Stereochemistry of actinomycin binding to DNA

Sobell, Henry M.; Jain, Shri C.

doi:10.1016/0022-2836(72)90259-8

Cited by 385 publications

(101 citation statements)

References 25 publications

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“…This is at variance with the prediction of the model developed for the actinomycin . DNA complex by Sobell and Jain [29]. They proposed that hydrogenbonding interactions between a peptide ring and a G .…”

Section: Implications For Actinomycin Specificitymentioning

confidence: 99%

Interactions of Heteroaromatic Compounds with Nucleic Acids

Müller

Crothers

1975

European Journal of Biochemistry

359

188

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We have examined the origins of base specificity in intercalating ligands by studying the interaction with DNA of a series of proflavine and acridine orange analogs differing in the heteroatoms present in the chromophore. Base specificity was determined by differential dialysis of the dye against DNA samples of differing G . C content. We find that G . C specificity increases as the visible absorbance band of the chromophore moves to longer wavelength, implying a relation between specificity and polarizability of the chromophore. This can be rationalized by recognizing that the G . C pair is more polar than A . T, and should therefore interact more favorably with an easily polarized ring system.We find in addition that dimethylation of the chromophore amino groups increases specificity which we discuss in terms of steric and coupled steric-electronic contributions.Our results also bear on the origin of G . C specificity in binding actinomycin to DNA. Some of the compounds studied are as G . C specific as actinomycin, yet they lack hydrogen-bonding functions as plausible determinants of specificity. This observation gives new life to the hypothesis that the specificity of actinomycin is determined primarily by preferential interaction of the chromophore with a G . C pair.It has long been known that many small, positively charged molecules interact with nucleic acids; these compounds have been widely used for analytical, diagnostic and therapeutic purposes. Of special importance in this regard are planar, heterocyclic molecules, including many natural and synthetic dyestuffs [I]. In this series of papers we address ourselves to an important but relatively neglected aspect of their interaction with DNA, namely the nature and origin In this paper we report a systematic examination of the influence of heteroatoms X and Y on the base and sequence specificity of DNA ligands of the type I. The starting point for this series of experiments was the observation of Muller and Crothers [4] that Eur.

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Section: Implications For Actinomycin Specificitymentioning

confidence: 99%

Interactions of Heteroaromatic Compounds with Nucleic Acids

Müller

Crothers

1975

European Journal of Biochemistry

359

188

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“…Similarly, the metaphase chromosomes (Caspersson et al, 1969a; biological effects of a wide variety of drugs, such as 1969b). There is also a strong medical interest in antibiotic, anticancer, and antimalarial (Miiller and chemical mutagens, for mutations appear to contrib- Crothers, 1968;Sobell and Jain, 1972;Pigram et al, ute significantly to the causes of several serious dis-1972; OBrien et al 1966), as well as those of aromatic eases (Childs et al, 1972) as well as to aging (Burnet, carcinogens (Craig and Isenberg, 1970) have their pri-1974). 59 The purpose of this paper is to review the present state of our knowledge regarding the interaction with DNA as well as to evaluate the importance of the results of recent experiments which employ complexes of the drugs with the monomeric building blocks of nucleic acids as model systems.…”

