CRYSTALLOGRAPHIHC STUDIES ON THE NITRIC OXIDE SYNTHASES

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。 一氧化氮合酶 (NOS) 是一类含血红素和黄素的酶，可催化 L-精氨酸形成一氧化氮。哺乳动物中三种不同 NOS 亚型产生的 NO 与多种生理功能和病理状况有关。异构体选择性 NOS 抑制剂的开发对于阻断病理环境下主要由神经元和/或诱导型 NOS 产生的 NO 过量产生具有治疗重要性，同时维持内皮 NOS 产生的 NO 的血管调节作用。三种 NOS 亚型的晶体结构揭示了高度相似的底物结合血红素活性位点。 NOS 活性位点的结构相似性使得异构体选择性抑制剂的搜索成为一项具有挑战性的任务。在提取有用信息之前，需要对各种结合配体进行广泛的结构表征。然后，结构知识可用于设计具有更好抑制效力和/或亚型选择性的新化合物。该提案的扩展对于这项研究的继续至关重要。

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. Nitric oxide synthases (NOS) are a family of heme- and flavin-containing enzymes that catalyze the NO formation from L-arginine. NO produced by three different NOS isoforms in mammals has been implicated in a wide range of physiological functions as well as pathological conditions. Development of isoform-selective NOS inhibitors is of therapeutic importance in blocking the NO overproductions mainly by neuronal and/or inducible NOS under the pathological settings while maintaining the vascular regulatory role of NO generated by endothelial NOS. Crystal structures of three NOS isoforms revealed a highly resembled substrate-binding heme active site. The structural similarity of the NOS active site makes the search of isoform selective inhibitors a challenging task. Extensive structural characterizations of a variety of bound ligands are required before useful information can be extracted. The structural knowledge can then be used in design of new compounds that bear better inhibitory potency and/or isoform selectivity. Extension of this proposal is vital to the continuation of this research.