Sequence, Stability, and Structure of G‐Quadruplexes and Their Interactions with Drugs

Yuwei Chen1, Danzhou Yang2

1 Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona, 2 Arizona Cancer Center, Tucson, Arizona
Publication Name:  Current Protocols in Nucleic Acid Chemistry
Unit Number:  Unit 17.5
DOI:  10.1002/0471142700.nc1705s50
Online Posting Date:  September, 2012
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Abstract

Although DNA is most widely known for its ability to store and pass along genetic information, the discovery of G‐quadruplex structures has illuminated a new role for DNA in biology. DNA G‐quadruplexes are four‐stranded globular nucleic acid secondary structures formed in specific G‐rich sequences with biological significance, such as human telomeres and oncogene promoters. This review focuses on the unimolecular DNA G‐quadruplexes, which can readily form in solution under physiological conditions and are considered to be the most biologically relevant. Available structural data show a great conformational diversity of unimolecular G‐quadruplexes, which are amenable to small‐molecule drug targeting. The relationships between sequence, structure, and stability of unimolecular DNA G‐quadruplexes, as well as the recent progress on interactions with small‐molecule compounds and insights into rational design of G‐quadruplex‐interactive molecules, will be discussed. Curr. Protoc. Nucleic Acid Chem. 50:17.5.1‐17.5.17. © 2012 by John Wiley & Sons, Inc.

Keywords: G‐quadruplexes; oncogene promoters; human telomeres; small‐molecule interactions; rational drug design

     
 
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Table of Contents

  • Introduction
  • DNA G‐Quadruplex Folds
  • Interactions of G‐Quadruplexes with Small Molecules
  • Conclusions and Future Direction
  • Acknowledgments
  • Literature Cited
  • Figures
     
 
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Materials

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Figures

  •   FigureFigure 17.5.1 (A) Schematic illustration of a G‐tetrad, a square planar alignment of four guanines connected by cyclic Hoogsteen hydrogen bonding of guanine bases. The H1–H1 (red) and H1–H8 (green) connectivity patterns detectable in nuclear Overhauser effect spectroscopy (NOESY) experiments are also shown. (B) An example of a G‐tetrad structure. The guanines in a G‐tetrad can adopt either syn or anti glycosidic conformation. The guanines from the parallel G‐strands adopt the same glycosidic conformation and the guanines from the antiparallel G‐strands adopt the opposite glycosidic conformations. (C) A schematic illustration of tetrameric and dimeric G‐ of quadruplexes composed of three G‐tetrads. Cations (K+ or Na+), shown as blue balls, are needed to stabilize G‐quadruplexes by coordinating with the eight electronegative carbonyl oxygen O6 atoms of the adjacent G‐tetrads. (D‐F) Examples of monomeric (unimolecular) G‐quadruplexes with parallel‐stranded (D), mixed parallel/antiparallel (E), and antiparallel folding (F).
  •   FigureFigure 17.5.2 Comparison of G‐quadruplex‐forming sequences in selected gene promoters and human telomeres. The types of G‐quadruplexes are indicated. The G3NG3 motifs (and a G2NG3 motif in PDGFR‐β) are boxed. The tetrad‐forming guanines are shaded.
  •   FigureFigure 17.5.3 (A) Folding structures of the basket‐type human telomeric G‐quadruplex formed in Na+ solution (left) and the parallel‐stranded human telomeric G‐quadruplex formed in the presence of K+ in crystalline state (right). (B) Folding structures of hybrid‐1 (left) and hybrid‐2 (right) human telomeric G‐quadruplexes present in equilibrium in K+ solution. Red box = ( anti) guanine, magenta box = ( syn) guanine. (C) The representative NMR structures of hybrid‐1 and hybrid‐2 telomeric G‐quadruplexes that are in equilibrium in K+ solution (guanine: yellow; adenine: red; thymine: blue). (D) A model showing a DNA secondary structure composed of compact‐stacking multimers of hybrid‐type G‐quadruplexes in human telomeres, with an equilibrium between the hybrid‐1 and hybrid‐2 forms. (E) A model of the interconversion between different forms of human telomeric G‐quadruplexes through a strand‐reorientation mechanism. A two‐tetrad form is likely to be a transition intermediate.
  •   FigureFigure 17.5.4 (A) The promoter structure of the human c‐MYC gene. The G‐rich NHE III1 is shown, with guanine runs underlined. (B) The c‐MYC promoter sequence and its modification mycPu22 forms the major c‐MYC promoter G‐quadruplex, MycG4. (C) The folding structure of the major G‐quadruplex formed in the c‐MYC promoter, MycG4, a parallel‐stranded structure with (1:2:1) loop‐size arrangement (left); and the representative NMR structure of MycG4, with two potassium ions coordinated between the G‐tetrads shown as green spheres (right). Guanine = yellow, adenine = red, thymine = blue.
  •   FigureFigure 17.5.5 (A) The sequence and folding structure of the major G‐quadruplex formed in the human VEGF promoter region. (B) The sequence and folding topology of the major G‐quadruplex formed in the human PDGFR‐β gene promoter. (C) The sequence of the G‐rich region of the human c‐MYB gene promoter.
  •   FigureFigure 17.5.6 (A) The promoter structure of the human BCL‐2 gene. The G/C‐rich region of the promoter is shown, with guanine runs underlined. The bcl2Mid sequence of the middle four G‐tracts is also shown. (B) The folding structure of the major G‐quadruplex formed in the BCL‐2 promoter, bcl2MidG4 (left), and its NMR K+‐solution structure (right).
  •   FigureFigure 17.5.7 Formulas of TMPYP4 (A), telomestatin (B), and quindoline (C).
  •   FigureFigure 17.5.8 (A) Imino proton regions of the 1D 1H NMR titration spectra of mycPu22 (MycG4) with quindoline in K+ solution. Drug equivalence values are shown above each spectrum; for example, 3N indicates a quindoline:DNA ratio of 3:1. The assignments of imino protons of the free DNA and 2:1 quindoline:DNA complex are shown above the spectra. The imino protons from the 5′ G‐tetrad are colored in red, the middle G‐tetrad in blue, and the 3′ G‐tetrad in green. (B) The imino regions of 1D 1H NMR spectra of MycG4 (left) and the 2:1 quindoline:MycG4 complex (right) at various temperatures in 10 mM K+ solution, pH 6. (C) A representative model of the NMR‐refined 2:1 quindoline:MycG4 complex structure from two different views. The quindoline molecules are shown in the space‐filling model in green. The two potassium ions are shown as white balls. Guanine is shown in yellow, adenine in red, and thymine in blue. (D) Different views of the drug‐induced binding pockets at the 5′‐end (left) and at the 3′‐end (right).

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