Specific Inhibition of an Conformationally Flexible t-RNA Modifying Enzyme by Ligands Synthesized by Combinatorial Chemistry

组合化学合成的配体对构象灵活的 t-RNA 修饰酶的特异性抑制

• 批准号: 14577246
• 负责人: Professor Dr. Gerhard Klebe
• 金额: --
• 依托单位: Institut für Pharmazeutische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2005
• 资助国家: 德国
• 起止时间: 2004-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/14577246?language=en
• 关键词: Specific; Inhibition; Conformationally; Flexible; RNA

The functional and conformational properties of tRNA modifyingenzymes, catalyzing the exchange reaction of bases in tRNA,will be studied by chemical probes synthesized in awell-planned strategy using the concepts of combinatorialchemistry. Different members of this enzyme family originatingfrom the three kingdoms of life operate on deviating ranges ofsubstrates. The differences in substrate recognition areachieved by conformational adaptations of the proteins and theinvolvement of a water molecule in ligand binding. Usingwell-tailored libraries of specific inhibitors, accessiblethrough combinatorial synthesis, we want to address thedifferent conformational states that demonstrate a surprisingversatility of substrate recognition intimately related to thefunctional role of these enzymes. The protein from Shigellaflexneri has been characterized as a target for a specificantibiotics therapy, thus potential leads could possibly servefor a subsequent drug development program. The present researchproposal uses a combined approach of chemical synthesis,molecular modeling, X-ray crystallography, site-directedmutagenesis and molecular dynamics simulations to give accessto specific molecular probes which address differentconformational states among the members of this enzyme class,required to accomplish their functional role. They will help tounderstand the enzymatic properties, in particular with respectto adaptability and substrate specificity.

tRNA修饰酶催化tRNA中碱基交换反应的功能和构象性质，将利用组合化学的概念，通过精心策划的策略合成的化学探针进行研究。这个酶家族的不同成员来自生命的三个王国，它们在不同范围的底物上起作用。底物识别的差异是通过蛋白质的构象适应和参与配体结合的水分子来实现的。使用精心定制的特定抑制剂文库，通过组合合成可获得，我们希望解决不同的构象状态，这些构象状态显示出与这些酶的功能作用密切相关的底物识别的惊人多功能性。从志贺氏菌中提取的蛋白质被认为是一种特殊抗生素治疗的靶标，因此潜在的线索可能为后续的药物开发计划服务。本研究计划采用化学合成、分子建模、x射线晶体学、位点定向诱变和分子动力学模拟相结合的方法来获得特定的分子探针，这些探针可以处理该酶类成员之间的不同构象状态，以完成其功能作用。它们将有助于理解酶的性质，特别是在适应性和底物特异性方面。