Structure-Guided Designing Pre-Organization in Bivalent Aptamers
Structure-Guided Designing Pre-Organization in Bivalent Aptamers
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DOI：
10.1021/jacs.1c12593
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发表时间：
2022-03-16
影响因子：
15
通讯作者：
Zuo, Hua
中科院分区：
文献类型：
--
作者：
Hu, Xiaoli;Tang, Linlin;Zuo, Hua
多价相互作用常用于分子设计，并导致工程多价配体与目标分子的结合能力增加。由此产生的结合亲和度主要依赖于连接多个配体的刚性支架，因为支架控制着靶分子的相对空间位置和方向。目前，没有通用的设计规则来构建一个简单而刚性的DNA支架来正确地连接多个配体。在此，我们报告了一种晶体结构引导策略，用于合理设计刚性二价适配体，并精确控制空间分离和取向。这样的预组织允许两个适体片段同时以其天然构象与目标蛋白结合。二价适体结合已被广泛地表征，并且明显地观察到一种增强的结合。我们相信，这种策略可能普遍适用于设计多价适体。
Multivalent interaction is often used in molecular design and leads to engineered multivalent ligands with increased binding avidities toward target molecules. The resulting binding avidity relies critically on the rigid scaffold that joins multiple ligands as the scaffold controls the relative spatial positions and orientations toward target molecules. Currently, no general design rules exist to construct a simple and rigid DNA scaffold for properly joining multiple ligands. Herein, we report a crystal structure-guided strategy for the rational design of a rigid bivalent aptamer with precise control over spatial separation and orientation. Such a pre-organization allows the two aptamer moieties simultaneously to bind to the target protein at their native conformations. The bivalent aptamer binding has been extensively characterized, and an enhanced binding has been clearly observed. This strategy, we believe, could potentially be generally applicable to design multivalent aptamers.