Structure of a dinucleoside phosphate–drug complex as model for nucleic acid–drug interaction

Neidle, Stephen; Achari, A.; Taylor, G.L.; Berman, Helen M.; Carrell, H. L.; Glusker, Jenny P.; Stallings, William C.

doi:10.1038/269304a0

Cited by 114 publications

(34 citation statements)

References 26 publications

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“…Instead of having unwinding associated with the bases surrounding the intercalator, there is unwinding associated with the base pair one removed from the intercalator. A 00 unwinding angle has already been observed in the r(CpG)-proflavin complex (6). The total amount of unwinding seen per daunomycin is 80, compared with 26°observed with ethidium (5).…”

Section: Resultsmentioning

confidence: 81%

See 1 more Smart Citation

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.

335

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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Section: Resultsmentioning

confidence: 81%

“…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.

335

142

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“…According to this principle, every second (next-neighbor) intercalation site along the length of the DNA double helix remains unoccupied. Experimental evidence for this principle has been found in fiber diffraction studies on nucleic acid fibers bound to metallointercalative agents (2,3), in single-crystal studies (4)(5)(6)(7)(8) on complexes between dinucleoside monophosphates complexed with intercalating drugs, and solution studies on binding of ethidium ion to oligonucleotides of ribose and deoxyribose sugars (9). Based on earlier crystallographic studies (4-6) that suggested mixed sugar puckering at the intercalation site, a stereochemical basis for the neighbor-exclusion principle was proposed.…”

mentioning

confidence: 99%

“…Based on earlier crystallographic studies (4-6) that suggested mixed sugar puckering at the intercalation site, a stereochemical basis for the neighbor-exclusion principle was proposed. However, this mixed sugar puckering scheme has not been shown to be essential for creating intercalating sites in double-helical DNA through several crystal structure and model building studies (7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Molecular mechanical simulations on double intercalation of 9-amino acridine into d(CGCGCGC) X d(GCGCGCG): analysis of the physical basis for the neighbor-exclusion principle.

Rao¹,

Kollman²

1987

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

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The neighbor-exclusion principle is one of the most general and interesting rules describing intercalative DNA binding by small molecules. It suggests that such binding can only occur at every other base-pair site, reflecting a very large negative cooperativity in the binding process. We have carried out molecular mechanics and molecular dynamics simulations to study intercalation complexes between 9-amino acridine and the base-paired heptanucleotide d(CGCGCGC) d(GCGCGCG), in which the neighbor-exclusion principle was both obeyed and violated. Our studies find no stereochemical preference that favors the neighbor-exclusion-obeying structures over the neighbor-exclusion-violating structures. Alternative explanations for the existence of the neighbor-exclusion principle are vibrational entropy effects that we calculate to favor the more flexible neighbor-exclusion models over the more rigid neighbor-exclusion-violating models and polyelectrolyte (counterion release) effects.The neighbor-exclusion principle proposed by Crothers (1) is one of the most general rules for intercalative binding of planar drugs to DNA. According to this principle, every second (next-neighbor) intercalation site along the length of the DNA double helix remains unoccupied. Experimental evidence for this principle has been found in fiber diffraction studies on nucleic acid fibers bound to metallointercalative agents (2, 3), in single-crystal studies (4-8) on complexes between dinucleoside monophosphates complexed with intercalating drugs, and solution studies on binding of ethidium ion to oligonucleotides of ribose and deoxyribose sugars (9). Based on earlier crystallographic studies (4-6) that suggested mixed sugar puckering at the intercalation site, a stereochemical basis for the neighbor-exclusion principle was proposed. However, this mixed sugar puckering scheme has not been shown to be essential for creating intercalating sites in double-helical DNA through several crystal structure and model building studies (7-11).The first evidence suggesting violation of the neighborexclusion model was obtained from viscometric studies (12-14) on interactions between bi-and triderivatives of acridine and DNA, where it was suggested that a single base pair was sandwiched between two acridines. 1H NMR studies on the binding of a series of bis(acridine) compounds to d(AT)5d(AT)5, in which the two acridine rings were linked through linker chains of various lengths, found no evidence of violation of the neighbor-exclusion principle (15,16).However, it was also noted that these studies have not ruled out violation of the neighbor-exclusion principle under different salt conditions and temperatures or a different nucleotide sequence (15). It has been postulated (17) that the anticooperativity of ethidium binding to DNA could be explained without reference to the neighbor-exclusion rule and is solely due to polyelectrolyte effects.Why do some simple monofunctional intercalators such as 9-amino acridine not intercalate at neighboring sites and viol...

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“…It may be of interest that a recent study (Neidle, Achari, Berman, Glusker and Stalling 1977) has shown that both proflavine and ethionine bind to the DNA molecule, being inserted into the double helix.…”

Section: "Nodules" (Table 2)mentioning

confidence: 99%

Ultrastructure of chromocentres and the question of the nucleolar organiser in a green alga.

Ashraf

Godward

1982

CYTOLOGIA

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Structure of a dinucleoside phosphate–drug complex as model for nucleic acid–drug interaction

Cited by 114 publications

References 26 publications

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

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

Molecular mechanical simulations on double intercalation of 9-amino acridine into d(CGCGCGC) X d(GCGCGCG): analysis of the physical basis for the neighbor-exclusion principle.

Ultrastructure of chromocentres and the question of the nucleolar organiser in a green alga.

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