CRYSTALLOGRAPHIHC STUDIES ON THE NITRIC OXIDE SYNTHASES

一氧化氮合酶的晶体学研究

• 批准号: 8169925
• 负责人: HUIYING LI
• 金额: $ 0.27万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169925
• 关键词: Active Sites; Arginine; Binding; Blood Vessels; Computer Retrieval of Information on Scientific Projects Database; Development; Enzymes; Family; Flavins; Funding; Grant; Heme; Institution; Knowledge; Ligand Binding; Mammals; Neurons; Nitric Oxide Synthase; Physiological; Protein Isoforms; Research; Research Personnel; Resources; Role; Source; Structure; Therapeutic; United States National Institutes of Health; Ursidae Family; design; human NOS2A protein; human NOS3 protein; inhibitor/antagonist

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 一氧化氮合酶（NOS）是一类催化L-精氨酸生成NO的酶。在哺乳动物中，由三种不同的NOS同工型产生的NO与广泛的生理功能以及病理条件有关。亚型选择性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过度产生NO，同时维持内皮NOS产生的NO的血管调节作用具有重要的治疗意义。三种NOS异构体的晶体结构揭示了一个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，需要对各种结合的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。扩大这一建议对继续进行这项研究至关重要。