Molecular structure of a double helical DNA fragment intercalator complex between deoxy CpG and a terpyridine platinum compound

Wang, Andrew H.‐J.; Nathans, Jeremy; Marel, Gijs van der; Boom, Jacques H. van; Rich, Alexander

doi:10.1038/276471a0

Cited by 208 publications

(108 citation statements)

References 22 publications

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“…The doubling of the rise at the intercalation region is similar to that which occurs when drugs or small molecules intercalate between base pairs (39)(40)(41)(42)(43)(44)(45). However, the helix unwinding at the intercalation step in our structure is very different.…”

Section: Figmentioning

confidence: 57%

Crystal structure of an RNA·DNA hybrid reveals intermolecular intercalation: Dimer formation by base-pair swapping

Han

Kopka

Langs

et al. 2003

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

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An intermolecular intercalation of base pairs was found at the CA step in the I222 crystal structure of the RNA⅐DNA hybrid, r(CAAAGAAAAG)⅐d(CTTTTCTTTG), which contains two-thirds of the polypurine tract sequence of HIV-1 with a substitution of cytosine for the initial adenine. This sequence crystallized in both P2 12121 and I222 space groups, with an rms difference of only 0.63 Å between residues 3 to 18 of the two forms. P2 12121 and I222 helices are both A-like, but intercalation occurs only in the I222 crystal form. The present structure shows bases stacked in parallel rather than perpendicular as in intercalated DNA (I-DNA). The base intercalation is also different from zipper-like meshing of bases seen in the center of the crystal structure of d(GCGAAAGCT), which does not have Watson-Crick base pairing. The base-step intercalation seen here is reminiscent of domain swapping in proteins; therefore, we call this phenomenon ''base-pair swapping.'' It involves a highly mobile CA step and seems to be sequence-specific and electrostatically stable without disrupting Watson-Crick interactions. It also exhibits a large rise concurrent with unwinding of the helix (low twist). We present a base-pair swapping dimer in nucleic acids.RNA⅐DNA polypurine tract ͉ DNA intercalation

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Section: Figmentioning

confidence: 57%

Crystal structure of an RNA·DNA hybrid reveals intermolecular intercalation: Dimer formation by base-pair swapping

Han

Kopka

Langs

et al. 2003

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

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“…This result correlates reasonably well with solution studies on superhelical DNA in which the unwinding associated with daunomycin has been estimated to be near 11° (18,19). The modifications of the geometry of the double helix and the unwinding associated with this intercalator suggest that there are not likely to be general rules that can be applied for all intercalators, as had been suggested by some previous studies (4,7). Instead, we may expect different effects to be seen, and many will be quite specific to the individual drug.…”

Section: Resultsmentioning

confidence: 89%

“…Up to the present, only structures of dinucleoside phosphates associated with intercalators have been determined (4)(5)(6)(7)(8). These generally yielded an unwinding angle but provided no information about perturbations farther away.…”

Section: Resultsmentioning

confidence: 99%

Molecular structure of an anticancer drug-DNA complex: daunomycin plus d(CpGpTpApCpG).

