Deciphering the relationship between structure, dynamics and function in helical bundle proteins

解读螺旋束蛋白的结构、动力学和功能之间的关系

• 批准号: 10406742
• 负责人: WILLIAM DEGRADO
• 金额: $ 66.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406742
• 关键词: Alkali Metals; Amantadine; Amantadine resistance; Amino Acids; Binding Proteins; Computing Methodologies; Coronavirus; Crystallography; Drug Design; Future; Hydration status; Influenza; Influenza A virus; Ion Channel; Ions; Membrane; Membrane Proteins; Metalloporphyrins; Movement; Nutrient; Pathway interactions; Pharmaceutical Preparations; Protein Engineering; Proteins; Protons; Stretching; Structure; Testing; Therapeutic; Viral; Virus; Water; Work; design; in vivo; protein structure function; resistant strain; small molecule

Project Summary/Abstract This proposal combines work on viral ion channels and de novo protein design. Our work on the M2 proton channel from influenza A virus focuses on the mechanism of inhibition and proton movement through the channel. M2 is also the target of the amantadine class of influenza drugs, and most isolates of influenza A virus are now amantadine-resistant. Crystallography, computation and 2DIR will be used to interrogate the mechanism and aid in design of drugs that inhibit M2 in amantadine-resistant strains of the virus. In parallel, we will expand our studies to examine the mechanism of conduction and inhibition of the E-proteins from coronaviruses, which have structures and functions largely similar to M2. De novo protein design provides a means to test and refine our understanding of protein structure and function. We are developing computational methods to design proteins that bind small molecules such as drugs and metalloporphyrins. We are also designing membrane proteins to elucidate the principles by which they fold and function. To probe the mechanisms of highly selective proton conduction proteins, we are designing proton-selective channels that test a hypothesis that networks of water molecules (water wires) can form dynamically and transiently through apolar stretches of the proton conduction pathway in proteins. The water wires would allow conduction of protons but not large hydrated alkali metal ions such as K+ or Na+. We also are engaged in design of proteins that bind to and transport nutrients such as amino acids across membranes, and devising screens to test them in vivo.

项目摘要/摘要 该提案结合了病毒离子通道和从头蛋白质设计的工作。我们在M2上的工作 流感的质子通道A病毒侧重于抑制和质子运动的机理 频道。 M2也是阿甘丹丁类药物类别的靶标，大多数流感株 病毒现在是抗肿瘤的。晶体学，计算和2DIR将用于询问 机理和帮助设计抑制M2的药物中抗肿瘤的抗肿瘤病毒菌株的药物。并联， 我们将扩大研究，以检查来自 具有结构和功能的冠状病毒在很大程度上与M2相似。 从头蛋白质设计提供了一种测试和完善我们对蛋白质结构和的理解的方法 功能。我们正在开发计算方法来设计结合小分子的蛋白质（例如 药物和金属甲丁物。我们还在设计膜蛋白，以阐明 他们折叠并功能。为了探测高度选择性质子传导蛋白的机制，我们是 设计质子选择通道，该通道检验了水分子网络（水线）的假设 通过蛋白质中质子传导途径的极性拉伸动态和瞬时形成。这 水线将允许传导质子，但不能传导大型水合碱金属离子，例如K+或Na+。我们 还从事与氨基酸结合和运输诸如氨基酸之类的蛋白质的设计 膜，并设计屏幕以在体内测试它们。