CRYSTALLOGRAPHIHC STUDIES ON THE NITRIC OXIDE SYNTHASES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。一氧化氮合酶是一类含血红素和黄素的酶，催化L-精氨酸生成NO。在哺乳动物中，由三种不同的一氧化氮合酶亚型产生的NO参与了广泛的生理功能和病理状态。开发具有异构体选择性的一氧化氮合酶抑制剂，在维持内皮型一氧化氮合酶对血管的调节作用的同时，主要通过神经元型和/或诱导型一氧化氮合酶在病理环境下阻断一氧化氮的过度产生，具有重要的治疗意义。三种一氧化氮合酶亚型的晶体结构显示了一个高度相似的底物结合的血红素活性部位。一氧化氮合酶活性部位的结构相似性使得寻找异构体选择性抑制剂成为一项具有挑战性的任务。在提取有用的信息之前，需要对各种结合配体进行广泛的结构表征。然后，结构知识可以用于设计具有更好的抑制效力和/或异构体选择性的新化合物。这一建议的推广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.