STRUCTURAL BASIS FOR SIGNAL TRANSDUCTION BY HEMOPROTEIN SENSORS

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。 我们研究的重点是了解NO、CO和O2等气体信使是如何通过血红蛋白传感器传递信号的。我们已经开始通过解决含有血红素的关键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。第一个项目是关于我们在细菌中发现的一种新的祖先一氧化氮合酶(NOS)，它和真核酶一样是二聚体，但缺乏锌结合结构域。此外，他们不使用四氢生物蝶呤作为辅因子。第二个项目涉及可溶性鸟苷酸环化酶(SGC)的结构，它与NO结合并催化GTP转化为cGMP。确定一氧化氮合酶中的电子转移途径和确定一氧化氮合酶-抑制剂相互作用的结构决定因素构成了第三个项目的基础。一氧化氮合酶-辅因子相互作用的结构特征也令人感兴趣。我们一直致力于阐明一氧化氮合酶结合部位的化学反应活性和基于形状的分子识别作用。第四个项目涉及确定氧与一个结构域的结合如何通过另一个结构域的结构变化来调节趋氧性的分子基础。Bnos、sgc和空气传感器的结构尚不清楚。

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.