Quigley¹,

Wang²,

Ughetto³

et al. 1980

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

334

142

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The structure of the crystalline daunomycind(CpGpTpApCpG) complex has been solved by x-ray diffraction analysis. The DNA forms a six-base-pair right-handed double helix with two daunomycin molecules intercalated in the d(CpG) sequences. The daunomycin aglycone chromophore is oriented at right angles to the long dimension of the DNA base pairs and the cyclohexene ring rests in the minor groove. Substituents on this ring have hydrogen bonding interactions to the base pairs above and below the intercalation site. These appear to be specific for anthracycline antibiotics. The amino sugar lies in the minor groove of the double helix without bonding to the DNA. The DNA double helix is distorted in a novel manner in accommodating the drug.An important group of antibiotics are those that interact with DNA and have antitumor activity. Daunomycin, an anthracycline antibiotic, has been found to inhibit virus multiplication and shows considerable activity against tumors; it was the first antibiotic to show activity against acute leukemia in man. It has an aglycone chromophore containing four fused rings and an amino sugar (Fig. 1). The closely related antitumor agent adriamycin (14-hydroxydaunomycin) is widely used in treating various solid tumors. These compounds have been the subject of intensive chemical and biological research since their discovery 17 years ago. More than 500 compounds of this type have been synthesized or isolated from nature and tested for activity (1, 2). These agents are believed to act by binding to DNA and inhibiting both DNA replication and transcription. Several studies suggest that the unsaturated chromophore intercalates between DNA base pairs (1, 2). However, the complexity of the molecule makes its mode of interaction with DNA a matter of considerable interest.Here we report the crystal structure of daunomycin with a self-complementary DNA fragment, d(CpGpTpApCpG). The structure has been solved by x-ray diffraction methods. A sixbase-pair fragment of double-helical DNA was found with two molecules of daunomycin bound to it, plus 80 mM spermine, and 30 mM cacodylate buffer (pH 6.5) was equilibrated with 30% (vol/vol) 2-methyl-2,4-pentanediol. After 1 week, attractive bright red-orange, tetragonal, rod-like crystals appeared. Spectroscopic analysis of the dissolved crystal revealed a 1:1 ratio of hexanucleotide to daunomycin. X-ray diffraction studies indicated a tetragonal crystal system with space group P4 212 or P43212, a = b = 27.92 A, c = 52.89 A.The asymmetric unit contained one hexanucleotide and one daunomycin molecule. Intense meridional reflections at 3.3 A along the c axis strongly suggested that the bases were stacked perpendicular to that direction. Three-dimensional data were collected on a Nicolet x-ray diffractometer to a resolution of

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“…The specificity of these ligands may well be consequent upon the presence of the platinum atom, since the 2,2':6',2"-terpyridine and 1,10-phenanthroline complexes are structurally quite dissimilar. In this regard it is notable that in the crystal structure of the (hydroxyethanethiolato)-(2,2': 6',2"-terpyridine)platinum(II)-deoxyCpG intercalation complex (Wang et al, 1978) the thiolato tail is located in the major groove of the DNA mini-helix and the platinum atom lies sandwiched directly between the 0-6 atoms of the guanine residues. As we have noted previously (Wakelin et al, 1984), if G-C-base-pair specificity arises from maximum monopole-monopole interactions between the ligand and base-pair (Muller & Crothers, 1975), then it is just this orientation of the positively charged platinum atom (formal charge 2 +) and the large residual negative charge on the 0-6 atom of guanine (Dean & Wakelin, 1979) that would give rise to specificity.…”

Section: Discussionmentioning

confidence: 99%

The binding of binuclear platinum(II)-terpyridine complexes to DNA

McFadyen¹,

Wakelin²,

Roos³

et al. 1987

Biochemical Journal

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The binding of platinum (II)-terpyridine complexes to DNA was studied by using equilibrium dialysis.Optical absorption methods were used to measure the ability of the ligands to aggregate in aqueous buffer. requirement for a single G C base-pair at the highest-affinity site. However, in the binuclear ligands chromophore specificity is severely compromised. Similar experiments indicate that 9-aminoacridine and selected methylene-linked diacridines show no significant sequence selectivity.

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Molecular structure of a double helical DNA fragment intercalator complex between deoxy CpG and a terpyridine platinum compound

Cited by 208 publications

References 22 publications

Crystal structure of an RNA·DNA hybrid reveals intermolecular intercalation: Dimer formation by base-pair swapping

Crystal structure of an RNA·DNA hybrid reveals intermolecular intercalation: Dimer formation by base-pair swapping

Molecular structure of an anticancer drug-DNA complex: daunomycin plus d(CpGpTpApCpG).

The binding of binuclear platinum(II)-terpyridine complexes to DNA

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