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Imposing a Three-Way Junction on DNA or Recognizing One A Metal Triple Helicate Meets Double Helix.

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DOI: 10.1002/anie.200600031
Bioinorganic Chemistry
Imposing a Three-Way Junction on DNA or Recognizing
One: A Metal Triple Helicate Meets Double Helix
Jens Mller* and Bernhard Lippert*
DNA recognition · DNA structure ·
metal helicate · noncovalent interactions ·
supramolecular chemistry
etal triple helicates, supramolecular
constructs made up of three bis-ditopic,
flexible, linear organic ligands and two
octahedrally coordinate metal ions, have
presented a synthetic challenge for quite
a while. Now well understood, the
interactions of such supramolecules with
another one, a double-stranded DNA,
have lately attracted attention.[1] It was
originally the idea to take advantage of
the complementarity between charge
(positive for the helicate, negative for
DNA) and shape (for major-groove
binding), which prompted this research.
An X-ray crystal structure analysis reported by Hannon, Coll et al. has now
revealed an unexpected and truly remarkable interaction between the tetracationic [Fe2L3]4+ triple helicate (Figure 1, L = bis(pyridylimine) ligand:
C25H20N4) and the palindromic DNA
sequence 5’-dACHTUNGRE(CGTACG).[2] Rather
than sitting in the major groove of a
double-stranded DNA hexamer, as had
been expected based on earlier spectroscopic studies,[1c] the metal helicate with
its trigonal antiprismatic geometry occupies the central hydrophobic cavity of
a three-way (Y-shaped) junction generated by three single strands that are
linked by nine Watson–Crick base pairs
(Figure 2). The base pairing results in
the formation of three minihelices.
The association between DNA and
the metal helicate is accomplished by
the interplay of numerous noncovalent
forces: In addition to the electrostatic
interaction between the positively
charged supramolecule and the negatively charged DNA backbone that is
also present in related major-groove
binding double-helical copper(i) complexes,[3] this new structure also features
six extensive p-stacking interactions between the phenyl rings of the helicate
and the adenine and thymine bases of
the DNA strands as well as strong van
der Waals interactions between the
helicate and the sugar–phosphate backbone reminiscent of those observed in
minor groove binders. Hannon, Coll
et al describe this unexpected finding
in terms of a selection of an otherwise
energetically unfavorable structural element out of a dynamic combinatorial
library[4] of palindromic DNA oligomers. On the other hand, it is reasonable
to expect that the metal helicate can
recognize a naturally occurring threeway junction and bind to it. These two
possibilities represent two sides of the
same coin. Supportive of this scenario is
that the three-way junction is not significantly perturbed from its Y-structure
upon binding of the metal complex. This
feature suggests that the three-way
junction serves as a structural-recognition target not only for proteins as
previously observed but also for synthetic small molecules. Helical junctions,
such as the three-way junction, are
numerous as structural elements in
RNA and are significant as intermediates in both homologous and site-spe-
Figure 1. Self-assembly and schematic view of
Fe2 triple helicate; orange Fe, blue N,
gray C.[20]
[*] Dr. J. M5ller, Prof. Dr. B. Lippert
Fachbereich Chemie
Universit9t Dortmund
44221 Dortmund (Germany)
Fax: (+ 49) 231-755-3797
Angew. Chem. Int. Ed. 2006, 45, 2503 – 2505
Figure 2. A) Top and B) side view of DNA three-way junction stabilized by Fe2 triple helicate.
Gray spheres C, blue spheres N, orange sphere Fe, all the bases of each of the three DNA
strands have a different color: blue, red, or yellow.[20]
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
cific recombination,[5] and in the replication fork during DNA duplication.
The replication fork might be seen as
one example for a naturally occurring,
transient three-way DNA junction.[6]
The binding of small molecules to
DNA or to nucleic acids in general is of
great interest because of its enormous
potential in the fields of anticancer
drugs, gene therapy, or biochemical
methods for specific DNA recognition
and/or modification.[7] The following
discussion focuses on the binding of
metal complexes to nucleic acids and
hence represents a bioinorganic view of
DNA recognition.[8]
Although well established, the direct
covalent binding of metal ions or complexes to DNA is rather the exception
not the rule. Cisplatin (cis-[PtCl2ACHTUNGRE(NH3)2]), binding to purine nucleobases
from the major groove, is a prime
example.[9] There are also rare cases of
direct binding of [MgACHTUNGRE(H2O)n]2+ (n = 4 or
5) to nucleobase donor atoms in nucleic
acid structures. Coordinative binding in
the minor groove is also known, for
example, for sodium ions.[10] However,
the recognition process of nucleic acids
and their stabilization by most other
metal complexes can best be described
as a noncovalent interaction. Various
nucleic acid structures are known displaying binding of the [CoACHTUNGRE(NH3)6]3+ ion,
mainly through outer-sphere hydrogen
bonding to the DNA donor atoms. A
preference of this well-studied complex
for a distinct DNA conformation could
not be unambiguously delineated to
date; apparently its binding merely
destabilizes B-type DNA, and the respective nucleic-acid sequence is the
main determinant of whether the A- or
Z-type conformation is adopted upon
interaction with the cobalt complex.[11]
Other examples for outer-sphere hydrogen bonding interactions include those
of the [MgACHTUNGRE(H2O)6]2+ ion.
Intercalating metal complexes represent another important group of
DNA-binding molecules. They are able
to attach to the DNA in either groove[12]
or even in both grooves at the same time
by threading through the DNA.[13] Initially synthesized as square-planar reagents the first metallointercalators
were without any significant sequence
specificity.[14] However new examples of
octahedral metallointercalators permit
the targeting of specific DNA sites with
high affinity by matching shape, symmetry, and functionalities of the metal
complex to that of the nucleic acid
target.[12a] The X-ray crystal-structure
analysis of a rhodium complex intercalated into DNA provides a rationale
how such a sequence specificity can be
obtained.[15] By using this strategy of
applying specifically designed ligands,
even preferential binding to oligonucleotides with mismatches can be observed.[16] Including an alkylating agent
in the intercalator conjugate, covalent
tagging of mismatched DNA and potentially an application in the development
of new chemotherapeutic agents is feasible.[17] However, not every metal complex that could potentially intercalate
through its planar aromatic ligand(s)
necessarily does so. Several examples
are known where the mode of binding
has been proposed to depend on various
factors including DNA base sequence,
substitution pattern of the aromatic
ligand, and relative concentrations of
DNA and metal coordination compound. The metal compound can under
certain conditions be located in either
groove without intercalating into the
nucleic acid.[18]
The three-way junction-directed
binding mode observed for the metal
triple helicate by Hannon, Coll et al.[2]
opens up an entirely new range of
possible DNA-interacting therapeutic
agents based on metal complexes. Their
cylinder-shaped molecule is reported to
potentially have a preference for binding a three-way junction with a central
TA sequence, raising the question
whether other palindromic sequences
might be recognized with structurally
related compounds, such as an extended
cylinder[1a] or a tetranuclear triplestranded lanthanide helicate.[19] How
the chirality of the complex influences
the recognition process is another subject of interest. Time will tell whether a
chemistry as rich as that of the intercalating drugs will develop around this
new DNA recognition mode.
Published online: March 20, 2006
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[20] Figures have been prepared with MOLMOL: R. Koradi, M. Billeter, K. WKthrich, J. Mol. Graphics 1996, 14, 51 – 55.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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