STRUCTURAL BASIS OF CELLULAR SIGNALING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们正在提议进行与血管生物学和免疫缺陷广泛相关的尖端结构研究。我们将继续对前列环素(PS)和血栓素合成酶(TS)进行结晶学研究，以更好地了解血管内皮细胞如何介导血管扩张剂和血管收缩剂的生物合成。这项研究对于更好地了解万络和西乐等药物如何减少前列环素的产生也很重要。此外，PS是落建有效成分米诺地尔的靶标。我们还计划将从我们对PS和TS的研究中获得的结构信息与丙二烯氧化物合成酶(AOS)相结合，以提供关于血红素蛋白如何利用内源和氢过氧化氢底物的整体观点。此外，通过询问CYP8B1的结构，我们将能够为新的功能如何从先前存在的细胞色素P450模板进化提供分子基础，并获得对胆结石形成的见解。在免疫缺陷方面，我们将确定激活诱导脱氨酶(AID)的结构，它与DNA和其他蛋白质的复合体。我们还将探索属于G蛋白偶联受体超家族的趋化因子受体。

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. We are proposing cutting-edge structural studies that are broadly relevant to vascular biology and immune deficiency. We will pursue crystallographic investigations on prostacyclin (PS) and thromboxane synthases (TS) to better understand how vasodilator and vasoconstrictor biosynthesis is mediated in vascular endothelial cells. This study is also important for gaining a better understanding of how drugs like Vioxx¿ and Celebrex¿ diminish prostacyclin production. Furthermore PS is a target for minoxidil ¿ the active ingredient of Rogaine¿. We also plan to combine the structural information obtained from our studies on PS and TS with allene oxide synthase (AOS) to provide a holistic view of how heme proteins utilize endo- and hydroperoxide substrates. Furthermore, by interrogating the structure of CYP8B1 ¿sterol 12alpha hydroxylase¿ we will be able to provide a molecular basis for how novel functions evolve from preexisting cytochromes P450 templates and also gain insights into gallstone formation. On the immunodeficiency front we will determine the structure of activation-induced deaminase (AID), its complexes with DNA and other proteins. We will also probe chemokine receptors that belong to the G-protein couple receptor superfamily.