Interactions of retroviral and host proteins guided by advanced modeling

先进模型指导下的逆转录病毒和宿主蛋白的相互作用

• 批准号: 10551964
• 负责人: MONICA J ROTH
• 金额: $ 64.43万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551964
• 关键词: Address; Affinity; Area; Artificial Intelligence; Binding; Binding Proteins; Bioinformatics; Cell physiology; Computer Assisted; Development; Disease; Drug Design; Foundations; Generations; Genes; Integrase; Knowledge; Lead; Life; Membrane Proteins; Modeling; Molecular; Mus; Oncogenes; Orphan; Pathogenesis; Protein Family; Proteins; Public Health; Receptor Cell; Regulation; Research; Specificity; Structure; Tissues; Viral; Viral Pathogenesis; Virus; Virus Receptors; design; drug discovery; env Gene Products; inhibitor; leukemia; novel; novel strategies; programs; protein structure prediction; receptor; small molecule; small molecule inhibitor; tool; virology

ABSTRACT With the recent revolution in artificial intelligence for molecular design and protein structure prediction, we were motivated to apply these new tools to address bottlenecks in our research focusing on retroviral entry, integration, and drug design. Viral entry and receptor usage has become a major focus with the emergence of new viruses with expanded host and tissue specificities. Our research focuses on the ability of retroviral Envelopes to select and utilize novel host cell receptors. In this proposal, we are utilizing new approaches to identify and study two novel retroviral Env proteins and their host cell receptors. These include the binding of the A5/A9a Env protein to the host membrane protein SLC35F2 and the identification of the cognate receptor(s) for the L1 Env. Applying AlphaFold2, Phyre2 and Evolutionary Covariance structure prediction programs, we have a first generation model for SLC35F2, which serves as the foundation for a broad number of questions relating to the function of this orphan receptor. The second area of focus builds on the gammaretroviral Integrase (IN) protein binding to the host BET proteins. Through our structural studies of both the Murine Leukemia Leukemia (MLV) IN protein and the host NSD3 protein binding to the ET domain of the Brd3 BET protein, we are now able to apply our knowledge of the common binding pocket to advance approaches for studies of alternative binding substrates and small molecule inhibitors. The ET domain of the BET family of proteins serves as a node for multi-protein assemblies. Understanding the affinity of different proteins and small molecules to this ET binding pocket can have profound effects of gammaretroviral pathogenesis as well as gene and oncogene regulation. Using computer-aided drug discovery approaches, we have identified first-in-class lead compounds targeting the ET domain. These studies build on our cohesive collaborative research team with expertise in virology, NMR structural studies, and bioinformatics.

抽象的 随着分子设计和蛋白质结构的人工智能的最新革命 预测，我们有动力应用这些新工具来解决我们的研究中的瓶颈 专注于逆转录病毒进入，整合和药物设计。病毒输入和受体使用情况 随着新病毒的出现而随着扩展的宿主和组织的出现而成为主要重点 特殊性。我们的研究重点是逆转录病毒选择和利用新颖的能力 宿主细胞受体。在此提案中，我们正在利用新方法来识别和研究两个 新型逆转录病毒ENV蛋白及其宿主细胞受体。这些包括A5/A9A的结合 宿主膜蛋白SLC35F2的env蛋白和同源的鉴定 L1 Env的受体。应用Alphafold2，Phyre2和进化协方差结构 预测程序，我们有SLC35F2的第一代模型，它用作 与该孤儿受体功能有关的广泛问题的基础。这 焦点的第二区域建立在γ-逆转录病毒整合酶（IN）蛋白与宿主下注的结合 蛋白质。通过我们对蛋白质鼠白血病（MLV）的结构研究 宿主NSD3蛋白与BRD3 BET蛋白的ET结构域结合，我们现在能够 应用我们对共同约束口袋的知识来推进研究的方法 替代结合底物和小分子抑制剂。 BET家族的ET域 蛋白质是多蛋白组件的节点。了解不同的亲和力 该ET结合口袋的蛋白质和小分子可以产生深远的影响 γ逆转录病毒发病机理以及基因和癌基因调节。使用计算机辅助 药物发现方法，我们已经确定了针对ET的第一类铅化合物 领域。这些研究以我们具有专业知识的凝聚力协作研究团队为基础 病毒学，NMR结构研究和生物信息学。