64%

AIMing towards improved antitumor efficacy

Weaver¹,

Kearns²,

Stump³

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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“…The size of the cation is critical, as potassium ions support G-quadruplex assembly whereas smaller lithium ions do not (Neidle, 2012). Potassium equilibration reduces the mobility of r(G4C2)4 in native gels, a phenomenon that is not observed with lithium equilibration (Fig S6A), consistent with rG4C2 forming a G-quadruplex (Fratta et al, 2012; Haeusler et al, 2014; Reddy et al, 2013; Su et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…G-quadruplexes are stable structures formed by stacks of four guanosine residues hydrogen bonded via Hoogsteen base pairing and stabilized by specific metal cations (Neidle, 2012). The availability of structural data combined with the link to neurodegenerative disease makes rG4C2 an ideal candidate to study the mechanisms by which specific RNAs modulate RNA granule assembly.…”

Section: Introductionmentioning

confidence: 99%

ALS/FTD-Associated C9ORF72 Repeat RNA Promotes Phase Transitions In Vitro and in Cells

2017

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Summary Membraneless RNA granules originate via phase separation events driven by multivalent interactions. As RNA is the defining component of such granules, we examined how RNA contributes to granule assembly. Expansion of hexanucleotide GGGGCC (G4C2) repeats in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). We describe a biophysical phenomenon whereby G4C2 RNA (rG4C2) promotes the phase separation of RNA granule proteins in vitro and in cells. The ability of rG4C2 to promote phase separation is dependent on repeat length and RNA structure, as rG4C2 must assume a G-quadruplex conformation to promote granule assembly. We demonstrate a central role for RNA in promoting phase separations and implicate rG4C2 G-quadruplex structures in the pathogenesis of C9-ALS/FTD.

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“…[2] Each guanineb ase in the G-quartet shares four hydrogen bonds ( Figure 1) with two neighboring bases through the N7 and O6 atoms as hydrogenbond acceptors andt he N1ÀHa nd N2ÀHg roups as hydrogenbond donors. [3] In the DNA quadruplex stems, the neighboring G-quartets interact with each other through quartet stacking. [4][5][6][7] Finally,substantial stability is imparted to the G-quadruplex arrangementb yt he monovalent ions, which coordinate with the carbonyl oxygen atoms (O6) inside the quadruplex Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Designing a New Class of Bases for Nucleic Acid Quadruplexes and Quadruplex‐Active Ligands

Bazzi

Novotný

Yurenko

et al. 2015

Chemistry A European J

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A new class of quadruplex nucleobases, derived from 3-deazaguanine, has been designed for various applications as smart quadruplex ligands as well as quadruplex-based aptamers, receptors, and sensors. An efficient strategy for modifying the guanine quadruplex core has been developed and tested by using quantum chemistry methods. Several potential guanine derivatives modified at the 3- or 8-position or both are analyzed, and the results compared to reference systems containing natural guanine. Analysis of the formation energies (BLYP-D3(BJ)/def2-TZVPP level of theory, in combination with the COSMO model for water) in model systems consisting of two and three stacked tetrads with Na(+) /K(+) ion(s) inside the internal channel indicates that the formation of structures with 3-halo-3-deazaguanine bases leads to a substantial gain in energy, as compared to the corresponding reference guanine complexes. The results cast light on changes in the noncovalent interactions (hydrogen bonding, stacking, and ion coordination) in a quadruplex stem upon modification of the guanine core. In particular, the enhanced stability of the modified quadruplexes was shown to originate mainly from increased π-π stacking. Our study suggests the 3-halo-3-deazaguanine skeleton as a potential building unit for quadruplex systems and smart G-quadruplex ligands.

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The Determination of Quadruplex Structures

Cited by 21 publications

References 36 publications

AIMing towards improved antitumor efficacy

AIMing towards improved antitumor efficacy

ALS/FTD-Associated C9ORF72 Repeat RNA Promotes Phase Transitions In Vitro and in Cells

Designing a New Class of Bases for Nucleic Acid Quadruplexes and Quadruplex‐Active Ligands

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