Structural basis of viral RBDs binding to cell receptors

我最近的研究工作的一个重要部分集中在研究分子系统的自关联决定因素，这是由它们在几个层面上的结构对称性所揭示的：从蛋白质组装到蛋白质超二级结构成分（原结构域）[Youkharibache 2019]。我们已经特别表明，多聚螺旋膜蛋白的许多重要结构家族在其结构中遵循共同的伪对称进化过程[Youkharibache， Tran, and Abrol 2020]。G蛋白偶联受体（gpcr），具有MFS折叠的SLCs，如SLC2A1/GLUT1（一种葡萄糖转运蛋白，被HTLV用作受体）或SLC7A1/CAT1（一种精氨酸转运蛋白，小鼠和牛白血病逆转录病毒的受体）就是这种情况。我们的结构分析已经通过我们与NCBI合作开发的创新软件实现[Wang et al. 2020]，并且已经获得了大量的结构数据，我们现在正在利用这些数据来研究它们与细胞表面蛋白质配体的相互作用。不同的脊椎动物逆转录病毒，如人类t细胞白血病病毒（HTLV）和牛白血病病毒，类人猿/鼠/猫白血病病毒大家族，以及人类基因组中存在的许多非传染性人类内源性逆转录病毒（HERV）成员，利用病毒包膜糖蛋白中的受体结合域（RBDs）结合SLC家族的营养转运蛋白，作为进入细胞的第一步。SLCs调节细胞代谢，其表达在正常细胞分化和致癌过程中被系统地改变。我们与IGMM（法国蒙彼利埃CNRS）和初创公司Metafora-biosystems（巴黎，法国）合作，旨在研究结合在致癌过程和免疫反应中起关键作用的SLCs的RBDs：特别是葡萄糖和氨基酸（包括谷氨酰胺、丝氨酸和精氨酸）的转运体。在通常或独特结合谷氨酰胺和/或其他中性氨基酸转运体（分别为SLC1A5/ASCT2和SLC1A4/ASCT1）的rbd家族中，有BaEV和HERV-W rbd。另一种特异性结合葡萄糖或精氨酸转运蛋白的rbd家族- SLC2A1/GLUT1和SLC7A1/CAT1 -分别包括HTLV和BLV rbd。我们的目的是研究病毒rbd和SLCs之间的结构相互作用，以及SLCs在病毒感染、肿瘤发生和免疫反应中的作用。阐明RBD-SLC相互作用也将有助于设计直接从rbd衍生或重新设计的合成SLC调制器。最近，研究表明SARS-CoV2 RBD与一个受体复合物结合，该受体复合物包括ACE2、TMPRSS2和SLC6A19， SLC6A19是一种谷氨酰胺和其他中性氨基酸转运体，也属于SLC超家族。我们已经进行了初步的结构分析，并开发了结构分析工具，以实现合作研究，特别是在细胞表面蛋白- rbd相互作用方面[Youkharibache et al. 2020]。软件和管道正在得到改进，以支持项目的目标。

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.