CRYSTALLOGRAPHIC STUDIES ON CYTOCHROME P450

这个项目的长期目标是研究结构-功能 细胞色素P-450及其相关蛋白的X射线分析 结晶学、分子生物学和生物化学。唯一已知的 P-450的晶体结构为P-450cam。此外，该结构 几种底物和缓蚀剂复合体加上一个突变结构 都是已知的。这些信息将用于指导设计， 基因定位变异体的生产和结构测定 探讨P-450作用机制的目的及新型药物的设计 P-450催化剂。从这些先前的研究中已知的也将是 用于设计P-450凸轮的抑制剂，以开发一个模型 合理设计实用的P-450治疗剂。这些将是 并测定了它们的结合常数和晶体结构。 测定了P-450CaM-抑制剂络合物。 研究新的P-450和相关蛋白质的工作也将继续进行。在……里面 特别是使脂肪酸羟化的P-45OBM-3酶。这 P-450含有血红素结构域和FAD/FMN P450还原酶结构域 在单一的多肽链中。序列比较还表明， 这株细菌P-450是研究真核生物P-450的良好模型。水晶 整个蛋白质及其结构域的结构将被确定。 其他结晶学项目包括一种P-450，它可以去甲基化 芳香族甲氧基酸(P-450RR1)与芳樟醇羟基酶 (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专一性和 P-450中蛋白质间的电子转移反应。来自这些的结果 研究也应该在P-450的设计中具有实际意义 作为有用治疗药物的抑制剂和新型药物的设计 羟基酶。

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.