Metalloenzyme Structure and Function

描述（由申请人提供）：我们的长期目标是加强我们对金属蛋白结构，功能和抑制的理解。我们将使用理论化学、计算化学和药物化学的工具。本提案的长期目标是利用这些技术来了解锌（和镁）依赖的硫烷基化酶家族的结构、功能和抑制作用，称为蛋白质戊烯基转移酶。特别是，我们将使用量子力学（QM）， QM/分子力学（MM），分子动力学模拟，基于QM的X射线细化和对接/评分研究来研究法尼基转移酶（FTase）和香叶基转移酶I型（GGTase）。我们正在解决的首要生物学问题是锌催化蛋白质烯酰化的催化机制，以及如何抑制这一过程以产生与癌症治疗以及其他疾病相关的化合物。为了达到这一重要的生物学目标，我们建议使用我们的理论工具来研究小分子/酶的相互作用以及这些锌催化酶反应的机制。为了提高我们计算工作的质量，我们正在与FTase和GGTase的结构、功能和抑制方面的专家合作。我们的实验合作者将协助进行基于QM/MM的x射线细化研究，将根据我们的计算观察产生突变酶以测试我们的模型，将对我们鉴定和购买的新型小分子抑制剂进行结合试验，并将合成我们提出的新化合物。随着拟议项目的成功完成，我们将产生机制见解，这将转化为设计新的FTase和GGTase抑制剂，可以作为人类癌症的治疗方法进行测试。

DESCRIPTION (provided by applicant): Our long-term goal is to enhance our understanding of metalloprotein structure, function and inhibition. The tools we will use are those of theoretical, computational and medicinal chemistry. The long-term goal of the present proposal is to use these techniques to understand the structure, function and inhibition of the family of zinc (and magnesium) dependent sulfur alkylation enzymes called protein prenyltransferases. In particular, we will be study farnesyltransferase (FTase) and geranylgeranyltransferase type I (GGTase) using quantum mechanical (QM), QM/molecular mechanical (MM), molecular dynamics simulations, QM based X- ray refinement and docking/scoring studies. The overarching biological question we are addressing is the catalytic mechanism of zinc catalyzed protein prenylation and how this process can be inhibited to generate compounds relevant to cancer treatment, as well as other diseases. To reach this important biological goal we propose to study small molecule/enzyme interactions and the mechanism of these zinc catalyzed enzyme reactions using our theoretical tools. In order to enhance the quality of our computational efforts we are collaborating with experimentalists who are expert in the structure, function and inhibition of FTase and GGTase. Our experimental collaborators will assist in QM/MM based X-ray refinement studies, will generate mutant enzymes based on our computational observation in order to test our models, will carry out binding assays on novel small molecule inhibitors we identify and purchase and will synthesize novel compounds we propose. With the successful completion of the proposed project we will have generated mechanistic insights that will be translated into the design of novel inhibitors of FTase and GGTase that can be tested as treatment for human cancer.