NITROGEN OXIDE MODIFICATIONS OF PROTEIN STRUCTURE AND PROTEIN-PROTEIN INTERACTIO

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 一氧化氮（NO）在神经传递、血压调节和免疫应答等多种生理过程中起着关键作用。NO通过与金属和半胱氨酸巯基结合（S-亚硝化）来修饰蛋白质，以调节酶活性、定位和与其他蛋白质的结合。重要的是，半胱氨酸的S-亚硝基化在血管稳态中起关键作用。HNO是NO的还原同系物，也修饰半胱氨酸硫醇，是心力衰竭的潜在治疗剂。氮氧化物（NO和HNO）调节蛋白质功能的机制在很大程度上尚不清楚。因此，为了阐明NO和HNO在生物学作用中的中心作用，本提议解决以下问题：1）NO诱导可溶性鸟苷酸环化酶（sGC）产生cGMP的活化机制是什么？2)影响蛋白质活性、蛋白质-蛋白质结合和信号转导的变构NO和HNO修饰的结构基础是什么？这些结构分析将为设计用于治疗高血压、心力衰竭、动脉粥样硬化、糖尿病、代谢综合征和血管疾病（阿尔茨海默病？的疾病）与神经退行性后果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Nitric oxide (NO) plays key roles in various physiological processes including neurotransmission, blood pressure regulation and the immune response. NO modifies proteins by binding to metals and cysteine thiol groups (S-nitrosation) to modulate enzyme activity, localization, and association with other proteins. Importantly, S-nitrosation of cysteines plays key roles in vascular homeostasis. HNO, a reduced congener of NO, also modifies cysteine thiols and is a potential therapeutic agent for heart failure. The mechanism by which nitrogen oxides, both NO and HNO, regulate protein function is largely unknown. Therefore, to clarify central roles for NO and HNO in biology roles, this proposal addresses the following questions: 1) What is the mechanism for NO-induced activation of cGMP production by soluble guanylate cyclase (sGC)? 2) What is the structural basis for allosteric NO and HNO modifications that affect protein activity, protein-protein association, and signal transduction? These structural analyses will provide a powerful molecular framework for the design of novel small molecules compounds for the treatment of hypertension, heart failure, atherosclerosis, diabetes, metabolic syndrome, and vascular disorders (Alzheimer?s disease) with neurodegenerative consequences.