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

基本信息

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

项目摘要

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修饰酶的功能和构象性能，催化tRNA中碱基的交换反应，通过使用组合化学的概念在Awell计划的策略中合成的化学探针进行研究。这个酶家族的不同成员起源于生命的三个王国，依靠偏离substrates的范围。通过蛋白质的构象适应和配体结合中水分子的侵入的底物识别差异。使用特定抑制剂的使用Well-Tail-Tail-Tail-Tail-Tail-Tailblethrough组合合成，我们希望解决各种构象状态，这些构象状态表现出与这些酶的功能性作用密切相关的底物识别的令人惊讶的呈现性。 Shigellaflexneri的蛋白质已被视为鉴定抗生素疗法的靶标，因此潜在铅可能会为随后的药物开发计划提供服务。目前的研究普罗帕萨具有化学合成，分子建模，X射线晶体学，定位型造成作用和分子动力学模拟的联合方法，以使该酶类别成员之间的不同声音状态访问该酶类成员的特定分子探针，以实现其功能作用。它们将有助于提出酶特性，特别是针对适应性和底物特异性。