Structural basis of SARS-CoV-2 and other viruses RBDs binding to cell receptors

SARS-CoV-2和其他病毒RBD与细胞受体结合的结构基础

• 批准号: 10262594
• 负责人: Philippe Youkharibache
• 金额: $ 2.86万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262594
• 关键词: 2019-nCoV; Amino Acid Transporter; Amino Acids; Animals; Antiviral Agents; Arginine; Binding; Biological Markers; Bovine Leukemia Virus; Bovine leukemia; CCL21 gene; Cell Differentiation process; Cell Surface Proteins; Cell Surface Receptors; Cell surface; Cells; Cellular Metabolic Process; Collaborations; Complex; Computer software; Coronavirus; Data; Development; Endogenous Retroviruses; Epitopes; Family; Feline Leukemia Virus; France; G-Protein-Coupled Receptors; Glucose; Glucose Transporter; Glutamine; Glycoproteins; Goals; Human; Human Genome; Human T-Cell Leukemia Viruses; Immune response; Inflammation; Ligands; Membrane Proteins; Methodology; Molecular; Mus; Neutral Amino Acid Transport Systems; Normal Cell; Nutrient; Oncogenic; Papio; Paris, France; Play; Process; Proteins; Receptor Cell; Research; Retroviridae; Role; SLC2A1 gene; Serine; Specificity; Structure; Supersecondary Protein Structure; System; TMPRSS2 gene; Therapeutic; Virus Diseases; Virus Receptors; anti-cancer; computational pipelines; design; family structure; improved; innovation; member; model building; receptor; receptor binding; software development; structured data; syncytin; tool; tumorigenesis; virus envelope

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.

我最近的研究工作的一个重要部分是集中在研究分子系统的自缔合决定因素，如它们在几个层次上的结构对称性所揭示的：从蛋白质组装到它们的蛋白质超二级结构成分（原结构域）[Youkharibache 2019]。我们已经特别证明，多位螺旋膜蛋白的许多重要结构家族在其构建中遵循共同的伪对称进化过程[Youkharibache，Tran和Abrol 2020]。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，精氨酸转运蛋白和小鼠和牛白血病逆转录病毒的受体。我们的结构分析是通过我们与NCBI合作开发的创新软件实现的[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。脊椎动物逆转录病毒与人T细胞白血病病毒（HTLV）和牛白血病病毒、猿/鼠/猫白血病病毒大家族以及组成性存在于人类基因组中的非感染性人内源性逆转录病毒（HERV）的许多成员不同，利用病毒包膜糖蛋白中的受体结合域（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调节细胞代谢，并且它们的表达在正常细胞分化和致癌过程中系统地改变。与IGMM（法国CNRS蒙彼利埃）和初创公司Metafora-biosystems（法国巴黎）合作，我们的目标是研究结合SLC的RBD，这些SLC在致癌过程和免疫反应中发挥关键作用：特别是葡萄糖和氨基酸（包括谷氨酰胺、丝氨酸和精氨酸）的转运蛋白。在通常或独特地结合谷氨酰胺和/或其他中性氨基酸转运蛋白（分别为SLC 1A 5/ASCT 2和SLC 1A 4/ASCT 1）的RBD家族中，有BaEV和HERV-W RBD。另一个与葡萄糖或精氨酸转运蛋白特异性结合的RBD家族-SLC 2A 1/GLUT 1和SLC 7A 1/CAT 1-分别包括HTLV和BLV RBD。我们的目的是研究病毒RBD和SLC之间的结构相互作用，以及SLC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衍生自RBD或从头设计的合成SLC调节剂。最近，研究表明SARS-CoV 2 RBD与一种受体复合物结合，该受体复合物包括ACE 2、TMPRSS 2，但也包括SLC 6A 19，一种谷氨酰胺和其他中性氨基酸转运蛋白，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]。正在改进软件和管道，以支持该项目的目标。