Section: Introductionmentioning

confidence: 99%

Interaction of Acridine Drugs With Dna and Nucleotides

Georghiou

1977

Photochem & Photobiology

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Abstract-At high phosphate-to-drug ratios acridine drugs intercalate between hydrogen bonded DNA base pairs causing significant changes in the physico-chemical properties of DNA. The determination of the nature of the strong (or primary) interaction between acridine drugs and DNA is of great importance for elucidating the mode of the biological action of the drugs.Nanosecond measurements have revealed a fast depolarization of the fluorescence of proflavine, one of the most extensively studied acridines, bound to DNA. The electronic structure of the complex, however, is not substantially altered during the lifetime of the excited singlet electronic state of the drug. Guanine has been shown to be responsible for the quenching of the proflavine fluorescence upon binding to DNA. A temperature-jump relaxation study has demonstrated a rather external complexation of this drug with the G-C base pairs; this complex, whose formation occurs in the strong binding region, is distinct from the weak electrostatic complex.The findings that the binding ability of a series of acridines correlates with their basicity and that the drug-binding behavior of methylated DNA is significantly different from that of DNA suggested that specific forces may be also involved in the drug-DNA binding in addition to hydrophobic forces. Recent experiments employing molecular complexes of acridines with nucleotides as model systems have provided strong support for the specificity of the drug-DNA interaction. Hydrogen bonding between the drug and reactive groups of the DNA bases that do not contribute directly to the stability of the helix may be involved in that interaction.The stoichiometry of the proflavine-guanosine 5'-phosphate complex is 1 : 1. Its association constant increases from 310 M -' , when proflavine is in its ground electronic state, to 1550 M -' , when proflavine is in its first excited singlet state. Thus, light absorbed by the drug alters its reactivity which, in turn, results in an appreciable increase in its ability to bind to the nucleotide. In view of the proposed importance of the drug-base interaction in explaining the mutagenic properties of acridine drugs and, in particular, of the proposed involvement of the G-C base pairs, this finding emphasizes the possible importance of drug photoexcitation in acridine mutagenesis; it also contributes to the elucidation of photodynamic action.X-ray diffraction studies have recently provided very interesting demonstrations of strong binding of 9-aminoacridine and of the phenanthridine drug ethidium bromide to adenine-uracil base pairs in the crystalline phase.The ability of photoexcited acridine drugs to inactivate viruses has been recently used for therapeutic purposes. The carcinogenic risk involved, however, is still under investigation.

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“…The information obtained from this study suggested a model to understand the general features of how actinomycin binds to DNA (8)(9)(10)(11). According to this model, the phenoxazone ring system on actinomycin intercalates between adjacent base pairs, while pentapeptide chains lie in the narrow groove of the B helix and form hydrogen bonds [in the case of d(pGpC) sequences] with guanine residues on opposite chains.…”

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confidence: 99%

Actinomycin and DNA transcription.

Sobell¹

1985

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

468

278

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Recent advances in understanding how actinomycin binds to DNA have suggested its mechanism of action. Actinomycin binds to a premelted DNA conformation present within the transcriptional complex. This immobilizes the complex, interfering with the elongation of growing RNA chains. The model has a number of implications for understanding RNA synthesis.Understanding the mechanism ofaction ofactinomycin D has long been a major goal in cancer research and in molecular biology. Actinomycin is a cyclic polypeptide-containing antibiotic that binds to DNA and inhibits RNA synthesis (1)(2)(3)(4) Here, I propose a modification to our actinomycin-DNA binding model that allows one to understand its mechanism of action. I propose that actinomycin binds to a premelted DNA conformation-called /3-DNA-found within the transcriptional complex. This acts to immobilize (or pin) the complex, preventing the elongation of growing RNA chains. The model has implications for understanding the early melting behavior of DNA and, along with this, suggests a mechanism to understand the formation of the RNA polymerase-promoter tight binding complex. Other possible implications are discussed.Actinomycin-DNA Binding Model. Fig. la summarizes key structural features of my model to understand how actinomycin binds to DNA.As in our earlier model, the phenoxazone ring system on actinomycin intercalates between (base paired) dinucleotide sequences of the type d(pGpX) (where X = C, T, A, or G), while pentapeptide chains lie in the narrow groove of the structure, hydrogen bonding [in the case of d(pGpC) sequences] to guanine residues on opposite chains. Although

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Stereochemistry of actinomycin binding to DNA

Cited by 385 publications

References 25 publications

Interactions of Heteroaromatic Compounds with Nucleic Acids

Interactions of Heteroaromatic Compounds with Nucleic Acids

Interaction of Acridine Drugs With Dna and Nucleotides

Actinomycin and DNA transcription.

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