The investigation of the three-dimensional structure of the DNA aptamer d(G1G2T3-T4G5G6T7G8T9G10G11T12T13G14G15) which binds to and inhibits thrombin has been carried out by NMR methods. This DNA exhibits a number of long-range NOEs between residues which are not adjacent in sequence, which allowed the determination of the novel tertiary structure adopted. This DNA adopts a highly compact, highly symmetrical structure which consists of two tetrads of guanosine base pairs and three loops. The residues of the tetrads alternate anti-syn-anti-syn. This novel structural motif for DNA may also be relevant to the structure of telomere DNA.

The solution-state three-dimensional structure of the DNA aptamer d(G1G2T3T4G5G6T7G8T9G10G11T12T13G14G15) which binds to and inhibits thrombin has recently been determined by NMR methods (Wang et al., 1993). This DNA adopts a highly compact, highly symmetrical structure which consists of two tetrads of guanosine base pairs and three loops. The basic features of this three-dimensional structure are preserved when the aptamer binds to thrombin. The three-dimensional structure can be used as a basis for interpreting the relative activities of modified aptamers as well as for proposing a model for the aptamer-thrombin complex. This investigation also provides a demonstration of a novel approach to medicinal chemistry in which a wide range of molecules are synthesized, a lead molecule is identified, and the structural information on the lead compound allows for rational design of additional compounds of potential therapeutic value.

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The presence of dA tracts in DNA can lead to stable curvature of the DNA, and this curvature can be important in gene regulation, DNA packaging, and other processes. Since damage to DNA may eliminate this stable curvature, the solution state structure of the duplex of d(CGCAAAAATGCG) paired with d(CGCATTDTTCCG), with D indicating an abasic site, has been determined. The undamaged DNA bends into the major groove both in solution and in the crystal state. The presence of the abasic site in the dA tract region induces changes in the DNA structure up to four base pairs away from the damaged site. The structure of the DNA is dependent on whether the abasic site is in the alpha or beta hemiacetal form. These consequences are quite different from the more localized effects that have been observed for "normal" DNAs containing abasic sites. Thus, there appears to be a strong sequence dependence of the structural effects of abasic sites just as there is for undamaged DNA. Furthermore, these results indicate that the presence of an abasic site can alter DNA bending and hence is likely to have significant long range effects on gene regulation and other properties that are dependent on the stable curvature of DNA.

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