NITROGEN OXIDE MODIFICATIONS OF PROTEIN STRUCTURE AND PROTEIN-PROTEIN INTERACTIO

蛋白质结构和蛋白质-蛋白质相互作用的氮氧化物修饰

• 批准号: 8362206
• 负责人: ELSA GARCIN
• 金额: $ 0.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362206
• 关键词: Address; Affect; Alzheimer' s Disease; Atherosclerosis; Biology; Blood Vessels; Cysteine; Diabetes Mellitus; Funding; Grant; Heart failure; Homeostasis; Immune response; Metabolic syndrome; Metals; Modification; Molecular; National Center for Research Resources; Nerve Degeneration; Nitric Oxide; Nitrogen Oxides; Nitrosation; Physiological Processes; Play; Principal Investigator; Protein Binding; Proteins; Radiation; Research; Research Infrastructure; Resources; Role; Signal Transduction; Soluble Guanylate Cyclase; Source; Sulfhydryl Compounds; Therapeutic Agents; United States National Institutes of Health; Vascular Diseases; base; blood pressure regulation; cGMP production; cost; design; enzyme activity; hypertension treatment; neurotransmission; novel; protein function; protein structure; small molecule; structural biology

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 一氧化氮（NO）在各种生理过程中起关键作用，包括神经传递，血压调节和免疫反应。没有通过与金属和半胱氨酸硫醇基（S-硝化）结合来调节酶活性，定位和与其他蛋白质的关联来修饰蛋白质。重要的是，半胱氨酸的S-硝化在血管稳态中起关键作用。 HNO是NO的降低者，也修饰了半胱氨酸硫醇，并且是心力衰竭的潜在治疗剂。 NO和HNO调节蛋白质功能的氮氧化物的机制在很大程度上未知。因此，为了阐明NO和HNO在生物学角色中的中心作用，该提案解决了以下问题：1）1）可溶性鸟苷酸环化酶（SGC）无诱导CGMP产生的CGMP激活的机制是什么？ 2）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新型小分子化合物的设计提供强大的分子框架，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（阿尔茨海默氏病）与神经退行性后果。