CRYSTALLOGRAPHIC STUDIES ON CYTOCHROME P450

本项目的长期目标是研究结构-功能 细胞色素P-450与相关蛋白质的关系 晶体学、分子生物学和生物化学。 唯一已知的 P-450的晶体结构是P-450 cam的晶体结构。 且结构 几种底物和抑制剂复合物加上一种突变结构 是已知的。 这些信息将用于指导设计， 的定点变体的生产和结构测定。 目的探讨P-450的作用机制，并设计新型的 P-450催化剂 从这些先前的研究中所知道的也将是 用于设计P-450 cam的抑制剂，以便为 合理设计有用的P-450治疗剂。 这些将是 合成和结合常数和晶体结构的 测定P-450 cam-抑制剂复合物。 新的P-450和相关蛋白质的研究也将继续进行。 在 特别是使脂肪酸羟基化的P-45 OBM-3酶。 这 P-450含有血红素结构域和FAD/FMN P450还原酶结构域 在一条多肽链中。 序列比较还表明， 该细菌P-450是真核P-450的良好模型。 晶体 将确定整个蛋白质及其结构域的结构。 其他晶体学项目包括P-450， 芳香族甲氧基酸（P-450 RR 1）和芳樟醇羟化酶 （P-450lin）。 所有这些项目的共同主题是更好地 了解什么结构特征控制底物特异性， P-450中的蛋白质间电子转移反应。 从这些 这些研究还应该对P-450的设计具有实际意义 抑制剂作为有用的治疗剂和设计新的 羟化酶

The long range goal of this project is to study structure-function relationships in cytochromes P-450 and related proteins using x-ray crystallography, molecular biology, and biochemistry. The only known P-450 crystal structure is that of P-450cam. In addition, the structure of several substrate and inhibitor complexes plus one mutant structure are known. This information will be used to guide the design, production, and structure determination of site-directed variants for the purpose of probing the mechanism of P-450 action and the design of novel P-450 catalysts. What is known from these previous studies also will be used to design inhibitors of P-450cam in order to develop a model for the rational design of useful P-450 therapeutic agents. These will be synthesized and the binding constants and crystal structures of the P-450cam-inhibitor complexes determined. Work also will continue on new P-450s and related proteins. In particular is the P-45OBM-3 enzyme which hydroxylates fatty acids. This P-450 contains both the heme domain and the FAD/FMN P450 reductase domain in a single polypeptide chain. Sequence comparisons also indicate that this bacterial P-450 is a good model for eukaryotic P-450s. The crystal structure of the entire protein and its domains will be determined. Other crystallographic projects include a P-450 which demethylates aromatic methoxy acids (P-450RR1) and the linalool hydroxylase (P-450lin). The common theme of all these projects is to better understand what structural features control substrate specificity and inter-protein electron transfer reactions in P-450s. Results from these studies should also have practical relevance in the design of P-450 inhibitors as useful therapeutic agents and the design of novel hydroxylases.