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这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 (1)真核细胞色素P450（P450）是一种普遍存在的膜酶，催化大量外源性和内源性化合物的单加氧。这些反应包括清除环境毒素和致癌物的途径，甾醇、类固醇和前列腺素类的合成，以及在某些情况下化学致癌物的代谢活化。大量的实验室研究微粒体P450，并将大大受益于结构模型。我们建议：1）继续对哺乳动物P450进行更高分辨率的晶体学研究，以进一步表征膜|附着表面，2）以确定当底物结合和复合物还原时蛋白质结构发生的变化，和3）将结晶方法扩展到相关的药理学目的微粒体P450。在这些研究中确定的结构将解决有关蛋白质与膜的相互作用以及底物结合和识别的问题。此外，这些研究将产生重要的膜结合模式的新信息，并可能有助于推进膜蛋白的结构研究工程背后的方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. (1) Eukaryotic cytochromes P450 (P450s) are ubiquitous, integral membrane enzymes that catalyze the mono-oxygenation of a large number of both exogenous and endogenous compounds. These reactions include pathways for the purging of environmental toxins and carcinogens, the synthesis of sterols, steroids and prostanoids and, in some cases, the metabolic activation of chemical carcinogens. A large number of laboratories study microsomal P450s and will benefit greatly from a structural model. We propose 1) to continue crystallographic studies of mammalian P450s to higher resolution in order to further characterize the membrane |attachment surface, 2) to determine what changes occur in the structure of the protein when substrate binds and the complex is reduced, and 3) to extend the crystallization methodology to related microsomal P450s of pharmacological interest. The structures to be determined in these studies will address questions about the interaction of the protein with the membrane as well as substrate binding and recognition. In addition, these studies will yield significant new information regarding modes of membrane binding, and may help to advance the methodology behind the engineering of membrane proteins for structural studies.