STRUCTURAL BASIS FOR SIGNAL TRANSDUCTION BY HEMOPROTEIN SENSORS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。我们的研究重点是了解气体信使如NO， CO和O2如何通过血红蛋白传感器传递信号。我们已经开始通过解决关键含血红素蛋白质的晶体结构来解决这个问题，这些蛋白质要么生物合成信使，要么被它激活。第一个项目是我们在细菌中发现了一种新的祖先一氧化氮合酶（NOS），它像真核酶一样是二聚体，但缺乏锌结合结构域。此外，它们不利用四氢生物蝶呤作为辅助因子。第二个项目涉及可溶性关酰环化酶（sGC）的结构，该酶结合NO并催化GTP转化为cGMP。确定NOS中的电子转移途径和确定NOS-抑制剂相互作用的结构决定因素是第三个项目的基础。nos -辅因子相互作用的结构特征也令人感兴趣。我们的工作重点是阐明NOS结合位点的化学反应性和基于形状的分子识别。第四个项目涉及识别氧如何通过另一个结构域的结构变化与一个结构域结合介导可氧性的分子基础。bNOS， sGC和气动传感器的结构是未知的。

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. The focus of our research is to understand how gaseous messengers such as NO, CO, and O2 transduce signals via hemoprotein sensors. We have begun to address this by solving crystal structures of key heme-containing proteins that either biosynthesize the messenger or get activated by it. The first project is related to our discovery of a novel ancestral nitric oxide synthases (NOS) in bacteria, which like the eukaryotic enzymes are dimeric, but lack the Zn-binding domain. In addition, they do not utilize tetrahydrobiopterin as a cofactor. The second project concerns the structure of soluble guanylyl cyclase (sGC), which binds NO and catalyzes the conversion of GTP to cGMP. Identification of the electron-transfer pathway in NOS and determination of the structural determinants of NOS-inhibitor interactions form the basis of the third project. The structural features of NOS-cofactor interactions are also of interest. We have focused our efforts on elucidating the chemical reactivity and shape-based molecular recognition at work in NOS binding sites. The fourth project deals with identifying the molecular basis of how oxygen binding to one domain mediates aerotaxis via structural changes at another domain. Structures of bNOS, sGC, and the aerotransducer are unknown.