Structural basis of viral RBDs binding to cell receptors

我最近的研究工作的一个重要部分是集中在研究 结构对称性揭示的分子体系的自缔合决定簇 从蛋白质组装到蛋白质超二级结构 成分（protodomains）[Youkharibache 2019]。我们特别指出， 多位螺旋膜蛋白的重要结构家族遵循共同的 伪对称进化过程在其建设[Youkharibache，Tran和Abrol 2020年]。这是G蛋白偶联受体（GPCR）的情况，具有MFS折叠的SLC，如 SLC 2A 1/GLUT 1，HTLV用作受体的葡萄糖转运蛋白，或SLC 7A 1/CAT 1，精氨酸 小鼠和牛白血病逆转录病毒的转运蛋白和受体。我们的结构分析 我们与NCBI合作开发的创新软件[Wang et 2020年]，并已获得了大量的结构数据，我们现在 用来研究它们与细胞表面蛋白质配体的相互作用。脊椎动物 逆转录病毒与人类T细胞白血病病毒（HTLV）和牛白血病病毒不同， 病毒，猴/鼠/猫白血病病毒的大家族，以及许多成员的 非感染性人内源性逆转录病毒（HERV），其组成性存在于 人类基因组，利用病毒包膜糖蛋白中的受体结合结构域（RBD）， 结合SLC家族的营养转运蛋白作为进入细胞的初始步骤。SLC条件 细胞代谢及其表达在正常细胞生长过程中发生系统性改变， 分化和致癌过程。在与IGMM（CNRS蒙彼利埃， 法国）和初创公司Metafora-biosystems（巴黎，法国），我们的目标是研究RBD结合 SLC在致癌过程和免疫反应中发挥关键作用：特别是转运蛋白 葡萄糖和氨基酸，包括谷氨酰胺，丝氨酸和精氨酸。在RBD家族中， 其可共同或独特地结合谷氨酰胺和/或其它中性氨基酸转运蛋白 （分别为SLC 1A 5/ASCT 2和SLC 1A 4/ASCT 1）是BaEV和HERV-W RBD。的另一家族 特异性结合葡萄糖或精氨酸转运蛋白的RBD-SLC 2A 1/GLUT 1和SLC 7A 1/CAT 1- 包括HTLV和BLV RBD。我们的目标是研究结构之间的相互作用 病毒RBD和SLC以及SLC在病毒感染、肿瘤发生和免疫学中的作用 应答阐明RBD-SLC相互作用也将有助于设计合成SLC调节剂 直接从RBD衍生或重新设计。最近的研究表明，SARS-CoV 2 RBD与受体复合物结合，该受体复合物包括ACE 2、TMPRSS 2，但也包括SLC 6A 19、谷氨酰胺和 也属于SLC超家族的其他中性氨基酸转运蛋白。我们有 进行初步结构分析，并开发结构分析工具， 合作研究，特别是对细胞表面蛋白-RBD相互作用[Youkharibache et 2020年]。正在改进软件和管道，以支持 项目

A significant part of my recent research efforts is focused on studying self-association determinants of molecular systems as revealed by their structural symmetries at several levels: from proteins assemblies to their protein supersecondary structures constituents (protodomains) [Youkharibache 2019]. We have shown in particular that many important structural families of Polytopic Helical Membrane Proteins followed a common Pseudo-Symmetric evolutionary process in their construction [Youkharibache, Tran, and Abrol 2020]. This is the case for G protein-coupled receptors (GPCRs), SLCs with an MFS fold such as SLC2A1/GLUT1, a glucose transporter used as a receptor by HTLV, or SLC7A1/CAT1, an arginine transporter and a receptor for mouse and bovine leukemia retroviruses. Our structural analyses have been enabled by innovative software that we developed in collaboration with NCBI [Wang et al. 2020], and a significant body of structural data has been obtained, that we are now harnessing to study their interactions with protein ligands on cell surfaces. Vertebrate retroviruses as different as the Human T-cell leukemia virus (HTLV) and the bovine leukemia virus, the large family of simian/murine/feline leukemia viruses, and many members of the non-infectious human endogenous retroviruses (HERV) that are constitutively present in the human genome, use their receptor-binding domains (RBDs) in the virus envelope glycoprotein to bind nutrient transporters of the SLC family as an initial step in cell entry. SLCs condition cell metabolism and their expression is systematically altered during normal cell differentiation and oncogenic processes. In collaboration with the IGMM (CNRS Montpellier, France) and the start-up Metafora-biosystems (Paris, France), we aim to study RBDs that bind SLCs that play a key role in oncogenic processes and immune response: notably the transporters of glucose and amino acids including glutamine, serine, and arginine. Among the family of RBDs that can commonly or distinctively bind glutamine and/or other neutral amino acid transporters (SLC1A5/ASCT2 and SLC1A4/ASCT1, respectively) are the BaEV and HERV-W RBDs. Another family of RBDs that distinctively bind glucose or arginine transporters - SLC2A1/GLUT1 and SLC7A1/CAT1 - includes the HTLV and BLV RBDs, respectively. We aim to study structural interactions between viral RBDs and SLCs and the role of SLCs in viral infections, oncogenesis, and immunological responses. Elucidating RBD-SLC interactions will also help designing synthetic SLC modulators either directly derived from RBDs or designed de novo. Recently, it was shown that SARS-CoV2 RBD binds to a receptor complex that includes ACE2, TMPRSS2, but also SLC6A19, a glutamine and other neutral amino acids transporters that also belongs to the SLC superfamily. We have performed initial structural analyses and developed structural analysis tools to enable collaborative research, especially on cell surface proteins-RBD interactions [Youkharibache et al. 2020]. The software and pipelines are being improved to support the aims of the project.