X-ray crystallographic visualization of drug-nucleic acid intercalative binding: structure of an ethidium-dinucleoside monophosphate crystalline complex, ethidium: 5-iodouridylyl(3'-5')adenosine (drug-nucleic acid interactions/intercalation/double helix unwinding)

Content Provider	Semantic Scholar
Author	Tsai, C.-C. Jain, Shri C. Sobell, Henry M.
Copyright Year	1975
Abstract	We have cocrystallized the drug ethidium bromide with the dinucleoside monophosphate 5-iodouridylyl(3'-5')adenosine and have solved the three-dimensional structure to atomic resolution by x-ray crystallography. This has allowed the direct visualization of intercalative binding by this drug to a fragment of a nucleic acid double helix. Ethidium bromide is one in a class of phenanthridinium drugs that has been found to be useful in the treatment of certain trypanosome infections (1). See Fig. 1. Its medicinal action stems from the ability of the drug to bind to DNA and RNA and to inhibit nucleic acid function (2, 3). The precise nature of ethidium binding to nucleic acids has been the object of study by many workers over the years (3-9). It is generally thought that ethidium binds to DNA (and perhaps to RNA) through intercalation in much the same manner as that postulated for the aminoacridines (10, 11). Evidence for this has been advanced by means of a variety of physical techniques. Viscometric and hydrodynamic measurements with linear DNA molecules indicate a lengthening and stiffening of the helix in the presence of increasing concentrations of the drug (3), an interpretation directly supported by electron microscopic measurements (4). The ability of this drug to unwind circular supercoiled DNA is also considered to be another sensitive criteria for intercalative binding (5, 6). This is thought to reflect unwinding of the DNA helix by the drug at the immediate site of intercalation. The enhancement of fluorescence and a red shift in the ethidium absorption spectrum accompany the binding reaction (7, 8). These spectral perturbations are most easily explained by the stacking of the phenanthridinium ring system on the nucleic acid base pairs. Fiber x-ray diffraction studies have been carried out on the complex, and a tentative molecular model for ethidium-DNA interaction has been proposed (9). We have previously reported the successful cocrystallization of ethidium with several self-complementary dinucleoside monophosphates (12). We have now solved the three-dimensional structure of one of these [ethidium: 5-iodouridylyl(3'-
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