Propeller-Type Parallel-Stranded G-Quadruplexes in the Human<i>c-myc</i>Promoter

Phan, Anh Tuân; Modi, Yasha S.; Patel, Dinshaw J.

doi:10.1021/ja048805k

Cited by 489 publications

(637 citation statements)

References 47 publications

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“…13 G-quadruplexes, which may have transient stability by themselves when embedded within the double-stranded DNA of a eukaryotic gene, may be stabilized further by a small-molecule ligand such as the porphyrin molecule TMPyP4. 12 The topology and structure of the c-myc DNA quadruplexes containing four 14 and five 15 G-tracts have been determined by nuclear magnetic resonance (NMR) spectroscopy, together with that of a TMPyP4 complex for the five-guanine-tract quadruplex. 15 The latter are parallel-stranded quadruplexes, with several strand-reversal loops and base-pair platforms.…”

Section: Introductionmentioning

confidence: 99%

Structure of an Unprecedented G-Quadruplex Scaffold in the Human c-kit Promoter

et al. 2007

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The c-kit oncogene is an important target in the treatment of gastrointestinal tumors. A potential approach to inhibition of the expression of this gene involves selective stabilization of Gquadruplex structures that may be induced to form in the c-kit promoter region. Here we report on the structure of an unprecedented intramolecular G-quadruplex formed by a G-rich sequence in the c-kit promoter in K + solution. The structure represents a new folding topology with several unique features. Most strikingly, an isolated guanine is involved in G-tetrad core formation, despite the presence of four three-guanine tracts. There are four loops: two single-residue double-chainreversal loops, a two-residue loop, and a five-residue stem-loop, which contain base-pairing alignments. This unique structural scaffold provides a highly specific platform for the future design of ligands specifically targeted to the promoter DNA of c-kit.

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Section: Introductionmentioning

confidence: 99%

Structure of an Unprecedented G-Quadruplex Scaffold in the Human c-kit Promoter

et al. 2007

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“…Most of the structural studies on these elements have been performed by NMR spectroscopy. In most cases the related nucleotide sequence bearing the actual physiological function in vivo needs to be truncated/ elongated and/or mutated in order to obtain a successful candidate for NMR structure determination [3][4][5][6][7]13]. This NMR candidate should be a well-defined molecular entity in physiologically relevant solution conditions (ionic strength, pH, temperature) representing the same conformation as the original sequence.…”

Section: Introductionmentioning

confidence: 99%

“…Analytical ultracentrifugation has the same working concentration as CD spectroscopy. In contrast, NMR titration methods can be used for the determination of the extent of oligomerization of G-quadruplexes in the actual NMR sample environment [5,6,13,15]. During the analysis, the melting point of the DNA structural element is determined first (50% transformation to the unfolded conformation of a single strand, represented by very sharp resonances in the 1D 1 H NMR spectrum).…”

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Diffusion-ordered nuclear magnetic resonance spectroscopy for analysis of DNA secondary structural elements

Ambrus¹,

Yang²

2007

Analytical Biochemistry

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Structure determination of secondary DNA structural elements, such as G-quadruplexes, gains an increasing importance as fundamental physiological roles are being associated with the formation of such structures in vivo. A truncated native DNA sequence generally requires further optimization to obtain a candidate with desired NMR properties for structural analysis in solution. The optimum sequence is expected to form one dominant, stable molecular entity in solution with well-resolved NMR peaks. However, DNA sequences are prone to form structures composed of one, two, three or four strands depending on sequence and solution conditions. The thorough characterization of the molecularity (stoichiometry and molecular weight) and appropriate solution conditions for sequences with different modifications traditionally applies analytical techniques that generally do not represent the solution conditions for NMR structure determination. Here we present the application of diffusion ordered NMR spectroscopy as a useful analytical tool for the optimization and analysis of DNA secondary structural elements, specifically, the DNA G-quadruplex structures, including those formed in the human telomeric sequence and in the promoter regions of bcl-2 and c-myc genes. KeywordsDNA; NMR; DOSY; quadruplex; bcl-2; human telomere; c-myc Structural analysis of unusual DNA motifs with particular emphasis on G-quadruplexes and imotifs has a central role in the identification and characterization of molecular targets related to these structures [1][2][3][4][5][6][7]. Such structures are implicated in several physiologically important regulatory processes, with special emphasis on carcinogenesis [4][5][6][7][8][9][10][11][12]. Most of the structural studies on these elements have been performed by NMR spectroscopy. In most cases the related nucleotide sequence bearing the actual physiological function in vivo needs to be truncated/ elongated and/or mutated in order to obtain a successful candidate for NMR structure determination [3][4][5][6][7]13]. This NMR candidate should be a well-defined molecular entity in physiologically relevant solution conditions (ionic strength, pH, temperature) representing the same conformation as the original sequence. Appropriate modification of the sequence by mutation/truncation/elongation will force the molecule to form a single stable structure without altering crucial connectivities (conformation) of the structure.* To whom correspondence should be addressed at the Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 E. Mabel St., P.O. Box 210207, room 101/406, Tucson, Arizona 85721, USA; Tel: +1 520 626 6749/626 5969, Fax: +1 520 626 2466, E-mail: ambrus@pharmacy.arizona.edu, yangd@pharmacy.arizona.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of ...

