Structure of a left-handed DNA G-quadruplex

Chung, Wan Jun; Heddi, Brahim; Schmitt, Emmanuelle; Lim, Kah Wai; Mechulam, Yves; Phan, Anh Tuân

doi:10.1073/pnas.1418718112

Cited by 119 publications

(177 citation statements)

References 41 publications

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“…For 24TTG, the third 2-K + species (2c), is never very abundant over time, so the molar ellipticity coefficients are entailed with larger errors and the reconstruction of its CD spectrum gave different results depending on the kinetic model. Using the model 0×((1-2)|(1×(2|2))) , a negative band at around 270–280 nm is obtained, which is reminiscent of the recently published CD spectrum of a left handed G-quadruplex (73) (even though less intense in our case). Using the model 0×(1|2|(1×(2|2))) (Supplementary Figure S40), however, two positive peaks between 250 and 290 nm are obtained, reminiscent of the CD spectrum reported for the Giardia telomeric sequence d(TAGGG) 4 , which folds into an antiparallel 2-quartet form (26,74).…”

Section: Resultssupporting

confidence: 76%

Folding and misfolding pathways of G-quadruplex DNA

Marchand¹,

Gabelica²

2016

Nucleic Acids Res

155

245

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G-quadruplexes adopt various folding topologies, but information on their folding pathways remains scarce. Here, we used electrospray mass spectrometry to detect and quantify the specifically bound potassium ions, and circular dichroism to characterize the stacking topology of each ensemble. For human telomeric (hTel) sequences containing the d((GGGTTA)3GGG) core, K+ binding affinity and cooperativity strongly depends on the chosen construct. The shortest sequences bind only one K+ at low KCl concentration, and this 2-quartet G-quadruplex is antiparallel. Flanking bases increase the K+ binding cooperativity. To decipher the folding pathways, we investigated the kinetics of K+ binding to telomeric (hybrid) and c-myc (parallel) G-quadruplexes. G-quadruplexes fold via branched pathways with multiple parallel reactions. Up to six states (one ensemble without K+, two ensembles with 1-K+ and three ensembles with 2-K+) are separated based on their formation rates and ion mobility spectrometry. All G-quadruplexes first form long-lived misfolded structures (off-pathway compared to the most stable structures) containing one K+ and two quartets in an antiparallel stacking arrangement. The results highlight the particular ruggedness of G-quadruplex nucleic acid folding landscapes. Misfolded structures can play important roles for designing artificial G-quadruplex based structures, and for conformational selection by ligands or proteins in a biological context.

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Section: Resultssupporting

confidence: 76%

Folding and misfolding pathways of G-quadruplex DNA

Marchand¹,

Gabelica²

2016

Nucleic Acids Res

155

245

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“…RHAU-G4 recognition might be more directly associated to an exposed G-tetrad rather than a specific G4 topology (parallel vs. nonparallel). It should be noted that a lefthanded parallel G4 structure with well-covered terminal G-tetrads has been recently reported (33); on the other hand, the formation of a nonparallel G4 with exposed G-tetrad might be possible. The G4 binding mode of RHAU is strikingly similar to that of most small molecules selected for specific G4 binding (34), which occur through stacking interactions on the terminal G-tetrads and electrostatic interactions with the phosphate backbone.…”

Section: Resultsmentioning

confidence: 94%

Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of a peptide–quadruplex complex

Heddi

Cheong

Martadinata

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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134

201

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Four-stranded nucleic acid structures called G-quadruplexes have been associated with important cellular processes, which should require G-quadruplex-protein interaction. However, the structural basis for specific G-quadruplex recognition by proteins has not been understood. The DEAH (Asp-Glu-Ala-His) box RNA helicase associated with AU-rich element (RHAU) (also named DHX36 or G4R1) specifically binds to and resolves parallel-stranded G-quadruplexes. Here we identified an 18-amino acid G-quadruplex-binding domain of RHAU and determined the structure of this peptide bound to a parallel DNA G-quadruplex. Our structure explains how RHAU specifically recognizes parallel G-quadruplexes. The peptide covers a terminal guanine base tetrad (G-tetrad), and clamps the G-quadruplex using three-anchor-point electrostatic interactions between three positively charged amino acids and negatively charged phosphate groups. This binding mode is strikingly similar to that of most ligands selected for specific G-quadruplex targeting. Binding to an exposed G-tetrad represents a simple and efficient way to specifically target G-quadruplex structures.G-quadruplex | RHAU helicase | DHX36 | DEAH-box family | NMR

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“…However, essentially the same features are shared by the complex formed with wtTel26, which cannot possibly assume a double-stranded Z conformation and the Z-G4 CD spectrum of which is expected to show an intense negative ellipticity at lower wavelength (275 versus 290 nm for G4 and the double helix, respectively). [21] Interestingly, at 100 mm KCl, the structural variation induced by L3 on the double helix is conserved, whereas it is completely suppressed on wtTel26; this is likely the result of the selective structural stabilization of the tetrahelical arrangement provided by the K + ions (figure S2 in the Supporting Information). We therefore interpret the observed spectral changes as the sum of a strong ICD overlapping the DNA bands and modest nucleic acid structural distortions.…”

Section: Resultsmentioning

confidence: 98%

Molecular Basis for Differential Recognition of G‐Quadruplex versus Double‐Helix DNA by Bis‐Phenanthroline Metal Complexes

et al. 2016

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1,10-Phenanthroline (Phen) derivatives are attractive ligands to provide metal complexes that are selective for different DNA secondary structures. Herein, we analyze the binding processes of two bis-Phen analogues and their Ni(II) complexes toward double-stranded DNA and telomeric G-quadruplex DNA by calorimetric and spectroscopic techniques. The free ligands can adapt to both DNA arrangements. Conversely, metal ion coordination produces an increase in ligand affinity for the tetrahelical structure, whereas it dramatically decreases binding to double-stranded DNA as a result of distinct binding modes on the two templates. In fact, Ni(II) complexes effectively stack on the G-quadruplex terminals, with an entropic loss counterbalanced by favorable enthalpy changes, whereas they cause a conformational reshaping of the double-helix form with a substantial decrease in the binding free energy. Consistently, no Ni(II) -DNA ionic pair has ever been identified. These results provide a rationale for the selective recognition of distinct DNA arrangements in view of targeted pharmacological applications.

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Structure of a left-handed DNA G-quadruplex

Cited by 119 publications

References 41 publications

Folding and misfolding pathways of G-quadruplex DNA

Folding and misfolding pathways of G-quadruplex DNA

Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of a peptide–quadruplex complex

Molecular Basis for Differential Recognition of G‐Quadruplex versus Double‐Helix DNA by Bis‐Phenanthroline Metal Complexes

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