STRUCTURAL BASIS FOR SIGNAL TRANSDUCTION BY HEMOPROTEIN SENSORS

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们研究的重点是了解 NO、CO 和 O2 等气体信使如何通过血红素传感器转导信号。 我们已经开始通过解析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，要么被信使激活。 第一个项目与我们在细菌中发现的一种新型祖先一氧化氮合酶（NOS）有关，它与真核酶一样是二聚体，但缺乏锌结合域。 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鸟苷酸环化酶 (sGC) 的结构，它结合 NO 并催化 GTP 转化为 cGMP。 NOS 中电子转移途径的鉴定和 NOS-抑制剂相互作用的结构决定因素的确定构成了第三个项目的基础。 NOS-辅因子相互作用的结构特征也很有趣。 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。 第四个项目涉及确定氧与一个域结合如何通过另一个域的结构变化介导趋气性的分子基础。 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.