Aminoglycoside binding to the hammerhead ribozyme: A general model for the interaction of cationic antibiotics with RNA
Aminoglycoside binding to the hammerhead ribozyme: A general model for the interaction of cationic antibiotics with RNA
复制标题
DOI：
10.1006/jmbi.1997.1590
复制
发表时间：
1998-03-13
影响因子：
5.6
通讯作者：
Westhof, E
中科院分区：
文献类型：
--
作者：
Hermann, T;Westhof, E
多种药物通过与特定RNA成分结合来抑制生物关键过程。在这里，我们专注于分析锤头状核酶RNA被抑制的氨基糖苷类抗生素，一个过程被认为是一个范例，研究药物/RNA相互作用。从分子动力学模拟中获得的洞察力的核酶在Mg 2+的存在下，通过晶体学和氨基糖苷类化合物在溶液中，氨基糖苷类化合物结合到RNA的一般模型提出。一个惊人的基于结构的互补性之间的氨基糖苷类和金属结合位点的锤头带电荷的铵基团被发现。尽管动态灵活的氨基糖苷类药物，几个带电荷的铵基团的药物之间的分子内距离被发现是相当恒定的。氨基糖苷类的分子内铵距离的跨度范围类似于锤头状的Mg 2+之间的离子距离。氨基糖苷类与锤头状核酶的成功对接可以通过将铵基团定位在Mg 2+占据的位点来实现。因此，氨基糖苷类的共价连接的铵基团能够在空间中补充由三维RNA折叠产生的负静电势。因此，它建议，氨基糖苷衍生的糖可以构成一个基本的一套理想的理性和组合合成的药物靶向在生物相关的RNA折叠的标准的化合物。(C)出版社：Academic Press Limited。
A variety of drugs inhibit biological key processes by binding to a specific RNA component. We focus here on the well-analysed hammerhead ribozyme RNA that is inhibited by aminoglycoside antibiotics, a process considered as a paradigm for studying drug/RNA interactions. With insight gained from molecular dynamics simulations of the ribozyme in the presence of Mg2+ identified by crystallography and of aminoglycosides in solution, a general model for aminoglycoside binding to RNA is proposed. A striking structurally based complementarity between the charged ammonium groups of the aminoglycosides and the metal binding sites in the hammerhead was uncovered. Despite dynamical flexibility of the aminoglycosides, several of the intramolecular distances between the charged ammonium groups of the drugs were found to be rather constant. Intramolecular ammonium distances of the aminoglycosides span ranges similar to the interionic distances between Mg2+ in the hammerhead. Successful docking of aminoglycosides to the hammerhead ribozyme could be achieved by positioning the ammonium groups at the sites occupied by Mg2+. The covalently linked ammonium groups of the aminoglycosides are thus able to complement in space the negative electrostatic potential created by a three-dimensional RNA fold. Consequently, it is suggested that aminoglycoside-derived sugars could constitute a basic set of yardstick synthons ideal for rational and combinatorial synthesis of drugs targeted at biologically relevant RNA folds. (C) 1998 Academic Press Limited.