Interactions of retroviral and host proteins guided by advanced modeling

摘要 随着最近人工智能在分子设计和蛋白质结构方面的革命 预测，我们有动力应用这些新工具来解决我们研究中的瓶颈 专注于逆转录病毒的进入，整合和药物设计。病毒进入和受体的使用 随着具有扩展的宿主和组织的新病毒的出现， 特殊性我们的研究重点是逆转录病毒包膜选择和利用新的 宿主细胞受体在这项建议中，我们正在利用新的方法来确定和研究两个 新型逆转录病毒Env蛋白及其宿主细胞受体。这些包括A5/A9 a的结合 Env蛋白与宿主膜蛋白SLC 35 F2的同源性分析及同源物鉴定 L1 Env的受体应用AlphaFold 2、Phyre 2和进化协方差结构 预测程序，我们有SLC 35 F2的第一代模型，它作为 该研究为与这种孤儿受体的功能有关的大量问题奠定了基础。的 第二个重点领域建立在与宿主BET结合的γ逆转录病毒整合酶（IN）蛋白上 proteins.通过对小鼠白血病（MLV）IN蛋白的结构研究， 以及宿主NSD 3蛋白与Brd 3 BET蛋白的ET结构域结合，我们现在能够 应用我们对共同结合口袋的了解， 替代的结合底物和小分子抑制剂。BET家族的ET结构域 蛋白质充当多蛋白质组装的节点。了解不同的亲和力 蛋白质和小分子到这个ET结合口袋可以有深远的影响， γ逆转录病毒的发病机制以及基因和癌基因调控。使用计算机辅助 药物发现方法，我们已经确定了一流的先导化合物靶向ET 域这些研究建立在我们具有凝聚力的合作研究团队的基础上， 病毒学、NMR结构研究和生物信息学。

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.