The tertiary structure of a DNA aptamer which binds to and inhibits thrombin determines activity

Abstract

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.