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loops restrict access to the grooves, while the outer G-quartets represent large
planar surface areas that were hoped to rationalize the selective binding of aromatic
ligands. The 5
-ends are at the opposite ends of the G-quadruplex (Figure
3.4b), which could support end-to-end stacking of successive G-quadruplexes in a
larger DNA molecule. The crystal structure, in addition, revealed the position of K
+
ions in the structure.
104
In this 2.1 Å resolution crystal structure (PDB ID 1KF1) K
+
ions are equidistant between the stacked G-quartets. The distances between K
+
ions
and each of the eight carbonyl oxygen atoms in the bipyramidal antiprismatic
arrangement are 2.7 Å .
104
Subsequently, several studies have demonstrated that an antiparallel G-
quadruplex is formed by the human telomere repeat sequence in the presence of
either Na
+
or K
+
ions in solution.
74,192,200 - 202
In low salt conditions the human telomere
DNA repeats tend to be either in disordered single-stranded states or parallel
tetramolecular G-quadruplex structures.
203
Determination of K
+
ion structure in
solution was elusive until recently when three groups reported the folding pattern
of four repeats of human telomere sequence in the presence of K
+
ions in solu-
tion.
204 - 209
The main limitation for structure determinations was the existence of
multiple conformers in equilibrium. The conformational equilibrium was driven into
distinct predominant conformers that were amenable for structure determination
by sequence modifi cations. Importantly, the modifi ed oligonucleotide exhibited
NMR spectral characteristics of the unmodifi ed sequence. All these structures
contain the (3 + 1) topology of the G-quadruplex core, in which three strands are
oriented in one direction and the fourth is in the opposite direction (Figure 3.4c).
The topology of this structure is different from the previously reported folds in the
presence of Na
+
ions in solution (Figure 3.4a) and K
+
ions in the crystal (Figure
3.4b). This quadruplex contains three G-quartets with one exhibiting
anti
-
syn
-
syn
-
syn
and two
syn
-
anti
-
anti
-
anti
conformations of guanine bases. One of the loops
adopts a double-chain reversal structure, whereas the other two are edge-wise loops.
In this fold, 5
′
- and 3
′
-ends of the sequence are located at opposite ends of the G-
quadruplex core (Figure 3.4c). A related NMR study on a 26-nucleotide telomeric
sequence d[(TTAGG)
3
TT] revealed that the wild-type human telomeric sequence
adopts Hybrid 1 and Hybrid 2 conformations (Figures 3.4c and 3.4d) with a low
energy barrier between them, which results in their coexistence in solution.
210
Perusal
of the topology of the Hybrid 2 structure shows the same (3+1) topology of the G-
quadruplex core (Figure 3.4d). It consists of a single G-quartet with
anti
-
syn
-
syn
-
syn
and two with
syn
-
anti
-
anti
-
anti
conformations of guanine bases. The fi rst two TTA
loops closer to the 5
′
- and 3
′
-end adopt an edge-wise structure, whereas the fi nal loop
adopts a double-chain reversal structure.
′
3.4 G - Quadruplexes Adopted by Promoter Regions
Potential G-quadruplex-forming sequences are widespread in gene promoters. The
analysis of bioinformatic data has shown that G-quadruplexes may be directly
involved in gene regulation at the level of transcription. The promoter regions of