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“…The chair form has been shown to be kinetically and biologically favored as it is 3-fold more stable than the basket one in transcriptional activity of the c-myc promoter [38]. 25 ]-3′ (termed c-myc-2345), was designed which could form stable parallel-stranded chair form G-quadruplex structure in K + solution [39,40]. As shown in Figure 1, NMRbased folding topology of c-myc-2345 in K + solution had been resolved, which presents a typical unimolecular parallel-stranded G-quadruplex motif, including three G-tetrads, one two-residual loop (G 14 A 15 ), two one-residual loops (T 10 and T 19 ) and two three-residual flanking sequences (T 4 G 5 A 6 at 5′-end and G 23 A 24 A 25 at 3′-end).…”

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confidence: 99%

“…As shown in Figure 1, NMRbased folding topology of c-myc-2345 in K + solution had been resolved, which presents a typical unimolecular parallel-stranded G-quadruplex motif, including three G-tetrads, one two-residual loop (G 14 A 15 ), two one-residual loops (T 10 and T 19 ) and two three-residual flanking sequences (T 4 G 5 A 6 at 5′-end and G 23 A 24 A 25 at 3′-end). Thanks to the stable Gquadruplex motif and the typical loop folding, c-myc-2345 is always considered as a model sequence in those in vitro (G-quadruplex)-ligands interaction studies [40].…”

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Roles of flanking sequences in the binding between unimolecular parallel-stranded G-quadruplexes and ligands

et al. 2013

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G-quadruplexes attract more and more attention in recent years. Numerous small molecules which can induce or stabilize the formation of G-quadruplexes have been investigated on the purpose of anticancer drug development. As a motif existed in physiological condition, flanking sequences are an important part of G-quadruplexes but the study on the impact of flanking sequences on (G-quadruplex)-ligand binding is rarely reported. In this paper, the effects of flanking sequences on binding affinity between a series of unimolecular parallel-stranded G-quadruplex sequences derived from c-myc oncogene promoter (termed as c-myc G-quadruplexes) and their ligands are discussed in detail. The results showed that the flanking sequences on c-myc G-quadruplexes play key roles in (G-quadruplex)-ligand interaction. When a c-myc G-quadruplex is bound to its ligands, the flanking sequences might form a binding cavity above the terminal G-quartet, which could provide a suitable site for ligands to dock in. Moreover, the bases on flanking sequences could interact with ligand through - stacking, and finally form a sandwich-stacking mode (terminal G-quartet, ligand and bases on the flanking sequence). This mode could stabilize the (G-quadruplex)-ligand complex effectively and enhance the binding affinity dramatically. However, flanking sequences are also found to exhibit steric hindrance effect which could impede the (G-quadruplex)-ligand binding. G-quadruplex

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Propeller-Type Parallel-Stranded G-Quadruplexes in the Humanc-mycPromoter

Cited by 489 publications

References 47 publications

Structure of an Unprecedented G-Quadruplex Scaffold in the Human c-kit Promoter

Structure of an Unprecedented G-Quadruplex Scaffold in the Human c-kit Promoter

Diffusion-ordered nuclear magnetic resonance spectroscopy for analysis of DNA secondary structural elements

Roles of flanking sequences in the binding between unimolecular parallel-stranded G-quadruplexes and ligands

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