NITROGEN OXIDE MODIFICATIONS OF PROTEIN STRUCTURE AND PROTEIN-PROTEIN INTERACTIO

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（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发挥着关键作用。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)变构NO和HNO修饰影响蛋白质活性、蛋白质-蛋白质结合和信号转导的结构基础是什么？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. 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 (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.