与凝血酶结合并抑制其活性的DNA适配体的三级结构决定了其活性。

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

作者信息

Wang K Y, Krawczyk S H, Bischofberger N, Swaminathan S, Bolton P H

机构信息

Chemistry Department, Wesleyan University, Middletown, Connecticut 06459.

出版信息

Biochemistry. 1993 Oct 26;32(42):11285-92. doi: 10.1021/bi00093a004.

DOI:10.1021/bi00093a004

PMID:8218193

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.

摘要

最近通过核磁共振方法确定了与凝血酶结合并抑制凝血酶的DNA适体d(G1G2T3T4G5G6T7G8T9G10G11T12T13G14G15)在溶液状态下的三维结构(Wang等人，1993年)。这种DNA采用高度紧凑、高度对称的结构，由两个鸟嘌呤碱基对四联体和三个环组成。当适体与凝血酶结合时，这种三维结构的基本特征得以保留。该三维结构可作为解释修饰适体相对活性的基础，也可用于提出适体-凝血酶复合物的模型。这项研究还展示了一种药物化学的新方法，即合成多种分子，鉴定出先导分子，先导化合物的结构信息有助于合理设计具有潜在治疗价值的其他化合物。