Investigation of Nitric Oxide Synthase Structure, Function and Inhibition

一氧化氮合酶结构、功能及抑制作用的研究

• 批准号: RGPIN-2017-04007
• 负责人: Guillemette, Joseph
• 金额: $ 1.89万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630021
• 关键词: Investigation; Nitric; Oxide; Synthase; Structure

Nitric oxide (NO) is an important endogenous messenger in a variety of physiological and pathophysiological processes. NO is synthesized by the three isoforms of nitric oxide synthase (NOS) that are encoded by different genes, neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). The dual role of NO in the body as a second messenger or cytotoxic agent shows the importance for tight regulation of the different NOS isoforms. Each subunit of NOS is composed of a reductase domain that contains the binding sites for NADPH, and two flavins as well as an oxygenase domain that contains the binding sites for heme, L-arginine and tetrahydrobiopterin. The two domains are linked by a calmodulin (CaM) binding domain that plays an important role in the activation of the enzyme. CaM is the primary protein mediator of the calcium cation that is also an important secondary messenger. CaM undergoes calcium-dependent conformational changes that allow it to bind and activate scores of target proteins including all three NOS isozymes. Two of the long-term goals of this research program are to: 1) understand the mechanism(s) of CaM binding and control for all three NOS isozymes; 2) study the selective ligand binding and inhibition of human NOS isozymes.

一氧化氮（NO）是多种生理和病理生理过程中重要的内源性信使。 NO 由一氧化氮合酶 (NOS) 的三种亚型合成，这三种亚型由不同基因编码：神经型 (nNOS)、内皮型 (eNOS) 和诱导型 (iNOS)。 NO 在体内作为第二信使或细胞毒剂的双重作用表明了严格调节不同 NOS 亚型的重要性。 NOS 的每个亚基均由一个包含 NADPH 结合位点的还原酶结构域、两个黄素以及一个包含血红素、L-精氨酸和四氢生物蝶呤结合位点的加氧酶结构域组成。这两个结构域通过钙调蛋白 (CaM) 结合结构域连接，该结合结构域在酶的激活中发挥重要作用。 CaM 是钙阳离子的主要蛋白质介体，也是重要的第二信使。 CaM 经历钙依赖性构象变化，使其能够结合并激活多种靶蛋白，包括所有三种 NOS 同工酶。该研究计划的两个长期目标是：1) 了解 CaM 结合和控制所有三种 NOS 同工酶的机制； 2）研究人NOS同工酶的选择性配体结合和抑制。